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Zhong X, Wei Q, Tiwari A, Wang Q, Tan Y, Chen R, Yan Y, Cox NJ, Li B. A Genetics-guided Integrative Framework for Drug Repurposing: Identifying Anti-hypertensive Drug Telmisartan for Type 2 Diabetes. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.03.22.25324223. [PMID: 40166562 PMCID: PMC11957187 DOI: 10.1101/2025.03.22.25324223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Drug development is a long and costly process, and repurposing existing drugs for use toward a different disease or condition may serve as a cost-effective alternative. As drug targets with genetic support have a doubled success rate, genetics-informed drug repurposing holds promise in translating genetic findings into therapeutics. In this study, we developed a Genetics Informed Network-based Drug Repurposing via in silico Perturbation (GIN-DRIP) framework and applied the framework to repurpose drugs for type-2 diabetes (T2D). In GIN-DRIP for T2D, it integrates multi-level omics data to translate T2D GWAS signals into a genetics-informed network that simultaneously encodes gene importance scores and a directional effect (up/down) of risk genes for T2D; it then bases on the GIN to perform signature matching with drug perturbation experiments to identify drugs that can counteract the effect of T2D risk alleles. With this approach, we identified 3 high-confidence FDA-approved candidate drugs for T2D, and validated telmisartan, an anti-hypertensive drug, in our EHR data with over 3 million patients. We found that telmisartan users were associated with a reduced incidence of T2D compared to users of other anti-hypertensive drugs and non-users, supporting the therapeutic potential of telmisartan for T2D. Our framework can be applied to other diseases for translating GWAS findings to aid drug repurposing for complex diseases.
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Affiliation(s)
- Xue Zhong
- Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN
| | - Qiang Wei
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
| | - Anshul Tiwari
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
| | - Quan Wang
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
| | - Yuting Tan
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
| | - Rui Chen
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
| | - Yan Yan
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Nancy J Cox
- Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN
| | - Bingshan Li
- Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN
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Natale P, Palmer SC, Navaneethan SD, Craig JC, Strippoli GF. Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev 2024; 4:CD006257. [PMID: 38682786 PMCID: PMC11057222 DOI: 10.1002/14651858.cd006257.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/01/2024]
Abstract
BACKGROUND Guidelines suggest that adults with diabetes and kidney disease receive treatment with angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). This is an update of a Cochrane review published in 2006. OBJECTIVES We compared the efficacy and safety of ACEi and ARB therapy (either as monotherapy or in combination) on cardiovascular and kidney outcomes in adults with diabetes and kidney disease. SEARCH METHODS We searched the Cochrane Kidney and Transplants Register of Studies to 17 March 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included studies evaluating ACEi or ARB alone or in combination, compared to each other, placebo or no treatment in people with diabetes and kidney disease. DATA COLLECTION AND ANALYSIS Two authors independently assessed the risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS One hundred and nine studies (28,341 randomised participants) were eligible for inclusion. Overall, the risk of bias was high. Compared to placebo or no treatment, ACEi may make little or no difference to all-cause death (24 studies, 7413 participants: RR 0.91, 95% CI 0.73 to 1.15; I2 = 23%; low certainty) and with similar withdrawals from treatment (7 studies, 5306 participants: RR 1.03, 95% CI 0.90 to 1.19; I2 = 0%; low certainty). ACEi may prevent kidney failure (8 studies, 6643 participants: RR 0.61, 95% CI 0.39 to 0.94; I2 = 0%; low certainty). Compared to placebo or no treatment, ARB may make little or no difference to all-cause death (11 studies, 4260 participants: RR 0.99, 95% CI 0.85 to 1.16; I2 = 0%; low certainty). ARB have uncertain effects on withdrawal from treatment (3 studies, 721 participants: RR 0.85, 95% CI 0.58 to 1.26; I2 = 2%; low certainty) and cardiovascular death (6 studies, 878 participants: RR 3.36, 95% CI 0.93 to 12.07; low certainty). ARB may prevent kidney failure (3 studies, 3227 participants: RR 0.82, 95% CI 0.72 to 0.94; I2 = 0%; low certainty), doubling of serum creatinine (SCr) (4 studies, 3280 participants: RR 0.84, 95% CI 0.72 to 0.97; I2 = 32%; low certainty), and the progression from microalbuminuria to macroalbuminuria (5 studies, 815 participants: RR 0.44, 95% CI 0.23 to 0.85; I2 = 74%; low certainty). Compared to ACEi, ARB had uncertain effects on all-cause death (15 studies, 1739 participants: RR 1.13, 95% CI 0.68 to 1.88; I2 = 0%; low certainty), withdrawal from treatment (6 studies, 612 participants: RR 0.91, 95% CI 0.65 to 1.28; I2 = 0%; low certainty), cardiovascular death (13 studies, 1606 participants: RR 1.15, 95% CI 0.45 to 2.98; I2 = 0%; low certainty), kidney failure (3 studies, 837 participants: RR 0.56, 95% CI 0.29 to 1.07; I2 = 0%; low certainty), and doubling of SCr (2 studies, 767 participants: RR 0.88, 95% CI 0.52 to 1.48; I2 = 0%; low certainty). Compared to ACEi plus ARB, ACEi alone has uncertain effects on all-cause death (6 studies, 1166 participants: RR 1.08, 95% CI 0.49 to 2.40; I2 = 20%; low certainty), withdrawal from treatment (2 studies, 172 participants: RR 0.78, 95% CI 0.33 to 1.86; I2 = 0%; low certainty), cardiovascular death (4 studies, 994 participants: RR 3.02, 95% CI 0.61 to 14.85; low certainty), kidney failure (3 studies, 880 participants: RR 1.36, 95% CI 0.79 to 2.32; I2 = 0%; low certainty), and doubling of SCr (2 studies, 813 participants: RR 1.14, 95% CI 0.70 to 1.85; I2 = 0%; low certainty). Compared to ACEi plus ARB, ARB alone has uncertain effects on all-cause death (7 studies, 2607 participants: RR 1.02, 95% CI 0.76 to 1.37; I2 = 0%; low certainty), withdrawn from treatment (3 studies, 1615 participants: RR 0.81, 95% CI 0.53 to 1.24; I2 = 0%; low certainty), cardiovascular death (4 studies, 992 participants: RR 3.03, 95% CI 0.62 to 14.93; low certainty), kidney failure (4 studies, 2321 participants: RR 1.15, 95% CI 0.67 to 1.95; I2 = 29%; low certainty), and doubling of SCr (3 studies, 2252 participants: RR 1.18, 95% CI 0.85 to 1.64; I2 = 0%; low certainty). Comparative effects of different ACEi or ARB and low-dose versus high-dose ARB were rarely evaluated. No study compared different doses of ACEi. Adverse events of ACEi and ARB were rarely reported. AUTHORS' CONCLUSIONS ACEi or ARB may make little or no difference to all-cause and cardiovascular death compared to placebo or no treatment in people with diabetes and kidney disease but may prevent kidney failure. ARB may prevent the doubling of SCr and the progression from microalbuminuria to macroalbuminuria compared with a placebo or no treatment. Despite the international guidelines suggesting not combining ACEi and ARB treatment, the effects of ACEi or ARB monotherapy compared to dual therapy have not been adequately assessed. The limited data availability and the low quality of the included studies prevented the assessment of the benefits and harms of ACEi or ARB in people with diabetes and kidney disease. Low and very low certainty evidence indicates that it is possible that further studies might provide different results.
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Affiliation(s)
- Patrizia Natale
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
| | - Suetonia C Palmer
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | | | - Jonathan C Craig
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Giovanni Fm Strippoli
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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Imenshahidi M, Roohbakhsh A, Hosseinzadeh H. Effects of telmisartan on metabolic syndrome components: a comprehensive review. Biomed Pharmacother 2024; 171:116169. [PMID: 38228033 DOI: 10.1016/j.biopha.2024.116169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/04/2024] [Accepted: 01/11/2024] [Indexed: 01/18/2024] Open
Abstract
Telmisartan is an antagonist of the angiotensin II receptor used in the management of hypertension (alone or in combination with other antihypertensive agents. It belongs to the drug class of angiotensin II receptor blockers (ARBs). Among drugs of this class, telmisartan shows particular pharmacologic properties, including a longer half-life than any other angiotensin II receptor blockers that bring higher and persistent antihypertensive activity. In hypertensive patients, telmisartan has superior efficacy than other antihypertensive drugs (losartan, valsartan, ramipril, atenolol, and perindopril) in controlling blood pressure, especially towards the end of the dosing interval. Telmisartan has a partial PPARγ-agonistic effect whilst does not have the safety concerns of full agonists of PPARγ receptors (thiazolidinediones). Moreover, telmisartan has an agonist activity on PPARα and PPARδ receptors and modulates the adipokine levels. Thus, telmisartan could be considered as a suitable alternative option, with multi-benefit for all components of metabolic syndrome including hypertension, diabetes mellitus, obesity, and hyperlipidemia. This review will highlight the role of telmisartan in metabolic syndrome and the main mechanisms of action of telmisartan are discussed and summarized. Many studies have demonstrated the useful properties of telmisartan in the prevention and improving of metabolic syndrome and this well-tolerated drug can be greatly proposed in the treatment of different components of metabolic syndrome. However, larger and long-duration studies are needed to confirm these findings in long-term observational studies and prospective trials and to determine the optimum dose of telmisartan in metabolic syndrome.
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Affiliation(s)
- Mohsen Imenshahidi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Roohbakhsh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Koumallos N, Sigala E, Milas T, Baikoussis NG, Aragiannis D, Sideris S, Tsioufis K. Angiotensin Regulation of Vascular Homeostasis: Exploring the Role of ROS and RAS Blockers. Int J Mol Sci 2023; 24:12111. [PMID: 37569484 PMCID: PMC10418800 DOI: 10.3390/ijms241512111] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 08/13/2023] Open
Abstract
Extensive research has been conducted to elucidate and substantiate the crucial role of the Renin-Angiotensin System (RAS) in the pathogenesis of hypertension, cardiovascular disorders, and renal diseases. Furthermore, the role of oxidative stress in maintaining vascular balance has been well established. It has been observed that many of the cellular effects induced by Angiotensin II (Ang II) are facilitated by reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In this paper, we present a comprehensive overview of the role of ROS in the physiology of human blood vessels, specifically focusing on its interaction with RAS. Moreover, we delve into the mechanisms by which clinical interventions targeting RAS influence redox signaling in the vascular wall.
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Affiliation(s)
- Nikolaos Koumallos
- Cardiothoracic Department, Hippokration Hospital of Athens, 11527 Athens, Greece; (E.S.); (T.M.); (N.G.B.)
| | - Evangelia Sigala
- Cardiothoracic Department, Hippokration Hospital of Athens, 11527 Athens, Greece; (E.S.); (T.M.); (N.G.B.)
| | - Theodoros Milas
- Cardiothoracic Department, Hippokration Hospital of Athens, 11527 Athens, Greece; (E.S.); (T.M.); (N.G.B.)
| | - Nikolaos G. Baikoussis
- Cardiothoracic Department, Hippokration Hospital of Athens, 11527 Athens, Greece; (E.S.); (T.M.); (N.G.B.)
| | - Dimitrios Aragiannis
- Cardiology Department, Hippokration Hospital of Athens, 11527 Athens, Greece; (D.A.); (S.S.); (K.T.)
| | - Skevos Sideris
- Cardiology Department, Hippokration Hospital of Athens, 11527 Athens, Greece; (D.A.); (S.S.); (K.T.)
| | - Konstantinos Tsioufis
- Cardiology Department, Hippokration Hospital of Athens, 11527 Athens, Greece; (D.A.); (S.S.); (K.T.)
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Prastaro M, Nardi E, Paolillo S, Santoro C, Parlati ALM, Gargiulo P, Basile C, Buonocore D, Esposito G, Filardi PP. Cardiorenal syndrome: Pathophysiology as a key to the therapeutic approach in an under-diagnosed disease. JOURNAL OF CLINICAL ULTRASOUND : JCU 2022; 50:1110-1124. [PMID: 36218199 PMCID: PMC9828083 DOI: 10.1002/jcu.23265] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/13/2022] [Accepted: 06/20/2022] [Indexed: 06/09/2023]
Abstract
Cardiorenal syndrome is a clinical condition that impacts both the heart and the kidneys. One organ's chronic or acute impairment can lead to the other's chronic or acute dysregulation. The cardiorenal syndrome has been grouped into five subcategories that describe the etiology, pathophysiology, duration, and pattern of cardiac and renal dysfunction. This classification reflects the large spectrum of interrelated dysfunctions and underlines the bidirectional nature of heart-kidney interactions. However, more evidence is needed to apply these early findings in medical practice. Understanding the relationship between these two organs during each organ's impairment has significant clinical implications that are relevant for therapy in both chronic and acute conditions. The epidemiology, definition, classification, pathophysiology, therapy, and outcome of each form of cardiorenal syndrome are all examined in this review.
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Affiliation(s)
- Maria Prastaro
- Department of Advanced Biomedical SciencesUniversity of Naples Federico IINaplesItaly
| | - Ermanno Nardi
- Department of Advanced Biomedical SciencesUniversity of Naples Federico IINaplesItaly
| | - Stefania Paolillo
- Department of Advanced Biomedical SciencesUniversity of Naples Federico IINaplesItaly
| | - Ciro Santoro
- Department of Advanced Biomedical SciencesUniversity of Naples Federico IINaplesItaly
| | - Antonio L. M. Parlati
- Department of Advanced Biomedical SciencesUniversity of Naples Federico IINaplesItaly
| | - Paola Gargiulo
- Department of Advanced Biomedical SciencesUniversity of Naples Federico IINaplesItaly
| | - Christian Basile
- Department of Advanced Biomedical SciencesUniversity of Naples Federico IINaplesItaly
| | - Davide Buonocore
- Department of Advanced Biomedical SciencesUniversity of Naples Federico IINaplesItaly
| | - Giovanni Esposito
- Department of Advanced Biomedical SciencesUniversity of Naples Federico IINaplesItaly
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Ambrosino P, Bachetti T, D’Anna SE, Galloway B, Bianco A, D’Agnano V, Papa A, Motta A, Perrotta F, Maniscalco M. Mechanisms and Clinical Implications of Endothelial Dysfunction in Arterial Hypertension. J Cardiovasc Dev Dis 2022; 9:136. [PMID: 35621847 PMCID: PMC9146906 DOI: 10.3390/jcdd9050136] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/19/2022] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
The endothelium is composed of a monolayer of endothelial cells, lining the interior surface of blood and lymphatic vessels. Endothelial cells display important homeostatic functions, since they are able to respond to humoral and hemodynamic stimuli. Thus, endothelial dysfunction has been proposed as a key and early pathogenic mechanism in many clinical conditions. Given the relevant repercussions on cardiovascular risk, the complex interplay between endothelial dysfunction and systemic arterial hypertension has been a matter of study in recent years. Numerous articles have been published on this issue, all of which contribute to providing an interesting insight into the molecular mechanisms of endothelial dysfunction in arterial hypertension and its role as a biomarker of inflammation, oxidative stress, and vascular disease. The prognostic and therapeutic implications of endothelial dysfunction have also been analyzed in this clinical setting, with interesting new findings and potential applications in clinical practice and future research. The aim of this review is to summarize the pathophysiology of the relationship between endothelial dysfunction and systemic arterial hypertension, with a focus on the personalized pharmacological and rehabilitation strategies targeting endothelial dysfunction while treating hypertension and cardiovascular comorbidities.
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Affiliation(s)
- Pasquale Ambrosino
- Istituti Clinici Scientifici Maugeri IRCCS, Cardiac Rehabilitation Unit of Telese Terme Institute, 82037 Telese Terme, Italy;
| | - Tiziana Bachetti
- Istituti Clinici Scientifici Maugeri IRCCS, Scientific Direction, 27100 Pavia, Italy;
| | - Silvestro Ennio D’Anna
- Istituti Clinici Scientifici Maugeri IRCCS, Pulmonary Rehabilitation Unit of Telese Terme Institute, 82037 Telese Terme, Italy;
| | - Brurya Galloway
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (B.G.); (A.B.); (V.D.); (F.P.)
| | - Andrea Bianco
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (B.G.); (A.B.); (V.D.); (F.P.)
| | - Vito D’Agnano
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (B.G.); (A.B.); (V.D.); (F.P.)
| | - Antimo Papa
- Istituti Clinici Scientifici Maugeri IRCCS, Cardiac Rehabilitation Unit of Telese Terme Institute, 82037 Telese Terme, Italy;
| | - Andrea Motta
- Institute of Biomolecular Chemistry, National Research Council, 80078 Pozzuoli, Italy;
| | - Fabio Perrotta
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (B.G.); (A.B.); (V.D.); (F.P.)
| | - Mauro Maniscalco
- Istituti Clinici Scientifici Maugeri IRCCS, Pulmonary Rehabilitation Unit of Telese Terme Institute, 82037 Telese Terme, Italy;
- Department of Clinical Medicine and Surgery, “Federico II” University, 80131 Naples, Italy
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Lapébie FX, Bura-Rivière A, Lacroix P, Constans J, Boulon C, Messas E, Aboyans V, Ferrières J, Bongard V. Impact of angiotensin receptor blockers on mortality after hospitalization for symptomatic lower extremity artery disease. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2021; 7:463-474. [PMID: 32271868 DOI: 10.1093/ehjcvp/pvaa026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 02/17/2020] [Accepted: 04/03/2020] [Indexed: 12/26/2022]
Abstract
AIMS The objective was to assess the association between angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) prescription at discharge in patients hospitalized for symptomatic lower extremity artery disease (LEAD) and 1-year mortality. METHODS AND RESULTS The COPART registry is a multicentre, prospective, observational, cohort study which includes consecutive patients hospitalized for symptomatic LEAD in four French academic centres. All-cause mortality during a 1-year follow-up after hospital discharge was compared between patients with ARB, patients with ACEI and patients without ARB or ACEI. Analyses were performed using Cox models. As a sensitivity analysis, a propensity score (PS)-matching analysis was carried out. Among 1981 patients, 421 had ARB (21.3%), 766 ACEI (38.7%), and 794 no ACEI/ARB (40.1%) at discharge. During the 1-year follow-up, incidence rates for mortality were 12.6/100 person-years [95% confidence interval (CI) 9.7-16.1] for patients with ARB, 15.8/100 person-years (95% CI 13.4-18.6) for patients with ACEI and 19.8/100 person-years for patients without ACEI/ARB (95% CI 17.2-22.8). In a multivariate Cox model, ARB at discharge was associated with decreased mortality compared with no ACEI/ARB, hazard ratio (HR) 0.68 (95% CI 0.49-0.95), and with ACEI, HR 0.69 (95% CI 0.49-0.97). These results are consistent with those obtained by the Cox analyses in the PS-matched sample: HR 0.68 (95% CI 0.47-0.98) for patients with ARB compared with no ARB. CONCLUSION Angiotensin receptor blockers at discharge after hospitalization for symptomatic LEAD is associated with a better survival compared with ACEI or no ACEI/ARB.
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Affiliation(s)
- François-Xavier Lapébie
- Department of Vascular Medicine, Toulouse University Hospital, Toulouse, France.,UMR 1027 INSERM, Toulouse III - Paul Sabatier University, 37 allées Jules Guesde, 31000 Toulouse, France
| | - Alessandra Bura-Rivière
- Department of Vascular Medicine, Toulouse University Hospital, Toulouse, France.,UMR 1031 INSERM, StromaLab, Toulouse III - Paul Sabatier University, 4 bis avenue Hubert Curien, 31100 Toulouse, France
| | - Philippe Lacroix
- Department of Cardiovascular and Thoracic Surgery - Vascular Medicine, Limoges University hospital, Limoges, France.,UMR 1094 INSERM, Limoges University, 2 rue du Dr Marcland, 87000 Limoges, France
| | - Joël Constans
- Department of Vascular Medicine, Bordeaux, Bordeaux University Hospital, France.,Bordeaux University School of Medicine, 146 rue Leo Saignat, 33000 Bordeaux, France
| | - Carine Boulon
- Department of Vascular Medicine, Bordeaux, Bordeaux University Hospital, France
| | - Emmanuel Messas
- Department of Vascular Medicine, Assistance Publique - Hôpitaux de Paris, Paris, France.,UMR 970 INSERM, Paris Descartes University, 56 rue Leblanc, 75015 Paris, France
| | - Victor Aboyans
- UMR 1094 INSERM, Limoges University, 2 rue du Dr Marcland, 87000 Limoges, France.,Department of Cardiology, Limoges University Hospital, Limoges, France
| | - Jean Ferrières
- UMR 1027 INSERM, Toulouse III - Paul Sabatier University, 37 allées Jules Guesde, 31000 Toulouse, France.,Department of Epidemiology, Toulouse University Hospital, Toulouse, France.,Federation of Cardiology, Toulouse University Hospital, 1 avenue du Pr Jean Poulhès, 31400 Toulouse, France
| | - Vanina Bongard
- UMR 1027 INSERM, Toulouse III - Paul Sabatier University, 37 allées Jules Guesde, 31000 Toulouse, France.,Department of Epidemiology, Toulouse University Hospital, Toulouse, France.,Federation of Cardiology, Toulouse University Hospital, 1 avenue du Pr Jean Poulhès, 31400 Toulouse, France
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Lee CH, Liu KS, Roth JG, Hung KC, Liu YW, Wang SH, Kuo CC, Liu SJ. Telmisartan Loaded Nanofibers Enhance Re-Endothelialization and Inhibit Neointimal Hyperplasia. Pharmaceutics 2021; 13:1756. [PMID: 34834171 PMCID: PMC8623288 DOI: 10.3390/pharmaceutics13111756] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/15/2021] [Accepted: 10/16/2021] [Indexed: 12/12/2022] Open
Abstract
Stent implantation impairs local endothelial function and may be associated with subsequent adverse cardiovascular events. Telmisartan, an angiotensin II receptor blocker that has unique peroxisome proliferator-activated-receptor-gamma-mediated effects on cardiovascular disease, has been shown to enhance endothelial function and limit neointimal hyperplasia. This study utilized hybrid biodegradable/stent nanofibers to facilitate sustained and local delivery of telmisartan to injured arterial vessels. Telmisartan and poly(d,l)-lactide-co-glycolide (PLGA) (75:25) were dissolved in hexafluoroisopropyl alcohol and electrospun into biodegradable nanofibrous tubes which were coated onto metal stents. By releasing 20% of the loaded telmisartan in 30 days, these hybrid biodegradable/stent telmisartan-loaded nanofibers increased the migration of endothelial progenitor cells in vitro, promoted endothelialization, and reduced intimal hyperplasia. As such, this work provides insights into the use of PLGA nanofibers for treating patients with an increased risk of stent restenosis.
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Affiliation(s)
- Chen-Hung Lee
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taoyuan 33305, Taiwan; (K.-C.H.); (Y.-W.L.); (S.-H.W.)
| | - Kuo-Sheng Liu
- Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
| | - Julien George Roth
- Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA;
| | - Kuo-Chun Hung
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taoyuan 33305, Taiwan; (K.-C.H.); (Y.-W.L.); (S.-H.W.)
| | - Yen-Wei Liu
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taoyuan 33305, Taiwan; (K.-C.H.); (Y.-W.L.); (S.-H.W.)
| | - Shin-Huei Wang
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taoyuan 33305, Taiwan; (K.-C.H.); (Y.-W.L.); (S.-H.W.)
| | - Chi-Ching Kuo
- Research and Development Center of Smart Textile Technology, Institute of Organic and Polymeric Materials, National Taipei University of Technology, Taipei 10608, Taiwan
| | - Shih-Jung Liu
- Department of Mechanical Engineering, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Linkou, Taoyuan 33305, Taiwan
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Kumar S, Mittal A, Mittal A. A review upon medicinal perspective and designing rationale of DPP-4 inhibitors. Bioorg Med Chem 2021; 46:116354. [PMID: 34428715 DOI: 10.1016/j.bmc.2021.116354] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/26/2021] [Accepted: 07/30/2021] [Indexed: 12/13/2022]
Abstract
Type 2 Diabetes Mellitus (T2DM) is one of the highly prevalence disorder and increasing day by day worldwidely. T2DM is a metabolic disorder, which is characterized by deficiency in insulin or resistance to insulin and thus increases the glucose levels in the blood. Various approaches are there to treat diabetes but still there is no cure for this disease. DPP-4 inhibitor is a privileged target in the field of drug discovery and provides various opportunities in exploring this target for development of molecules as antidiabetic agents. DPP-4 acts by inhibiting the incretin action and thus decreases the level of blood glucose by imparting minimal side effects. Sitagliptin, vildagliptin, linagliptin etc. are the different DPP-4 based drugs approved throughout the world for the treatment of diabetes mellitus. Cyanopyrrolidines, triazolopiperazine amide, pyrrolidines are basic core nucleus present in various DPP-4 inhibitors and has potential effects. In the past few years, researchers had applied various approaches to synthesize potent DPP-4 inhibitors as antidiabetic agent without side effects like weight gain, cardiovascular risks, retinopathy etc. This review will also emphasize the recent strategies and rationale utilized by researchers for the development of DPP-4 inhibitors. This review also reveals about the various other approaches like molecular modelling, ligand based drug designing, high throughput screening etc. are used by the various research group for the development of potential DPP-4 inhibitors.
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Affiliation(s)
- Shubham Kumar
- Faculty of Pharmaceutical Sciences, PCTE Group of Institutes, Campus-2, Near Baddowal Cantt. Ferozepur Road, Ludhiana 142021, India; Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road (NH-1), Phagwara, Punjab 144411, India
| | - Anu Mittal
- Department of Chemistry, Guru Nanak Dev University College, Patti, Distt. Tarn Taran, India
| | - Amit Mittal
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road (NH-1), Phagwara, Punjab 144411, India.
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10
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Ceravolo G, Macchia TL, Cuppari C, Dipasquale V, Gambadauro A, Casto C, Ceravolo MD, Cutrupi M, Calabrò MP, Borgia P, Piccolo G, Mancuso A, Albiero R, Chimenz R. Update on the Classification and Pathophysiological Mechanisms of Pediatric Cardiorenal Syndromes. CHILDREN (BASEL, SWITZERLAND) 2021; 8:528. [PMID: 34206173 PMCID: PMC8305733 DOI: 10.3390/children8070528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 11/16/2022]
Abstract
Cardiorenal syndrome (CRS) is defined as a disorder resulting from the abnormal interaction between the heart and kidney, in which acute or chronic dysfunction of one organ may lead to acute and/or chronic dysfunction of the other. The functional interplay between the heart and kidney is characterized by a complex bidirectional symbiotic interaction, regulated by a wide array of both genetic and environmental mechanisms. There are at least five known subtypes of CRS, based on the severity of clinical features and the degree of heart/renal failure. The fourth subtype (cardiorenal syndrome type 4 (CRS4)) is characterized by a primary chronic kidney disease (CKD), which in turn leads to a decreased cardiac function. Impairment of renal function is among the most important pathophysiological factors contributing to heart failure (HF) in the pediatric age group, and cardiovascular complications could be one of the most important causes of mortality in pediatric patients with advanced CKD. In this context, a loss of glomerular filtration rate directly correlates with both the progression of cardiovascular complications in CRS and the risk of HF. This review describes the interaction pathways between the heart and kidney and the recently identified pathophysiological mechanisms underlying pediatric CRS, with a special focus on CRS4, which encompasses both primary CKD and cardiovascular disease (CVD).
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Affiliation(s)
- Giorgia Ceravolo
- Unit of Emergency Pediatric, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, “G. Martino” Policlinic, 98124 Messina, Italy; (G.C.); (C.C.); (V.D.); (A.G.); (C.C.); (M.D.C.); (M.C.); (A.M.)
| | - Tommaso La Macchia
- Unit of Cardiology, Department of Clinical and Experimental Medicine, University of Messina, “G. Martino” Policlinic, 98124 Messina, Italy;
| | - Caterina Cuppari
- Unit of Emergency Pediatric, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, “G. Martino” Policlinic, 98124 Messina, Italy; (G.C.); (C.C.); (V.D.); (A.G.); (C.C.); (M.D.C.); (M.C.); (A.M.)
| | - Valeria Dipasquale
- Unit of Emergency Pediatric, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, “G. Martino” Policlinic, 98124 Messina, Italy; (G.C.); (C.C.); (V.D.); (A.G.); (C.C.); (M.D.C.); (M.C.); (A.M.)
| | - Antonella Gambadauro
- Unit of Emergency Pediatric, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, “G. Martino” Policlinic, 98124 Messina, Italy; (G.C.); (C.C.); (V.D.); (A.G.); (C.C.); (M.D.C.); (M.C.); (A.M.)
| | - Celeste Casto
- Unit of Emergency Pediatric, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, “G. Martino” Policlinic, 98124 Messina, Italy; (G.C.); (C.C.); (V.D.); (A.G.); (C.C.); (M.D.C.); (M.C.); (A.M.)
| | - Maria Domenica Ceravolo
- Unit of Emergency Pediatric, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, “G. Martino” Policlinic, 98124 Messina, Italy; (G.C.); (C.C.); (V.D.); (A.G.); (C.C.); (M.D.C.); (M.C.); (A.M.)
| | - Maricia Cutrupi
- Unit of Emergency Pediatric, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, “G. Martino” Policlinic, 98124 Messina, Italy; (G.C.); (C.C.); (V.D.); (A.G.); (C.C.); (M.D.C.); (M.C.); (A.M.)
| | - Maria Pia Calabrò
- Unit of Pediatric Cardiology, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, “G. Martino” Policlinic, 98124 Messina, Italy;
| | - Paola Borgia
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy; (P.B.); (G.P.)
| | - Gianluca Piccolo
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy; (P.B.); (G.P.)
- Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
| | - Alessio Mancuso
- Unit of Emergency Pediatric, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, “G. Martino” Policlinic, 98124 Messina, Italy; (G.C.); (C.C.); (V.D.); (A.G.); (C.C.); (M.D.C.); (M.C.); (A.M.)
| | - Remo Albiero
- Department of Cardiology, Sondrio General Hospital, 23100 Sondrio, Italy;
| | - Roberto Chimenz
- Unit of Pediatric Nephrology, and Rheumatology with Dialysis, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, “G. Martino” Policlinic, 98124 Messina, Italy
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Ayza MA, Zewdie KA, Tesfaye BA, Gebrekirstos ST, Berhe DF. Anti-Diabetic Effect of Telmisartan Through its Partial PPARγ-Agonistic Activity. Diabetes Metab Syndr Obes 2020; 13:3627-3635. [PMID: 33116714 PMCID: PMC7567533 DOI: 10.2147/dmso.s265399] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 09/10/2020] [Indexed: 12/19/2022] Open
Abstract
Telmisartan is an angiotensin II receptor antagonist, which selectively inhibits the angiotensin II type 1 receptor. Thus, it is widely used for hypertension management. Nowadays, telmisartan's effect on peroxisome proliferator-activated receptors (PPARs) is gaining wider attention. PPARs are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Telmisartan is reported to have a partial PPARγ-agonistic effect while avoiding the safety concerns found with full PPARγ agonists (thiazolidinediones). Telmisartan could be an alternative treatment option, with dual benefit for diabetes mellitus (DM) and hypertension. This review summarizes the anti-diabetic activity of telmisartan via its partial PPARγ-agonistic activity.
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Affiliation(s)
- Muluken Altaye Ayza
- Department of Pharmacology and Toxicology, School of Pharmacy, Mekelle University, Mekelle, Ethiopia
| | - Kaleab Alemayehu Zewdie
- Department of Pharmacology and Toxicology, School of Pharmacy, Mekelle University, Mekelle, Ethiopia
| | - Bekalu Amare Tesfaye
- Department of Pharmacology and Toxicology, School of Pharmacy, Mekelle University, Mekelle, Ethiopia
| | | | - Derbew Fikadu Berhe
- Department of Pharmacology and Toxicology, School of Pharmacy, Mekelle University, Mekelle, Ethiopia
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12
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Malek V, Gaikwad AB. Telmisartan and thiorphan combination treatment attenuates fibrosis and apoptosis in preventing diabetic cardiomyopathy. Cardiovasc Res 2020; 115:373-384. [PMID: 30184174 DOI: 10.1093/cvr/cvy226] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 08/28/2018] [Indexed: 01/02/2023] Open
Abstract
Aims LCZ696, a first-generation dual angiotensin receptor-neprilysin inhibitor (ARNi), is effective in treating heart failure patients. However, the role of ARNis in treating diabetic cardiomyopathy is poorly understood. This study evaluates the efficacy of a novel combination of telmisartan [angiotensin receptor blocker (ARB)] and thiorphan [neprilysin inhibitor (NEPi)] in ameliorating diabetic cardiomyopathy while, at the same time, exploring the relevant underlying molecular mechanism(s). Methods and results Diabetes was induced by administration of streptozotocin (55 mg/kg, i.p.) in male Wistar rats. After 4 weeks, diabetic rats were subjected to either thiorphan (0.1 mg/kg/day, p.o.) or telmisartan (10 mg/kg/day, p.o.) monotherapy, or their combination, for a period of 4 weeks. Metabolic and morphometric alterations, failing ventricular functions, and diminished baroreflex indicated development of diabetic cardiac complications. Apart from morphometric alterations, all pathological consequences were prevented by telmisartan and thiorphan combination therapy. Diabetic rats exhibited significant modulation of the natriuretic peptide system, a key haemodynamic regulator; this was normalized by combination therapy. Histopathological studies showed augmented myocardial fibrosis, demonstrated by increased % PSR-positive area, with combination therapy giving the best improvement in these indices. More importantly, the combination of thiorphan and telmisartan was superior in attenuating inflammatory (NF-κB/MCP-1), profibrotic (TGF-β/Smad7) and apoptotic (PARP/Caspase-3) cascades compared to respective monotherapies when treating rats with diabetic cardiomyopathy. In addition, diabetic heart chromatin was in a state of active transcription, indicated by increased histone acetylation (H2AK5Ac, H2BK5Ac, H3K9Ac, and H4K8Ac) and histone acetyltransferase (PCAF and Ac-CBP) levels. Interestingly, combination treatment was sufficiently potent to normalize these alterations. Conclusion The protective effect of novel ARB and NEPi combination against diabetic cardiomyopathy can be attributed to inhibition of inflammatory, profibrotic, and apoptotic cascades. Moreover, reversal of histone acetylation assists its protective effect.
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Affiliation(s)
- Vajir Malek
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
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13
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Icli B, Li H, Pérez-Cremades D, Wu W, Ozdemir D, Haemmig S, Guimaraes RB, Manica A, Marchini JF, Orgill DP, Feinberg MW. MiR-4674 regulates angiogenesis in tissue injury by targeting p38K signaling in endothelial cells. Am J Physiol Cell Physiol 2020; 318:C524-C535. [PMID: 31913696 PMCID: PMC7099516 DOI: 10.1152/ajpcell.00542.2019] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 12/27/2019] [Accepted: 01/03/2020] [Indexed: 01/22/2023]
Abstract
Neoangiogenesis is critical for tissue repair in response to injury such as myocardial ischemia or dermal wound healing. MicroRNAs are small noncoding RNAs and important regulators of angiogenesis under physiological and pathological disease states. Therefore, identification of microRNAs that may restore impaired angiogenesis in response to tissue injury may provide new targets for therapy. Using a microRNA microarray profiling approach, we identified a human-specific microRNA, miR-4674, that was significantly decreased in patients after myocardial tissue injury and had an endothelial cell (EC)-enriched expression pattern. Functionally, overexpression of miR-4674 markedly attenuated EC proliferation, migration, network tube formation, and spheroid sprouting, whereas blockade of miR-4674 had the opposite effects. Transcriptomic profiling, gene set enrichment analyses, bioinformatics, 3'-untranslated region (3'-UTR) reporter and microribonucleoprotein immunoprecipitation (miRNP-IP) assays, and small interfering RNA dependency studies revealed that miR-4674 regulates VEGF stimulated-p38 mitogen-activated protein kinase (MAPK) signaling and targets interleukin 1 receptor-associated kinase 1 (Irak1) and BICD cargo adaptor 2 (Bicd2) in ECs. Furthermore, Irak1 and Bicd2 were necessary for miR-4674-driven EC proliferation and migration. Finally, neutralization of miR-4674 increased angiogenesis, Irak1 and Bicd2 expression, and p38 phosphorylation in human skin organoids as a model of tissue injury. Collectively, targeting miR-4674 may provide a novel therapeutic target for tissue repair in pathological disease states associated with impaired angiogenesis.
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Affiliation(s)
- Basak Icli
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Hao Li
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Daniel Pérez-Cremades
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Physiology, University of Valencia and Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA) Biomedical Research Institute, Valencia, Spain
| | - Winona Wu
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Denizhan Ozdemir
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Medical Biology, Hacettepe University, Ankara, Turkey
| | - Stefan Haemmig
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Raphael Boesch Guimaraes
- Instituto de Cardiologia do Rio Grande do Sul, Fundação Universitária de Cardiologia (ICFUC), Porto Alegre, Rio Grande do Sul, Brazil
| | - Andre Manica
- Instituto de Cardiologia do Rio Grande do Sul, Fundação Universitária de Cardiologia (ICFUC), Porto Alegre, Rio Grande do Sul, Brazil
| | - Julio F Marchini
- Heart Institute, University of São Paulo Medical School, São Paulo, Brazil
| | - Dennis P Orgill
- Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Mark W Feinberg
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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Karan A, Bhakkiyalakshmi E, Jayasuriya R, Sarada DVL, Ramkumar KM. The pivotal role of nuclear factor erythroid 2-related factor 2 in diabetes-induced endothelial dysfunction. Pharmacol Res 2019; 153:104601. [PMID: 31838079 DOI: 10.1016/j.phrs.2019.104601] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 11/23/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023]
Abstract
Endothelial dysfunction (ED) is a key event in the onset and progression of vascular complications associated with diabetes. Regulation of endothelial function and the underlying signaling mechanisms in the progression of diabetes-induced vascular complications have been well established. Recent studies indicate that increased oxidative stress is an important determinant of endothelial injury and patients with hypertension display ED mediated by impaired Nitric Oxide (NO) availability. Further, oxidative stress is known to be associated with inflammation and ED in vascular remodeling and diabetes-associated hypertension. Numerous strategies have been developed to improve the function of endothelial cells and increasing number of evidences highlight the indispensable role of antioxidants in modulation of endothelium-dependent vasodilation responses. Nuclear factor Erythroid 2-related factor 2 (Nrf2), is the principal transcriptional regulator, that is central in mediating oxidative stress signal response. Having unequivocally established the relationship between type 2 diabetes mellitus (T2DM) and oxidative stress, the pivotal role of Nrf2/Keap1/ARE network, has taken the center stage as target for developing therapies towards maintaining the cellular redox environment. Several activators of Nrf2 are known to combat diabetes-induced ED and few are currently in clinical trials. Focusing on their therapeutic value in diabetes-induced ED, this review highlights some natural and synthetic molecules that are involved in the modulation of the Nrf2/Keap1/ARE network and its underlying molecular mechanisms in the regulation of ED. Further emphasis is also laid on the therapeutic benefits of directly up-regulating Nrf2-mediated antioxidant defences in regulating endothelial redox homeostasis for countering diabetes-induced ED.
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Affiliation(s)
- Amin Karan
- Life Science Division, SRM Research Institute, SRM Institute of Science & Technology, Kattankulathur, 603 203, Tamilnadu, India; Department of Biotechnology, School of Bioengineering, SRM Institute of Science & Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Elango Bhakkiyalakshmi
- Life Science Division, SRM Research Institute, SRM Institute of Science & Technology, Kattankulathur, 603 203, Tamilnadu, India; Department of Biotechnology, School of Bioengineering, SRM Institute of Science & Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Ravichandran Jayasuriya
- Life Science Division, SRM Research Institute, SRM Institute of Science & Technology, Kattankulathur, 603 203, Tamilnadu, India; Department of Biotechnology, School of Bioengineering, SRM Institute of Science & Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - D V L Sarada
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science & Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Kunka Mohanram Ramkumar
- Life Science Division, SRM Research Institute, SRM Institute of Science & Technology, Kattankulathur, 603 203, Tamilnadu, India; Department of Biotechnology, School of Bioengineering, SRM Institute of Science & Technology, Kattankulathur, 603 203, Tamil Nadu, India.
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Ostroumova OD, Kochetkov AI. Antihypertensive and Target-Organ Protective Properties of Telmisartan and Hydrochlorothiazide Single-Pill Combination. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2019. [DOI: 10.20996/1819-6446-2019-15-4-558-567] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The most important result of the revision of the European and Russian guidelines for the management of arterial hypertension (AH) was a special focus on initializing antihypertensive treatment with single-pill combinations (SPCs) in majority patients with AH. Combination of the angiotensin II receptor blocker and thiazide diuretic is one of the possible first line SPCs in the absence of specific clinical conditions according to the new guidelines. In this regard, SPC of telmisartan and hydrochlorothiazide (HCT), worth special noticing in the classes of sartans and thiazide diuretics, since both drugs have a long clinical experience and large body of evidence of antihypertensive efficacy and safety, as well as telmisartan also has a number of superior target-organ protective and metabolic properties distinguishing it from other members of the class. In real clinical practice TANDEM study telmisartan and its SPC with HCT showed high antihypertensive efficacy and good tolerability in patients with all AH grades and with isolated systolic AH and allowed to achieve target blood pressure levels in the most of patients. Long-lasting effect is another essential characteristic of telmisartan, this feature allows to control blood pressure throughout the day, including the morning surge, which is the most “dangerous” in terms of cardiovascular risk. Telmisartan also provide powerful target-organ protection realized at the level of all AH target-organs. Finally, another unique pharmacological property of telmisartan and its combination with HCT is a favourable effect on the carbohydrate and lipid profile, which comprises of increasing tissue sensitivity to insulin, normalizing blood glucose levels, reducing blood total cholesterol, low-density lipoprotein cholesterol and triglycerides and thereby reducing risk of atherosclerosis development and progression. Telmisartan/HCT SPC should be recommended for wide use in hypertensive patients to control blood pressure, protect end-organs, improve prognosis and reduce cardiovascular risk due to its high antihypertensive efficacy, the ability to provide the large target-organ protection and a beneficial metabolic effect.
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Affiliation(s)
- O. D. Ostroumova
- Pirogov Russian National Research Medical University, Russian Clinical and Research Center of Gerontology;
I.M. Sechenov First Moscow State Medical University (Sechenov University
| | - A. I. Kochetkov
- Pirogov Russian National Research Medical University, Russian Clinical and Research Center of Gerontology
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16
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Silva IVG, de Figueiredo RC, Rios DRA. Effect of Different Classes of Antihypertensive Drugs on Endothelial Function and Inflammation. Int J Mol Sci 2019; 20:ijms20143458. [PMID: 31337127 PMCID: PMC6678872 DOI: 10.3390/ijms20143458] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 06/05/2019] [Accepted: 06/06/2019] [Indexed: 12/12/2022] Open
Abstract
Hypertension is characterized by structural and functional changes in blood vessels that travel with increased arterial stiffness, vascular inflammation, and endothelial dysfunction. Some antihypertensive drugs have been shown to improve endothelial function and reduce levels of inflammatory markers regardless of the effect of blood pressure lowering. Third-generation β-blockers, such as nebivolol and carvedilol, because they have additional properties, have been shown to improve endothelial function in patients with hypertension. Calcium channel antagonists, because they have antioxidant effects, may improve endothelial function and vascular inflammation.The Angiotensin Receptor Blocker (ARBs) are able to improve endothelial dysfunction and vascular inflammation in patients with hypertension and other cardiovascular diseases. Angiotensin converting enzyme (ACE) inhibitors have shown beneficial effects on endothelial function in patients with hypertension and other cardiovascular diseases, however there are few studies evaluating the effect of treatment with this class on the reduction of C-reactive protein (CRP) levels. Further studies are needed to assess whether treatment of endothelial dysfunction and vascular inflammation may improve the prognosis of patients with essential hypertension.
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17
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Icli B, Wu W, Ozdemir D, Li H, Cheng HS, Haemmig S, Liu X, Giatsidis G, Avci SN, Lee N, Guimaraes RB, Manica A, Marchini JF, Rynning SE, Risnes I, Hollan I, Croce K, Yang X, Orgill DP, Feinberg MW. MicroRNA-615-5p Regulates Angiogenesis and Tissue Repair by Targeting AKT/eNOS (Protein Kinase B/Endothelial Nitric Oxide Synthase) Signaling in Endothelial Cells. Arterioscler Thromb Vasc Biol 2019; 39:1458-1474. [PMID: 31092013 PMCID: PMC6594892 DOI: 10.1161/atvbaha.119.312726] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 04/29/2019] [Indexed: 12/16/2022]
Abstract
Objective- In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro and antiangiogenic factors. We aimed to identify and characterize microRNAs that regulate angiogenesis in response to tissue injury. Approach and Results- We show that in response to tissue injury, microRNA-615-5p (miR-615-5p) is rapidly induced and serves as an antiangiogenic microRNA by targeting endothelial cell VEGF (vascular endothelial growth factor)-AKT (protein kinase B)/eNOS (endothelial nitric oxide synthase) signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes mellitus. Ectopic expression of miR-615-5p markedly inhibited endothelial cell proliferation, migration, network tube formation in Matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3' untranslated region reporter and microribonucleoprotein immunoprecipitation assays, and small interfering RNA dependency studies demonstrate that miR-615-5p inhibits the VEGF-AKT/eNOS signaling pathway in endothelial cells by targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras-associating domain family member 2). Local delivery of miR-615-5p inhibitors, markedly increased angiogenesis, granulation tissue thickness, and wound closure rates in db/db mice, whereas miR-615-5p mimics impaired these effects. Systemic miR-615-5p neutralization improved skeletal muscle perfusion and angiogenesis after hindlimb ischemia in db/db mice. Finally, modulation of miR-615-5p expression dynamically regulated VEGF-induced AKT signaling and angiogenesis in human skin organoids as a model of tissue injury. Conclusions- These findings establish miR-615-5p as an inhibitor of VEGF-AKT/eNOS-mediated endothelial cell angiogenic responses and that manipulating miR-615-5p expression could provide a new target for angiogenic therapy in response to tissue injury. Visual Overview- An online visual overview is available for this article.
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Affiliation(s)
- Basak Icli
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Winona Wu
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Denizhan Ozdemir
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
- Department of Medical Biology, Hacettepe University, Ankara, Turkey
| | - Hao Li
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Henry S. Cheng
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Stefan Haemmig
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Xin Liu
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Giorgio Giatsidis
- Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Seyma Nazli Avci
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Nathan Lee
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Raphael Boesch Guimaraes
- Instituto de Cardiologia do Rio Grande do Sul, Fundação Universitária de Cardiologia (ICFUC), Porto Alegre, RS, Brazil
| | - Andre Manica
- Instituto de Cardiologia do Rio Grande do Sul, Fundação Universitária de Cardiologia (ICFUC), Porto Alegre, RS, Brazil
| | - Julio F Marchini
- Heart Institute, University of São Paulo Medical School, São Paulo, Brazil
| | - Stein Erik Rynning
- Rheumatology, Lillehamer Hospital for Rheumatic Diseases, Lillehamer, Norway
| | - Ivar Risnes
- Rheumatology, Lillehamer Hospital for Rheumatic Diseases, Lillehamer, Norway
| | - Ivana Hollan
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
- Research Department, Lillehamer Hospital for Rheumatic Diseases, Lillehamer, Norway
| | - Kevin Croce
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | | | - Dennis P. Orgill
- Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Mark W. Feinberg
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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18
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Ott C, Bosch A, Winzer N, Friedrich S, Schinzel R, Tegtmeier F, Schmieder RE. Effects of the nitric oxide synthase inhibitor ronopterin (VAS203) on renal function in healthy volunteers. Br J Clin Pharmacol 2019; 85:900-907. [PMID: 30666700 PMCID: PMC6475696 DOI: 10.1111/bcp.13870] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/20/2018] [Accepted: 12/22/2018] [Indexed: 12/26/2022] Open
Abstract
AIMS Reduced nitric oxide (NO) availability may adversely affect renal perfusion and glomerular filtration. The aim of the present study was to characterize in detail the pharmacological effects of VAS203, an inhibitor of NO synthase, on renal haemodynamics in humans. METHODS This double-blind, randomized, placebo-controlled, cross-over phase-I-study comprised 18 healthy men. Renal haemodynamics were assessed with constant-infusion input-clearance technique with p-aminohippurate and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR), respectively. After baseline measurement, a constant infusion of the tetrahydrobiopterin analogue ronopterin (VAS203, total 10 mg/kg body weight) or placebo was administered at random order for 6 hours additionally. After a wash-out phase of 28 days, the second course was applied. In parallel, markers of early kidney injury and renal function were assessed repeatedly up to 48 hours after starting VAS203/placebo-infusion. RESULTS VAS203-infusion resulted in a significant decrease of RPF (P < .0001) and GFR (P < .001) compared to placebo, but magnitude was within the physiological range. RPF and GFR recovered partly 2 hours after end of VAS203-infusion and was normal at beginning of the second infusion period. Compared to placebo, preglomerular resistance (P < .0001), and to lesser extent postglomerular resistance (P < .0001) increased, resulting in a decrease of intraglomerular pressure (P < .01). No treatment related effect on markers of early kidney injury, and on renal function (P for all >.20) have been observed. CONCLUSIONS Our phase-I-study in healthy humans indicates that VAS203 (10 mg/kg body weight) reduces renal perfusion and glomerular function within the physiological range mainly due to vasoconstriction at the preglomerular site.
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Affiliation(s)
- Christian Ott
- Department of Nephrology and HypertensionFriedrich‐Alexander University Erlangen‐NürnbergGermany
- Department of Nephrology and HypertensionParacelsus Medical UniversityNürnbergGermany
| | - Agnes Bosch
- Department of Nephrology and HypertensionFriedrich‐Alexander University Erlangen‐NürnbergGermany
| | - Nicole Winzer
- Department of Nephrology and HypertensionFriedrich‐Alexander University Erlangen‐NürnbergGermany
| | - Stephanie Friedrich
- Department of Nephrology and HypertensionFriedrich‐Alexander University Erlangen‐NürnbergGermany
| | | | | | - Roland E. Schmieder
- Department of Nephrology and HypertensionFriedrich‐Alexander University Erlangen‐NürnbergGermany
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19
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Hong SJ, Jeong HS, Cho JM, Chang K, Pyun WB, Ahn Y, Hyon MS, Kang WC, Lee JH, Kim HS. Efficacy and Safety of Triple Therapy With Telmisartan, Amlodipine, and Rosuvastatin in Patients With Dyslipidemia and Hypertension: The Jeil Telmisartan, Amlodipine, and Rosuvastatin Randomized Clinical Trial. Clin Ther 2019; 41:233-248.e9. [DOI: 10.1016/j.clinthera.2018.12.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 11/29/2018] [Accepted: 12/08/2018] [Indexed: 10/27/2022]
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Radenkovic M, Stojanović M, Nešić IM, Prostran M. Angiotensin receptor blockers & endothelial dysfunction: Possible correlation & therapeutic implications. Indian J Med Res 2017; 144:154-168. [PMID: 27934794 PMCID: PMC5206866 DOI: 10.4103/0971-5916.195022] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The endothelium is one of the most important constituents of vascular homeostasis, which is achieved through continual and balanced production of different relaxing and contractile factors. When there is a pathological disturbance in release of these products, endothelial dysfunction (ED) will probably occur. ED is considered to be the initial step in the development of atherosclerosis. This pathological activation and inadequate functioning of endothelial cells was shown to be to some extent a reversible process, which all together resulted in increased interest in investigation of different beneficial treatment options. To this point, the pharmacological approach, including for example, the use of angiotensin-converting enzyme inhibitors or statins, was clearly shown to be effective in the improvement of ED. One of many critical issues underlying ED represents instability in the balance between nitric oxide and angiotensin II (Ang II) production. Considering that Ang II was confirmed to be important for the development of ED, the aim of this review article was to summarize the findings of up to date clinical studies associated with therapeutic application of angiotensin receptor blockers and improvement in ED. In addition, it was of interest to review the pleiotropic actions of angiotensin receptor blockers linked to the improvement of ED. The prospective, randomized, double-blind, placebo or active-controlled clinical trials were identified and selected for the final evaluation.
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Affiliation(s)
- Miroslav Radenkovic
- Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Marko Stojanović
- Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Ivana Milićević Nešić
- Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milica Prostran
- Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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Montanari A, Lazzeroni D, Pelà G, Crocamo A, Lytvyn Y, Musiari L, Cabassi A, Cherney DZI. Calcium channel blockade blunts the renal effects of acute nitric oxide synthase inhibition in healthy humans. Am J Physiol Renal Physiol 2017; 312:F870-F878. [DOI: 10.1152/ajprenal.00568.2016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 02/01/2017] [Accepted: 02/06/2017] [Indexed: 01/25/2023] Open
Abstract
Our aim was to investigate whether blockade of calcium channels (CCs) or angiotensin II type 1 receptors (AT1R) modulates renal responses to nitric oxide synthesis inhibition (NOSI) in humans. Fourteen sodium-replete, healthy volunteers underwent 90-min infusions of 3.0 μg·kg−1·min−1 NG-nitro-l-arginine methyl ester (l-NAME) on 3 occasions, preceded by 3 days of either placebo (PL), 10 mg of manidipine (MANI), or 50 mg of losartan (LOS). At each phase, mean arterial pressure (MAP), glomerular filtration rate (GFR; inulin), renal blood flow (RBF; p-aminohippurate), urinary sodium (UNaV), and 8-isoprostane (U8-iso-PGF2αV; an oxidative stress marker) were measured. With PL + l -NAME, the following changes were observed: +6% MAP ( P < 0.005 vs. baseline), −10% GFR, −20% RBF, −49% UNaV ( P < 0.001), and +120% U8-iso-PGF2αV ( P < 0.01). In contrast, MAP did not increase during LOS + l-NAME or MANI + l-NAME ( P > 0.05 vs. baseline), whereas renal changes were the same during LOS + l-NAME vs. PL + l-NAME (ANOVA, P > 0.05). However, during MANI + l-NAME, changes vs. baseline in GFR (−6%), RBF (−12%), and UNaV (−34%) were blunted vs. PL + l-NAME and LOS + l-NAME ( P < 0.005), and the rise in U8-iso-PGF2αV was almost abolished (+37%, P > 0.05 vs. baseline; P < 0.01 vs. PL + l-NAME or LOS + l-NAME). We conclude that, since MANI blunted l-NAME-induced renal hemodynamic changes, CCs participate in the renal responses to NOSI in healthy, sodium-replete humans independent of changes in MAP and without the apparent contribution of the AT1R. Because the rise in U8-iso-PGF2αV was essentially prevented during MANI + l-NAME, CC blockade may oppose the renal effects of NOSI in part by counteracting oxidative stress responses to acutely impaired renal NO bioavailability.
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Affiliation(s)
- Alberto Montanari
- Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy
| | - Davide Lazzeroni
- Prevention and Rehabilitation Unit at the Don Gnocchi Foundation and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; and
| | - Giovanna Pelà
- Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy
| | - Antonio Crocamo
- Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy
| | - Yuliya Lytvyn
- Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Luisa Musiari
- Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy
| | - Aderville Cabassi
- Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy
| | - David Z. I. Cherney
- Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Abstract
Hypertension, the most common preventable risk factor for cardiovascular disease and death, is a growing health burden. Serious cardiovascular complications result from target organ damage including cerebrovascular disease, heart failure, ischaemic heart disease and renal failure. While many systems contribute to blood pressure (BP) elevation, the vascular system is particularly important because vascular dysfunction is a cause and consequence of hypertension. Hypertension is characterised by a vascular phenotype of endothelial dysfunction, arterial remodelling, vascular inflammation and increased stiffness. Antihypertensive drugs that influence vascular changes associated with high BP have greater efficacy for reducing cardiovascular risk than drugs that reduce BP, but have little or no effect on the adverse vascular phenotype. Angiotensin converting enzyme ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve endothelial function and prevent vascular remodelling. Calcium channel blockers also improve endothelial function, although to a lesser extent than ACEIs and ARBs. Mineralocorticoid receptor blockers improve endothelial function and reduce arterial stiffness, and have recently become more established as antihypertensive drugs. Lifestyle factors are essential in preventing the adverse vascular changes associated with high BP and reducing associated cardiovascular risk. Clinicians and scientists should incorporate these factors into treatment decisions for patients with high BP, as well as in the development of new antihypertensive drugs that promote vascular health.
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Affiliation(s)
- Alan C Cameron
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK
| | - Ninian N Lang
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK
| | - Rhian M Touyz
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK.
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23
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Patel P. Telmisartan: clinical evidence across the cardiovascular and renal disease continuum. DRUGS & THERAPY PERSPECTIVES 2016. [DOI: 10.1007/s40267-016-0366-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Ott C, Kistner I, Keller M, Friedrich S, Willam C, Bramlage P, Schmieder RE. Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial. Diabetologia 2016; 59:2579-2587. [PMID: 27586249 DOI: 10.1007/s00125-016-4083-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 07/13/2016] [Indexed: 11/29/2022]
Abstract
AIMS/HYPOTHESIS Endothelial dysfunction predicts cardiovascular damage and renal involvement. Animal experiments and human studies indicate an increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in the early stage of type 2 diabetes. The aim of the study was to assess the effect of linagliptin on the endothelial function of the renal vasculature. METHODS In this randomised, double-blind, parallel-group, investigator-initiated trial, 62 patients with type 2 diabetes were randomly assigned (by computer-generated random code) to receive linagliptin 5 mg (n = 30) or placebo (n = 32) for 4 weeks. The primary objective was to assess endothelial function of the renal vasculature, by constant-infusion input-clearance and urinary albumin/creatinine ratio (UACR), both before and after blockade of NOS with N G-monomethyl-L-arginine (L-NMMA). RESULTS Treatment with linagliptin for 4 weeks reduced fasting, postprandial blood glucose and HbA1c, although not significantly; no change occurred with placebo. Renal plasma flow (RPF) did not change after linagliptin or placebo. After 4 weeks the absolute change in RPF due to L-NMMA was smaller in the linagliptin group than in the placebo group (-46.8 ± 34 vs -65.1 ± 36 ml/min, p = 0.045), indicating a lower basal NO activity after treatment with linagliptin. Consistently, the response of UACR to L-NMMA increased in the placebo group (p = 0.059) but not in the linagliptin group (p = 0.276), pointing to an upregulation of NO activity in the placebo group. No clinically meaningful safety concerns were evident. CONCLUSIONS/INTERPRETATION Our data suggest that treatment with the dipeptidyl peptidase-4 inhibitor linagliptin for 4 weeks prevented the impairment of renal endothelial function due to hyperglycaemia in type 2 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT01835678 FUNDING: : This study was funded by Boehringer Ingelheim.
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Affiliation(s)
- Christian Ott
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany
| | - Iris Kistner
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany
| | - Mirjam Keller
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany
| | - Stefanie Friedrich
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany
| | - Carsten Willam
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany
| | - Peter Bramlage
- Institute for Pharmacology and Preventive Medicine, Mahlow, Germany
| | - Roland E Schmieder
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany.
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25
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Abstract
Atherosclerotic coronary artery disease (CAD) is a major cause of morbidity and mortality in the developed world. Endothelial dysfunction plays an important role in the development of atherosclerosis and predicts cardiovascular (CV) outcomes independent of conventional CV risk factors. In recent years, there have been tremendous improvements in the pharmacological prevention and management of CAD. In this review, the pathophysiology of endothelial dysfunction in relation to CAD is discussed and various techniques of invasive and noninvasive assessments of peripheral and coronary endothelial function described. In addition, evidence for the association of endothelial dysfunction and CV outcomes has been examined and finally the role of therapeutic interventions in endothelial dysfunction has been discussed.
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26
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Lin JC, Lai MS. Antihypertensive Drugs and Diabetic Retinopathy in Patients with Type 2 Diabetes. Ophthalmologica 2015; 235:87-96. [PMID: 26695432 DOI: 10.1159/000441958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 10/12/2015] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To evaluate the association between the development of sight-threatening diabetic retinopathy (STDR) and antihypertensive drugs (AHDs) use among type 2 diabetic patients with concomitant hypertension. METHODS Type 2 diabetic patients aged 20-100 years who had at least one prescription for AHDs between 2000 and 2011 were identified from the Longitudinal Health Insurance Database (LHID) 2005. The incidence rates of STDR were followed and Cox proportional hazard models were used to analyze the risk associated with AHDs. RESULTS Users of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) were associated with a significantly higher risk than users of calcium channel blockers (CCBs), independent of baseline characteristics. After adjusting for time-varying use of concomitant medications for propensity score-matched or -unmatched cohorts, the results showed that patients receiving ACEIs/ARBs and CCBs were associated with a significantly greater risk compared with β-blocker users. CONCLUSIONS Our study did not support a superiority of ACEIs/ARBs and CCBs over β-blockers for lowering the progression of diabetic retinopathy.
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Affiliation(s)
- Jen-Chieh Lin
- Department of Ophthalmology, Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan, ROC
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27
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Futrakul N, Chanakul A, Futrakul P, Deekajorndech T. Early stage of vascular disease and diabetic kidney disease: an under-recognized entity. Ren Fail 2015; 37:1243-6. [PMID: 26365595 DOI: 10.3109/0886022x.2015.1073054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Early stage of vascular disease and diabetic kidney disease (DKD stages 1 and 2) has been under-recognized, under common practice worldwide. The lack of sensitive diagnostic marker leads to late diagnosis and a progression of underlying vascular disease associated with chronic renal ischemia, which eventually intensifies the magnitude of DKD damage. Treatment at this late stage fails to correct the renal ischemia, or restore renal function, due to the altered vascular homeostasis associated with an impaired nitric oxide production. In contrast to the above information, early recognition of vascular disease and DKD with sensitive diagnostic markers would be able to implement an effective prevention of progression of vascular disease and DKD. Treatment at early stage under environment favorable for adequate vascular homeostasis is able to correct the renal ischemia and improve the renal function.
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Affiliation(s)
- Narisa Futrakul
- a Renal Microvascular Research Group, Department of Physiology, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University , Bangkok , Thailand
| | - Ankanee Chanakul
- b Department of Pediatrics , King Chulalongkorn Memorial Hospital, Chulalongkorn University , Bangkok , Thailand , and
| | - Prasit Futrakul
- c Bhumirajanagarindra Kidney Institute, and Academy of Science, The Royal Institute of Thailand , Bangkok , Thailand
| | - Tawatchai Deekajorndech
- b Department of Pediatrics , King Chulalongkorn Memorial Hospital, Chulalongkorn University , Bangkok , Thailand , and
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Tousoulis D, Psaltopoulou T, Androulakis E, Papageorgiou N, Papaioannou S, Oikonomou E, Synetos A, Stefanadis C. Oxidative stress and early atherosclerosis: novel antioxidant treatment. Cardiovasc Drugs Ther 2015; 29:75-88. [PMID: 25410138 DOI: 10.1007/s10557-014-6562-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Atherosclerotic lesions initiate in regions characterized by low shear stress and reduced activity of endothelial atheroprotective molecules such as nitric oxide, which is the key molecule managing vascular homeostasis. The generation of reactive oxygen species from the vascular endothelium is strongly related to various enzymes, such as xanthine oxidase, endothelial nitric oxide synthase and nicotinamide-adenine dinucleotide phosphate oxidase. Several pharmaceutical agents, including angiotensin converting enzyme inhibitors, angiotensin receptors blockers and statins, along with a variety of other agents, have demonstrated additional antioxidant properties beyond their principal role. Reports regarding the antioxidant role of vitamins present controversial results, especially those based on large scale studies. In addition, there is growing interest on the role of dietary flavonoids and their potential to improve endothelial function by modifying the oxidative stress status. However, the vascular-protective role of flavonoids and especially their antioxidant properties are still under investigation. Indeed, further research is required to establish the impact of the proposed new therapeutic strategies in atherosclerosis.
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Affiliation(s)
- Dimitris Tousoulis
- Cardiology Department, University of Athens Medical School, "Hippokration" Hospital, Athens, Greece
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29
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Effects of folic acid on renal endothelial function in patients with diabetic nephropathy: results from a randomized trial. Clin Sci (Lond) 2014; 127:499-505. [PMID: 24724807 DOI: 10.1042/cs20140111] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
UNLABELLED Endothelial dysfunction has been shown to promote podocyte injury and albuminuria in diabetes, highlighting the importance of the interaction between renal endothelial cells and podocytes. Folic acid (FA) improves nitric oxide synthase (NOS) function and reduces progression of diabetic nephropathy in animal models. We tested whether high-dose FA treatment improves renal endothelial function and albuminuria in human subjects with incipient diabetic nephropathy. Following a double-blind, randomized, cross-over design, 28 patients with Type 2 diabetes and albuminuria were allocated to 4 weeks' treatment with placebo and high-dose FA (5 mg/day). Renal nitric oxide (NO) production determined as the response of renal plasma flow (RPF) to NOS inhibition with NG-monomethyl-L-arginine (L-NMMA) (4.25 mg/kg intravenously), renal oxidant stress as response of RPF to vitamin C infusion (3 mg/kg) and albuminuria were determined after each treatment phase. Neither the reduction in RPF to L-NMMA nor the increase in RPF to vitamin C infusion differed between treatment phases (ΔRPF to L-NMMA -74±71 ml/min per m2 during placebo compared with -63±56 ml/min per m2 during FA, P=0.57; ΔRPF to vitamin C: +93±118 ml/min per m2 compared with +94±108 ml/min per m2; P=0.70). In line with the lack of effect on the renal endothelium, albuminuria was not affected by FA treatment (110±179 mg/day during placebo compared with 87±146 mg/day during FA; P=0.12). High-dose FA treatment does not improve renal endothelial function and fails to reduce albuminuria in human subjects with diabetic nephropathy. Novel treatment options for oxidant stress and endothelial dysfunction in patients with diabetes are urgently needed.
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Ji X, Xia C, Wang J, Su M, Zhang L, Dong T, Li Z, Wan X, Li J, Li J, Zhao L, Gao Z, Jiang H, Liu H. Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors. Eur J Med Chem 2014; 86:242-56. [PMID: 25164763 DOI: 10.1016/j.ejmech.2014.08.059] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 08/15/2014] [Accepted: 08/16/2014] [Indexed: 01/25/2023]
Abstract
Based on the previous work in our group and the principle of computer-aided drug design, a series of novel β-amino pyrrole-2-carbonitrile derivatives was designed and synthesized. Compounds 8l and 9l were efficacious and selective DPP4 inhibitors resulting in decreased blood glucose in vivo. Compound 8l had moderate DPP4 inhibitory activity (IC50 = 0.05 μM) and good oral bioavailability (F = 53.2%). Compound 9l showed excellent DPP4 inhibitory activity (IC50 = 0.01 μM), good selectivity (selective ratio: DPP8/DPP4 = 898.00; DPP9/DPP4 = 566.00) against related peptidases, and good efficacy in an oral glucose tolerance tests in ICR mice and moderate PK profiles (F = 22.8%, t1/2 = 2.74 h). Moreover, compound 9l did not block hERG channel and exhibited no inhibition of liver metabolic enzymes such as CYP2C9.
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Affiliation(s)
- Xun Ji
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People's Republic of China
| | - Chunmei Xia
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Jiang Wang
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Mingbo Su
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China; East China of Normal University, 3663 Zhongshan Road, Shanghai 200062, People's Republic of China
| | - Lei Zhang
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Tiancheng Dong
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Zeng Li
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Xia Wan
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Jingya Li
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Jia Li
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
| | - Linxiang Zhao
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People's Republic of China
| | - Zhaobing Gao
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China
| | - Hualiang Jiang
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People's Republic of China.
| | - Hong Liu
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
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Shishkova VN. The mechanisms of developmentcardiovascular disease and type 2 diabetes: the role of insulin resistance, hyperinsulinemia and hypoadiponektinemia. Treatment and management. ACTA ACUST UNITED AC 2014. [DOI: 10.26442/sg29024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In the current paradigm, the primary insulin resistance plays a central role in the development of not only diabetes but also associated with cardiovascular complications, such as arterial hypertension, arteriosclerosis, heart failure, atrial fibrillation. Defense mechanism involves the secretion of adiponectin from adipoctyes and thus helps to block the development of these diseases. Modern antihypertensive treatment options of angiotensin-receptor blocker telmisartan show that, telmisartan can be used in patients with arterial hypertension because of improving insulin resistance and increasing adiponectin levels.
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A meta-analysis of randomized controlled trials of telmisartan for flow-mediated dilatation. Hypertens Res 2014; 37:845-51. [PMID: 24718299 DOI: 10.1038/hr.2014.81] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 03/03/2014] [Accepted: 03/04/2014] [Indexed: 01/06/2023]
Abstract
There have been a number of small-sized underpowered randomized controlled trials to assess effects of telmisartan on flow-mediated dilatation (FMD). To determine whether telmisartan increases FMD, we performed a meta-analysis of these trials. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched through December 2013. Eligible studies were prospective randomized controlled trials of telmisartan reporting FMD as an outcome. Search terms included: telmisartan; endothelial function/dysfunction; flow-mediated dilation/dilatation/vasodilation/vasodilatation; and randomized, randomly or randomization. Included studies were reviewed to determine the number of patients randomized, mean duration of treatment and percent changes of FMD. Of 25 potentially relevant articles screened initially, seven reports of randomized trials enrolling a total of 398 patients were identified and included. A pooled analysis of the seven trials demonstrated a statistically significant increase in FMD by 48.7%, with telmisartan relative to control in the random-effects model (mean difference, 48.72%; 95% confidence interval, 15.37-82.08%; P for effect=0.004; P for heterogeneity <0.00001). Exclusion of any single trial from the analysis did not substantively alter the overall result of our analysis. There was no evidence of significant publication bias. In conclusion, the present meta-analysis of seven randomized controlled trials enrolling a total of 398 patients confirmed the evidence of a significant increase in FMD with telmisartan, which suggests that telmisartan may improve endothelial dysfunction.
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McFarlane SI. Role of angiotensin receptor blockers in diabetes: implications of recent clinical trials. Expert Rev Cardiovasc Ther 2014; 7:1363-71. [DOI: 10.1586/erc.09.115] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Futrakul N, Futrakul P. Vascular response to vasodilator treatment in microalbuminuric diabetic kidney disease. World J Nephrol 2013; 2:125-128. [PMID: 24255895 PMCID: PMC3832868 DOI: 10.5527/wjn.v2.i4.125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Revised: 06/04/2013] [Accepted: 09/04/2013] [Indexed: 02/06/2023] Open
Abstract
Under common practice, the conventional diagnostic marker such as microalbuminuria determination does not recognized early stage of diabetic kidney disease (normoalbuminuria, chronic kidney disease stage 1, 2); due to the insensitiveness of the available marker. Treatment at later stage (microalbuminuria) simply slows the renal disease progression, but is rather difficult to restore the renal perfusion. Intrarenal hemodynamic study in these patients revealed an impaired renal perfusion and abnormally elevated renal arteriolar resistances. Treatment with vasodilators such as angiotensin converting enzyme inhibitor and angiotensin receptor blocker fails to correct the renal ischemia. Recent study on vascular homeostasis revealed a defective mechanism associated with an impaired nitric oxide production which would explain the therapeutic resistance to vasodilator treatment in microalbuminuric diabetic kidney disease. This study implies that the appropriate therapeutic strategy should be implemented at earlier stage before the appearance of microalbuminuria.
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Clementi A, Virzì GM, Goh CY, Cruz DN, Granata A, Vescovo G, Ronco C. Cardiorenal syndrome type 4: a review. Cardiorenal Med 2013; 3:63-70. [PMID: 23946725 DOI: 10.1159/000350397] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
There is a bidirectional and complex relationship between the heart and kidneys. This interaction is physical, chemical as well as biological and is also reflected in a strong connection between renal and cardiovascular diseases. Cardiorenal syndrome type 4 (CRS type 4) is characterized by primary chronic kidney disease (CKD) leading to an impairment of cardiac function, with ventricular hypertrophy, diastolic dysfunction, and/or increased risk of adverse cardiovascular events. The incidence of CKD is increasing, and CRS type 4 is becoming a major public health problem associated with a high morbidity and mortality. In this study, we briefly review the epidemiology and pathophysiology of CRS type 4, the role of biomarkers in its early identification, and its management.
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Mallat SG. Dual renin-angiotensin system inhibition for prevention of renal and cardiovascular events: do the latest trials challenge existing evidence? Cardiovasc Diabetol 2013; 12:108. [PMID: 23866091 PMCID: PMC3726294 DOI: 10.1186/1475-2840-12-108] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Accepted: 07/15/2013] [Indexed: 02/06/2023] Open
Abstract
Circulatory and tissue renin-angiotensin systems (RAS) play a central role in cardiovascular (CV) and renal pathophysiology, making RAS inhibition a logical therapeutic approach in the prevention of CV and renal disease in patients with hypertension. The cardio- and renoprotective effects observed with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) monotherapy, together with the availability of a direct renin inhibitor (DRI), led to the investigation of the potential benefits of dual RAS inhibition. In small studies, ARB and ACE inhibitor combinations were shown to be beneficial in patients with CV or renal disease, with improvement in surrogate markers. However, in larger outcome trials, involving combinations of ACE inhibitors, ARBs or DRIs, dual RAS inhibition did not show reduction in mortality in patients with diabetes, heart failure, coronary heart disease or after myocardial infarction, and was in fact, associated with increased harm. A recent meta-analysis of all major trials conducted over the past 22 years involving dual RAS inhibition has clearly shown that the risk-benefit ratio argues against the use of dual RAS inhibition. Hence, the recent evidence clearly advocates against the use of dual RAS inhibition, and single RAS inhibition appears to be the most suitable approach to controlling blood pressure and improving patient outcomes.
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Lyapina LA, Myasoedov NF, Grigor’eva ME, Shubina TA, Andreeva LA. The modern concept of the regulatory role of peptides of the glyproline family in the correction of hemostasis system function during development of diabetes mellitus. BIOL BULL+ 2013. [DOI: 10.1134/s1062359013040109] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Andreeva LA, Myasoedov NF, Shubina TA, Grigorieva ME, Ljapina LA. Arginine-containing tripeptide Pro-Arg-Gly is involved in the regulation of the function of anticoagulation and insular systems under persistent hyperglycemia. Bull Exp Biol Med 2013; 153:651-4. [PMID: 23113248 DOI: 10.1007/s10517-012-1789-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Intranasal administration of regulatory peptide PRG to rats against the background of persistent hyperglycemia improves blood antiplatelet and anticoagulant-fibrinolytic potential and normalizes blood sugar in comparison with the corresponding parameters in control animals that did not receive the peptide. The fibrinolytic and antiplatelet activities of blood plasma remained elevated 6 days after peptide withdrawal against the background of unchanged glucose administration.
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Affiliation(s)
- L A Andreeva
- Institute of Molecular Genetics, Russian Academy of Science, Moscow, Russia
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Patarroyo Aponte MM, Francis GS. Effect of Angiotensin-converting enzyme inhibitors and Angiotensin receptor antagonists in atherosclerosis prevention. Curr Cardiol Rep 2012; 14:433-42. [PMID: 22562592 DOI: 10.1007/s11886-012-0275-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Atherosclerosis is a highly complex biological process that has become the scourge of modern civilization. Endothelial dysfunction is the first step in the development of atherosclerosis. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the development of endothelial dysfunction and atherosclerosis. Several studies have shown that in vitro blockade of the RAAS is associated with improvement in markers of endothelial dysfunction and inflammation. Many clinical trials have demonstrated a clear benefit of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) manifested by a reduction of cardiovascular events. These findings suggest that ACEIs and ARBs can play an important role in prevention of atherosclerosis and in the delay of its progression. In this review we focus on the importance of RAAS blockade to prevent or delay progression of atherosclerosis and its impact on reduction of cardiovascular events.
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Affiliation(s)
- Maria M Patarroyo Aponte
- Division of Cardiovascular Medicine, Lillehei Heart Institute, University of Minnesota Medical Center, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
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Ott IM, Alter ML, von Websky K, Kretschmer A, Tsuprykov O, Sharkovska Y, Krause-Relle K, Raila J, Henze A, Stasch JP, Hocher B. Effects of stimulation of soluble guanylate cyclase on diabetic nephropathy in diabetic eNOS knockout mice on top of angiotensin II receptor blockade. PLoS One 2012; 7:e42623. [PMID: 22900035 PMCID: PMC3416804 DOI: 10.1371/journal.pone.0042623] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 07/10/2012] [Indexed: 01/13/2023] Open
Abstract
The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB) treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC) as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d), riociguat (3 mg/kg/d), riociguat+telmisartan (3+1 mg/kg/d), and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2±2.3 mmHg vs. 117.1±2.2 mmHg; p = 0.071). Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2±2.5 mmHg and 105.0±3.2 mmHg, respectively, vs. 117.1±2.2 mmHg). Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3±9.6 µg/24 h vs. 170.8±34.2 µg/24 h; p = 0.002) reaching levels similar to those of non-diabetic controls (34.4±10.6 µg/24 h), whereas the reduction by single treatment with either telmisartan (97.8±26.4 µg/24 h) or riociguat (97.1±15.7 µg/24 h) was not statistically significant. The combination treatment led to a significant (p<0.01) decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary albumin excretion in diabetic eNOS knockout mice treated already with ARB. Thus, this new drug class on top of standard ARBs administration may offer a new therapeutic approach for patients resistant to ARB treatment.
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Affiliation(s)
- Ina M. Ott
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
| | - Markus L. Alter
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
- Department of Nephrology, Charité Campus Benjamin Franklin, Berlin, Germany
| | - Karoline von Websky
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
| | | | - Oleg Tsuprykov
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
| | - Yuliya Sharkovska
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
| | - Katharina Krause-Relle
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
| | - Jens Raila
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Andrea Henze
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Johannes-Peter Stasch
- Bayer HealthCare AG, Wuppertal, Germany
- Institute of Pharmacy, University of Halle-Wittenberg, Halle (Saale), Germany
| | - Berthold Hocher
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
- * E-mail:
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Cao Z, Cooper ME. Efficacy of renin-angiotensin system (RAS) blockers on cardiovascular and renal outcomes in patients with type 2 diabetes. Acta Diabetol 2012; 49:243-54. [PMID: 21947383 DOI: 10.1007/s00592-011-0328-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 09/06/2011] [Indexed: 12/17/2022]
Abstract
Cardiovascular disease is the predominant cause of morbidity in people with type 2 diabetes. Hypertension frequently coexists with diabetes and substantially increases the risk of developing end-organ damage. Controlling hypertension in patients with diabetes is therefore critical to reducing microvascular and macrovascular complications. Agents that block the renin-angiotensin system are increasingly used in patients with diabetes based on their cardiovascular and renoprotective effects, in addition to their direct effects on reducing blood pressure. Telmisartan, an angiotensin II receptor blocker (ARB), has a number of distinguishing pharmacological properties such as having the longest half-life and highest lipophilicity in its class. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET(®)) trial showed that telmisartan reduces cardiovascular morbidity (including myocardial infarction and stroke) in subjects with a broad spectrum of cardiovascular risk factors, including type 2 diabetes. Telmisartan is the only ARB indicated for the reduction of cardiovascular morbidity in patients with diabetes and end-organ damage, as well as in patients without diabetes but with a history of coronary artery disease, peripheral artery disease, or previous stroke. Trials of telmisartan in patients with diabetes and varying degrees of nephropathy also suggest that this drug can slow the progression of renal disease, an effect that appears to be at least partly independent of reduction in blood pressure. Telmisartan is therefore an important therapeutic option for optimizing cardiovascular and renal protection in the type 2 diabetic population.
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Affiliation(s)
- Zemin Cao
- Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
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Verdecchia P, Gentile G, Angeli F, Reboldi G. Beyond blood pressure: evidence for cardiovascular, cerebrovascular, and renal protective effects of renin-angiotensin system blockers. Ther Adv Cardiovasc Dis 2012; 6:81-91. [PMID: 22528743 DOI: 10.1177/1753944712444866] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
For patients with hypertension, effective control of blood pressure (BP) reduces cardiovascular (CV), and renal risk. Antihypertensive agents that offer benefits that extend beyond those associated with BP reduction alone, to include tissue protective effects and effects on the vasculature, may be of benefit for many patients with increased CV risk due to comorbidities or prior history of CV events. Renin-angiotensin system (RAS) blockers [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs)] are guideline-recognized, highly effective antihypertensive agents that exert their BP-lowering action through different mechanisms at different levels of the RAS. Large-scale clinical studies suggest that small, between-treatment differences in BP lowering do not account for observed outcome differences between RAS blockers and other antihypertensive agents. Analysis of data from seminal clinical studies and meta-analyses identify that, controlling for effects on BP control, RAS blockers may be more effective than calcium channel blockers (CCBs) in reducing risk of myocardial infarction and congestive heart failure; ARBs may be more effective than either ACEIs or β blockers in stroke prevention; CCBs may be more effective than RAS blockers in stroke prevention; and ARBs may be more effective than β blockers in reducing left ventricular hypertrophy. This review considers the rationale and evidence for benefits of RAS blockade beyond BP lowering, and highlights the differences between ARBs and ACEIs, and between agents within these drug classes.
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Affiliation(s)
- Paolo Verdecchia
- Department of Medicine, Hospital of Assisi, Via Valentin Müller, 106081 Assisi PG, Italy.
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Hamilton SJ, Chew GT, Davis TME, Watts GF. Prevalence and predictors of abnormal arterial function in statin-treated type 2 diabetes mellitus patients. Metabolism 2012; 61:349-57. [PMID: 21944268 DOI: 10.1016/j.metabol.2011.07.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Revised: 06/26/2011] [Accepted: 07/18/2011] [Indexed: 11/18/2022]
Abstract
Arterial dysfunction (AD) in type 2 diabetes mellitus (T2DM) predicts cardiovascular events. The objective was to investigate the prevalence and predictors of AD in statin-treated T2DM patients. We measured flow-mediated (FMD) and nitrate-mediated (NMD) brachial artery dilatation in 86 statin-treated T2DM patients. Patients were classified into 2 groups: normal arterial function (FMD ≥3.7% with NMD ≥11.9%) or AD (FMD <3.7% with or without NMD <11.9%). Endothelial dysfunction without smooth muscle cell dysfunction (ED) was defined as FMD less than 3.7% with NMD of at least 11.9%, and endothelial dysfunction with smooth muscle cell dysfunction (ED/SMD) was defined as FMD less than 3.7% with NMD less than 11.9%. Predictors of arterial function were investigated using linear and logistic regression methods. The prevalence of AD was 33.7% (23.2% with ED and 10.5% with ED/SMD). In multivariate linear regression, history of hypertension (P < .01), statin dose (P < .05), and estimated glomerular filtration rate (eGFR) (P = .02) were significant predictors of FMD. Sex (P < .01) and creatinine (P = .03) or eGFR (P = .02) predicted NMD. In multivariate logistic regression, the independent predictors of AD were history of hypertension (odds ratio [OR], 8.79; 95% confidence interval, 2.14-36.12; P < .01), age (OR, 1.08; 1.01-1.17; P = .03), and statin dose (OR, 0.33; 0.12-0.87; P = .02). A history of hypertension (OR, 8.99; 1.87-43.26; P < .01) was the sole independent predictor of ED; eGFR (OR, 0.01; 0.00-0.26; P < .01) independently predicted ED/SMD. Our data suggest that one third of statin-treated diabetic patients have residual AD, mainly due to ED alone. Earlier identification and treatment of hypertension and renal impairment may improve AD and further decrease cardiovascular risk in such patients.
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Affiliation(s)
- Sandra J Hamilton
- School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia 6847, Australia
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Destro M, Cagnoni F, Dognini GP, Galimberti V, Taietti C, Cavalleri C, Galli E. Telmisartan: just an antihypertensive agent? A literature review. Expert Opin Pharmacother 2012; 12:2719-35. [PMID: 22077832 DOI: 10.1517/14656566.2011.632367] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION The modulation of the renin angiotensin aldosterone system (RAAS) is an important pathway in managing high blood pressure, and its overexpression plays a key role in target end-organ damage. Telmisartan is an angiotensin II receptor blocker (ARB) with unique pharmacologic properties, including the longest half-life among all ARBs; this leads to a significant and 24-h sustained reduction of blood pressure. Telmisartan has well-known antihypertensive properties, but there is also strong clinical evidence that it reduces left ventricular hypertrophy, arterial stiffness and the recurrence of atrial fibrillation, and confers renoprotection. AREAS COVERED This paper reviews telmisartan's pharmacological properties in terms of efficacy for hypertension control and, importantly, focuses on its new therapeutic indications and their clinical implications. EXPERT OPINION ONTARGET (ongoing telmisartan alone and in combination with ramipril global endpoint trial) demonstrated, that telmisartan confers cardiovascular protective effects similar to those of ramipril, but with a better tolerability. Moreover, recent investigations focused on the capability of telmisartan to modulate the peroxisome proliferator-activated receptor-gamma (PPAR-γ), an established target in the treatment of insulin resistance, diabetes and metabolic syndrome, whose activation is also correlated to anti-inflammatory and, finally, anti-atherosclerotic properties. Telmisartan shows peculiar features that go beyond blood pressure control. It presents promising and unique protective properties against target end-organ damage, potentially able to open a scenario of new therapeutic approaches to cardiovascular disease.
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Affiliation(s)
- Maurizio Destro
- General Medicine Unit, Treviglio-Caravaggio Hospital, Medical Department, A.O. Treviglio, 24047 Treviglio (BG), Italy.
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Vecchiet J, Ucciferri C, Falasca K, Mancino P, Di Iorio A, De Caterina R. Antihypertensive and metabolic effects of telmisartan in hypertensive HIV-positive patients. Antivir Ther 2012; 16:639-45. [PMID: 21817185 DOI: 10.3851/imp1809] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND Hypertension is more prevalent among HIV-infected individuals than in the general population and contributes to increased cardiovascular risk. The angiotensin II receptor blocker telmisartan is also a partial peroxisome proliferator activated receptor-γ agonist with documented effects on glucose and lipid homeostasis. The aim of this study was to evaluate the antihypertensive and metabolic effects of telmisartan in hypertensive HIV-positive patients. METHODS A total of 18 HIV-positive men treated with antiretroviral therapy and recently diagnosed with hypertension were administered 80 mg telmisartan daily. Systolic blood pressure (SBP) and diastolic blood pressure (DBP), viroimmunological and metabolic parameters, insulin resistance, C-reactive protein, microalbuminuria, cystatin C and plasma levels of interleukin-18 and endothelin-1 were measured at baseline (T0), 1 month (T1), 3 months (T3) and 6 months (T6). RESULTS Treatment with telmisartan not only decreased SBP and DBP levels, but also improved insulin resistance and microalbuminuria by T1. Levels of triglycerides significantly decreased and high-density lipoprotein cholesterol increased at T1, whereas total and low-density lipoprotein cholesterol levels were statistically reduced at T3 and T6. Cystatin C and endothelin-1 showed a significant reduction at T1, whereas interleukin-18 decreased at both T3 and T6. CONCLUSIONS Telmisartan was effective in reducing blood pressure and improving lipid metabolism and renal function. Reduction of endothelin-1 might be related to an endothelial protective effect. On the basis of these findings, and because of properties unrelated to blood pressure lowering, telmisartan might be the first choice antihypertensive drug for the treatment of HIV-positive patients.
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Affiliation(s)
- Jacopo Vecchiet
- Division of Infectious Diseases, Department of Medicine and Sciences of Aging, G d'Annunzio University School of Medicine, Chieti, Italy.
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Suksomboon N, Poolsup N, Prasit T. Systematic review of the effect of telmisartan on insulin sensitivity in hypertensive patients with insulin resistance or diabetes. J Clin Pharm Ther 2011; 37:319-27. [DOI: 10.1111/j.1365-2710.2011.01295.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Schneider MP, Schlaich MP, Harazny JM, Raff U, Ritt M, Ott C, Schmieder RE. Folic acid treatment normalizes NOS-dependence of vascular tone in the metabolic syndrome. Obesity (Silver Spring) 2011; 19:960-7. [PMID: 20864946 DOI: 10.1038/oby.2010.210] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Obese subjects with the metabolic syndrome (MS+) are more prone to microvascular complications than obese subjects without the metabolic syndrome (MS-). Excessive vascular nitric oxide (NO) production has been demonstrated in MS+ compared to MS-, perhaps driven by increased inflammation or oxidative stress. We tested whether in MS+, folic acid (FA) treatment could normalize NO synthase (NOS)-dependence of vascular tone in the retina and kidney. MS+ (n = 49) and MS- (n = 26) subjects were included in a randomized, double-blind, crossover trial. After 4-weeks' treatment with placebo or FA (5 mg/day), several cytokines (C-reactive protein (CRP), interleukin-1β, adiponectin), and markers of oxidative stress (glutathione/oxidized glutathione (GSH/GSSG) ratio, total antioxidant capacity (TAC)) were determined. NOS-dependence of retinal and renal vascular tone was assessed by retinal scanning laser Doppler flowmetry and renal clearance technique, respectively. FA had no effect on cytokine levels, but increased GSH/GSSG ratio overall (36 ± 76 vs. 102 ± 200, P = 0.04), indicative of a reduction in oxidative stress. In MS+, treatment with FA reduced NOS-dependence of retinal and renal vascular tone compared to placebo (P = 0.03 and P = 0.04, respectively). FA had no effect in MS-. After treatment with FA, NOS-dependence of retinal and renal vascular tone was similar between MS+ and MS-. Retinal and renal vascular tone in MS+ subjects is characterized by increased dependence on NOS. NOS-dependence in MS+ could be corrected by FA treatment to levels not dissimilar in MS-, and this was associated with a reduction in oxidative stress. Future trials should test whether these effects translate into a reduction of microvascular complications.
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Affiliation(s)
- Markus P Schneider
- Department of Nephrology and Hypertension, University of Erlangen, Nuremberg, Erlangen, Germany.
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Mizuguchi Y, Oishi Y, Miyoshi H, Iuchi A, Nagase N, Oki T. Telmisartan improves morphologic and functional changes in both left ventricular myocardium and carotid arterial wall in patients with hypertension: assessment by tissue Doppler imaging and carotid ultrasonography. Echocardiography 2011; 27:864-72. [PMID: 20456478 DOI: 10.1111/j.1540-8175.2010.01163.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE The aim of the present study was to clarify the beneficial effects of telmisartan on the morphologic and functional changes in left ventricular (LV) myocardium and carotid arterial wall in patients with hypertension (HT) using tissue Doppler imaging and carotid ultrasonography. METHODS Telmisartan (20-40 mg daily) was administered to 35 previously untreated patients with HT. Conventional and pulsed tissue Doppler echocardiography were performed after medication had been continued for 1-2 months with normal values for blood pressure (BP) (phase I) and for 12 months (phase II). Subclinical atherosclerosis also was determined by measuring the intima-media thickness (IMT) and stiffness β of the left and right common carotid arteries using B- and M-mode ultrasonography. RESULTS In the phase II, the LV mass index and isovolumic relaxation time were lower, the peak systolic and early diastolic mitral annular motion velocities were greater compared to the phase I. The stiffness β and mean IMT were lower in the phase II than in the phase I. On multivariate regression analyses, age, BP, and LV diastolic variables emerged as stronger predictors of carotid arterial IMT and stiffness β. CONCLUSIONS The 1-year use of telmisartan improved LV hypertrophy, regional LV myocardial contraction and relaxation, and carotid atherosclerosis in patients with HT. Our results support cardio- and arterioprotective benefits from continuous long-term telmisartan monotherapy, and combined analysis of tissue Doppler imaging and carotid ultrasonography may be a useful tool for understanding ventriculoarterial coupling in patients with HT.
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Affiliation(s)
- Yukio Mizuguchi
- Cardiovascular Section, Higashi Tokushima National Hospital, National Hospital Organization, Tokushima, Japan.
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Urinary proteomic diagnosis of coronary artery disease: identification and clinical validation in 623 individuals. J Hypertens 2010; 28:2316-22. [DOI: 10.1097/hjh.0b013e32833d81b7] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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