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Semenikhina M, Mathew RO, Barakat M, Van Beusecum JP, Ilatovskaya DV, Palygin O. Blood Pressure Management Strategies and Podocyte Health. Am J Hypertens 2025; 38:85-96. [PMID: 39269328 DOI: 10.1093/ajh/hpae120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 07/24/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024] Open
Abstract
Hypertension (HTN) is one of the key global cardiovascular risk factors, which is tightly linked to kidney health and disease development. Podocytes, glomerular epithelial cells that play a pivotal role in maintenance of the renal filtration barrier, are significantly affected by increased glomerular capillary pressure in HTN. Damage or loss of these cells causes proteinuria, which marks the initiation of the HTN-driven renal damage. It goes without saying that effective blood pressure (BP) management should not only mitigate cardiovascular risks but also preserve renal function by protecting podocyte integrity. This review offers a comprehensive examination of current BP management strategies and their implications for podocyte structure and function and emphasizes strategies for the reduction of proteinuria in HTN. We explore primary and secondary antihypertensive agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics, as well as newer therapies (sodium-glucose cotransporter-2 blocking and endothelin receptor antagonism), emphasizing their mechanistic roles in safeguarding podocytes and curtailing proteinuria.
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Affiliation(s)
- Marharyta Semenikhina
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Roy O Mathew
- Division of Nephrology, Department of Medicine, VA Loma Linda Healthcare System, Loma Linda, California, USA
| | - Munsef Barakat
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Justin P Van Beusecum
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
- Ralph H. Johnson VA Medical Center, Charleston, South Carolina, USA
| | - Daria V Ilatovskaya
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Oleg Palygin
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA
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An HJ, Jang JH, Lee S, Kim SG, Song HJ, Noh HM, Kim JK. Impact of age on eGFR dynamics following sodium-glucose cotransporter 2 inhibitor therapy: A real-world study. Diabetes Res Clin Pract 2024; 214:111796. [PMID: 39084294 DOI: 10.1016/j.diabres.2024.111796] [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] [Received: 06/21/2024] [Revised: 07/23/2024] [Accepted: 07/26/2024] [Indexed: 08/02/2024]
Abstract
AIM The initial decrease in estimated glomerular filtration rate (eGFR), often known as the "initial dip," associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i) is typically transient but may be more pronounced in older patients. METHODS We analyzed real-world data from 2,070 patients newly prescribed SGLT2i, tracking eGFR changes at baseline and 3, 6, 9, and 12 months after initiation. We defined a significant initial dip as over 10 % reduction in eGFR at 3 months. In addition, the 1-year change in eGFR after the initial decline was also assessed. RESULTS Of the total patients, 34.5 % were aged 60-69 years, 21.1 % were aged 70-79 years, and 11.5 % were aged 80 years or older. About 21.4 % experienced a significant dip at 3 months. The incidence of initial dip increases with age, with the highest incidence (38.7 %) in those aged 80 + . Despite the initial decline, subsequent eGFR was stable over one year in all age groups. Factors such as age, lower hemoglobin, higher uric acid levels, and use of RAS blockers were linked to the initial dip. CONCLUSIONS Older patients showed a more pronounced initial eGFR decline after starting SGLT2i, but it stabilized for one year without further deterioration, similar to younger patients.
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Affiliation(s)
- Hye-Ji An
- Department of Family Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea
| | - Jin Ha Jang
- Department of Internal Medicine & Kidney Research Institute, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea
| | - Sion Lee
- BigData Center, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea
| | - Sung Gyun Kim
- Department of Internal Medicine & Kidney Research Institute, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea
| | - Hong Ji Song
- Department of Family Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea
| | - Hye-Mi Noh
- Department of Family Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea.
| | - Jwa-Kyung Kim
- Department of Internal Medicine & Kidney Research Institute, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea.
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Richfield O, Cortez R, Navar LG. Modeling the interaction between tubuloglomerular feedback and myogenic mechanisms in the control of glomerular mechanics. Front Physiol 2024; 15:1410764. [PMID: 38966231 PMCID: PMC11223525 DOI: 10.3389/fphys.2024.1410764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 05/24/2024] [Indexed: 07/06/2024] Open
Abstract
Introduction: Mechanical stresses and strains exerted on the glomerular cells have emerged as potentially influential factors in the progression of glomerular disease. Renal autoregulation, the feedback process by which the afferent arteriole changes in diameter in response to changes in blood pressure, is assumed to control glomerular mechanical stresses exerted on the glomerular capillaries. However, it is unclear how the two major mechanisms of renal autoregulation, the afferent arteriole myogenic mechanism and tubuloglomerular feedback (TGF), each contribute to the maintenance of glomerular mechanical homeostasis. Methods: In this study, we made a mathematical model of renal autoregulation and combined this model with an anatomically accurate model of glomerular blood flow and filtration, developed previously by us. We parameterized the renal autoregulation model based on data from previous literature, and we found evidence for an increased myogenic mechanism sensitivity when TGF is operant, as has been reported previously. We examined the mechanical effects of each autoregulatory mechanism (the myogenic, TGF and modified myogenic) by simulating blood flow through the glomerular capillary network with and without each mechanism operant. Results: Our model results indicate that the myogenic mechanism plays a central role in maintaining glomerular mechanical homeostasis, by providing the most protection to the glomerular capillaries. However, at higher perfusion pressures, the modulation of the myogenic mechanism sensitivity by TGF is crucial for the maintenance of glomerular mechanical homeostasis. Overall, a loss of renal autoregulation increases mechanical strain by up to twofold in the capillaries branching off the afferent arteriole. This further corroborates our previous simulation studies, that have identified glomerular capillaries nearest to the afferent arteriole as the most prone to mechanical injury in cases of disturbed glomerular hemodynamics. Discussion: Renal autoregulation is a complex process by which multiple feedback mechanisms interact to control blood flow and filtration in the glomerulus. Importantly, our study indicates that another function of renal autoregulation is control of the mechanical stresses on the glomerular cells, which indicates that loss or inhibition of renal autoregulation may have a mechanical effect that may contribute to glomerular injury in diseases such as hypertension or diabetes. This study highlights the utility of mathematical models in integrating data from previous experimental studies, estimating variables that are difficult to measure experimentally (i.e. mechanical stresses in microvascular networks) and testing hypotheses that are historically difficult or impossible to measure.
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Affiliation(s)
- Owen Richfield
- Bioinnovation PhD Program, Tulane University, New Orleans, LA, United States
| | - Ricardo Cortez
- Department of Mathematics, Tulane University, New Orleans, LA, United States
| | - L. Gabriel Navar
- Department of Physiology, Tulane School of Medicine, New Orleans, LA, United States
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Hajdys J, Fularski P, Leszto K, Majchrowicz G, Stabrawa M, Młynarska E, Rysz J, Franczyk B. New Insights into the Nephroprotective Potential of Lercanidipine. Int J Mol Sci 2023; 24:14048. [PMID: 37762350 PMCID: PMC10531189 DOI: 10.3390/ijms241814048] [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: 08/26/2023] [Revised: 09/10/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Kidneys are responsible for many crucial biological processes in the human body, including maintaining the water-electrolyte balance, pH, and blood pressure (BP), along with the elimination of toxins. Despite this, chronic kidney disease (CKD), which affects more and more people, is a disease that develops insidiously without causing any symptoms at first. The main purpose of this article is to summarize the existing literature on lercanidipine, with a particular focus on its nephroprotective properties. Lercanidipine is a third-generation dihydropyridine (DHP) blocker of calcium channels, and as such it possesses unique qualities such as high lipophilicity and high vascular selectivity. Furthermore, it acts by reversibly inhibiting L-type and T-type calcium channels responsible for exerting positive renal effects. It has been shown to reduce tissue inflammation and tubulointerstitial fibrosis, contributing to a decrease in proteinuria. Moreover, it exhibited antioxidative effects and increased expression of molecules responsible for repairing damaged tissues. It also decreased cell proliferation, preventing thickening of the vascular lumen. This article summarizes studies simultaneously comparing the effect of lercanidipine with other antihypertensive drugs. There is still a lack of studies on the medications used in patients with CKD, and an even greater lack of studies on those used in patients with concomitant hypertension. Therefore, further studies on lercanidipine and its potential in hypertensive patients with coexisting CKD are required.
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Affiliation(s)
| | | | | | | | | | - Ewelina Młynarska
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Ul. Żeromskiego 113, 90-549 Lodz, Poland
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Leung N, Yip K, Pillinger MH, Toprover M. Lowering and Raising Serum Urate Levels: Off-Label Effects of Commonly Used Medications. Mayo Clin Proc 2022; 97:1345-1362. [PMID: 35787862 PMCID: PMC9575594 DOI: 10.1016/j.mayocp.2022.02.027] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 02/14/2022] [Accepted: 02/28/2022] [Indexed: 11/22/2022]
Abstract
Drug-induced hyperuricemia and gout present an increasingly prevalent problem in clinical practice. Herein, we review the urate-lowering or urate-raising effects of commonly used agents. We performed a PubMed search using the terms gout, urate, and medication, along with the specific agents/classes described herein. Reports were reviewed until 2022, and original studies were considered if they primarily or secondarily reported the effects of 1 or more drugs on serum urate level. Previous reviews were assessed for references to additional studies that described urate-altering effects of medications. Urate-changing drugs are summarized regarding their magnitude of effect, mechanism of action, and clinical significance. Potentially urate-lowering drugs include angiotensin II receptor blockers, calcium channel blockers, high-dose aspirin and salicylates, some nonsalicylate nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, sodium-glucose cotransporter 2 inhibitors, statins, and fenofibrate. Potentially urate-increasing drugs discussed include diuretics, β-blockers, insulin, pyrazinamide, ethambutol, calcineurin inhibitors, low-dose aspirin, testosterone, and lactate. In patients who have or are at risk for hyperuricemia or gout, an increased awareness of drugs that affect serum urate level may allow for prescribing that effectively treats the indicated problem while minimizing adverse effects on hyperuricemia and gout.
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Affiliation(s)
- Nicole Leung
- Divison of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Orthopedic Hospital, New York, NY.
| | - Kevin Yip
- Department of Rheumatology, Hospital for Special Surgery, Weill Cornell Medicine, New York, New York
| | - Michael H Pillinger
- Rheumatology Section, New York Harbor Healthcare System, New York Campus, U.S. Department of Veterans Affairs
| | - Michael Toprover
- Rheumatology Section, New York Harbor Healthcare System, New York Campus, U.S. Department of Veterans Affairs
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Kitamura K, Hayashi K, Ito S, Hoshina Y, Sakai M, Yoshino K, Endo K, Fujitani S, Suzuki T. Effects of SGLT2 inhibitors on eGFR in type 2 diabetic patients-the role of antidiabetic and antihypertensive medications. Hypertens Res 2020; 44:508-517. [PMID: 33311577 PMCID: PMC8099726 DOI: 10.1038/s41440-020-00590-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/29/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023]
Abstract
Recent randomized trials demonstrating the beneficial effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in type 2 diabetes suggest that early reductions in eGFR upon initiation of SGLT2i therapy are associated with improved renal outcomes. Multiple concomitant medications, including antidiabetic and antihypertensive agents, are commonly used, however, which may modify the renal hemodynamic action of SGLT2is. Here we found that background treatment with metformin diminished the SGLT2i-induced reductions in eGFR after 3 months of SGLT2i therapy in patients with type 2 diabetes and hypertension (-2.29 ± 0.90 vs -5.85 ± 1.27 mL/min/1.73 m2 for metformin users (n = 126) and nonusers (n = 97), respectively). Other antidiabetic agents (DPP4 inhibitors, sulfonylureas and insulin) had no effect on the eGFR response to SGLT2is. Antihypertensive drugs, including calcium channel blockers (CCBs) and β blockers, did not affect the SGLT2i-induced changes in eGFR, whereas renin-angiotensin system inhibitors (RASis) tended to enhance this response (p = 0.059). Next, we evaluated the interaction between metformin and RASis in the eGFR responses to SGLT2is. Under no background treatment with RASis, metformin abrogated the eGFR response to SGLT2is, but this response was preserved when RASis had been given along with metformin (decreases of 0.75 ± 1.28 vs. 4.60 ± 1.15 mL/min/1.73 m2 in eGFR, p = 0.028). No interaction between metformin and insulin or between metformin and DPP4 inhibitors was observed. In conclusion, metformin blunts the SGLT2i-induced decrease in eGFR, but coadministration of RASis ameliorates this response. Furthermore, the inability of CCBs to modify the SGLT2i-induced reduction in eGFR suggests that the SGLT2i-induced renal microvascular action is mediated predominantly by postglomerular vasodilation rather than preglomerular vasoconstriction.
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Affiliation(s)
| | - Koichi Hayashi
- Tokyo Bay Urayasu Ichikawa Medical Center, Chiba, Japan.,Department of Internal Medicine, Tokyo Dental College, Chiyoda City, Japan
| | - Shinsuke Ito
- Tokyo Bay Urayasu Ichikawa Medical Center, Chiba, Japan
| | - Yuiko Hoshina
- Tokyo Bay Urayasu Ichikawa Medical Center, Chiba, Japan
| | | | - Kaede Yoshino
- Tokyo Bay Urayasu Ichikawa Medical Center, Chiba, Japan
| | - Keita Endo
- Tokyo Bay Urayasu Ichikawa Medical Center, Chiba, Japan
| | - Shigeki Fujitani
- Department of Emergency and Critical Care Medicine, St Marianna University School of Medicine, Kawasaki, Japan
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Lin YC, Wang JC, Wu MS, Lin YF, Chen CR, Chen CY, Chen KC, Peng CC. Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study. Int J Mol Sci 2020; 21:ijms21124359. [PMID: 32575412 PMCID: PMC7352626 DOI: 10.3390/ijms21124359] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 12/15/2022] Open
Abstract
Dysregulation of fatty acid oxidation and accumulation of fatty acids can cause kidney injury. Nifedipine modulates lipogenesis-related transcriptional factor SREBP-1/2 in proximal tubular cells by inhibiting the Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) pathway in vitro. However, the mechanisms by which nifedipine (NF) modulates lipotoxicity in vivo are unclear. Here, we examined the effect of NF in a doxorubicin (DR)-induced kidney injury rat model. Twenty-four Sprague–Dawley rats were divided into control, DR, DR+NF, and high-fat diet (HFD) groups. The DR, DR+NF, and HFD groups showed hypertension and proteinuria. Western blotting and immunohistochemical analysis showed that NF significantly induced TNF-α, CD36, SREBP-1/2, and acetyl-CoA carboxylase expression and renal fibrosis, and reduced fatty acid synthase and AMPK compared to other groups (p < 0.05). Additionally, 18 patients with chronic kidney disease (CKD) who received renal transplants were enrolled to examine their graft fibrosis and lipid contents via transient elastography. Low-density lipoprotein levels in patients with CKD strongly correlated with lipid contents and fibrosis in grafted kidneys (p < 0.05). Thus, NF may initiate lipogenesis through the SREBP-1/2/AMPK pathway and lipid uptake by CD36 upregulation and aggravate renal fibrosis in vivo. Higher low-density lipoprotein levels may correlate with renal fibrosis and lipid accumulation in grafted kidneys of patients with CKD.
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Affiliation(s)
- Yen-Chung Lin
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-S.W.); (Y.-F.L.)
- TMU-Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
| | - Jhih-Cheng Wang
- Division of Urology, Department of Surgery, Chi-Mei Medical Center, Tainan City 71004, Taiwan;
- Department of Electric Engineering, Southern Taiwan University of Science and Technology, Tainan City 71005, Taiwan
| | - Mai-Szu Wu
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-S.W.); (Y.-F.L.)
- TMU-Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Yuh-Feng Lin
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-S.W.); (Y.-F.L.)
- TMU-Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Chang-Rong Chen
- International Medical Doctor Program, Vita-Salute San Raffaele University, 20132 Milan, Italy;
| | - Chang-Yu Chen
- Program of Biomedical Sciences, College of Arts and Sciences, California Baptist University, Riverside, CA 92504, USA;
| | - Kuan-Chou Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- TMU-Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
- Department of Urology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
- Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: (K.-C.C.); (C.-C.P.); Tel.: +886-02-22490088 (K.-C.C.); +886-02-27361661 (C.-C.P.)
| | - Chiung-Chi Peng
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Correspondence: (K.-C.C.); (C.-C.P.); Tel.: +886-02-22490088 (K.-C.C.); +886-02-27361661 (C.-C.P.)
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Effects of calcium channel blockers comparing to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with hypertension and chronic kidney disease stage 3 to 5 and dialysis: A systematic review and meta-analysis. PLoS One 2017; 12:e0188975. [PMID: 29240784 PMCID: PMC5730188 DOI: 10.1371/journal.pone.0188975] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 11/16/2017] [Indexed: 01/01/2023] Open
Abstract
Background Calcium channel blocker (CCB) or two renin angiotensin aldosterone system blockades (RAAS), angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are major potent and prevalently used as initial antihypertensive agents for mild to moderate hypertension, but no uniform agreement as to which antihypertensive drugs should be given for initial therapy, especially among chronic kidney disease (CKD) patients. Design A systematic review and meta-analysis comparing CCBs and the two RAAS blockades for hypertensive patients with CKD stage 3 to 5D. The inclusion criteria for this systematic review was RCT that compared the effects of CCBs and the two RAAS blockades in patients with hypertension and CKD. The exclusion criteria were (1) renal transplantation, (2) CKD stage 1 or 2, (3) combined therapy (data cannot be extracted separately). Outcomes were blood pressure change, mortality, heart failure, stroke or cerebrovascular events, and renal outcomes. Results 21 randomized controlled trials randomized 9,492 patients with hypertensive and CKD into CCBs and the two RAAS blockades treatments. The evidence showed no significant differences in blood presser change, mortality, heart failure, stroke or cerebrovascular events, and renal outcomes between CCBs group and the two RAAS blockades group. The publication bias of pooled mean blood presser change that was detected by Egger’s test was non-significant. Conclusions CCBs has similar effects on long term blood pressure, mortality, heart failure, stroke or cerebrovascular events, and renal function to RAAS blockades in patients CKD stage 3 to 5D and hypertension.
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Grassi G, Robles NR, Seravalle G, Fici F. Lercanidipine in the Management of Hypertension: An Update. J Pharmacol Pharmacother 2017; 8:155-165. [PMID: 29472747 PMCID: PMC5820745 DOI: 10.4103/jpp.jpp_34_17] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Revised: 09/14/2017] [Accepted: 12/11/2017] [Indexed: 01/08/2023] Open
Abstract
Calcium channel blockers (CCBs), particularly dihydropyridine-CCBs, (DHP-CCBs), have an established role in antihypertensive therapy, either as monotherapy or in combination with other antihypertensive drugs. Two hundred and fifty-one papers published in PubMed in English between January 1, 1990, and October 31, 2016, were identified using the keyword "lercanidipine." Lercanidipine is a lipophilic third-generation DHP-CCB, characterized by high vascular selectivity and persistence in the smooth muscle cell membranes. Lercanidipine is devoid of sympathetic activation, and unlike the first and second generation of DHP-CCBs, it dilates both the afferent and the efferent glomerular arteries, while preserving the intraglomerular pressure. In addition, lercanidipine prevents renal damage induced by angiotensin II and demonstrates anti-inflammatory, antioxidant, and anti-atherogenic properties through an increasing bioavailability of endothelial nitric oxide. It is associated with a regression of microvascular structural modifications in hypertensive patients. The efficacy of lercanidipine has been demonstrated in patients with different degrees of hypertension, in the young and elderly and in patients with isolated systolic hypertension. In patients with diabetes and renal impairment, lercanidipine displays a renal protection with a significant decrease of microalbuminuria and improvement of creatinine clearance. Lercanidipine is well tolerated and is associated with a very low rate of adverse events, particularly ankle edema, compared with amlodipine and nifedipine. In conclusion, lercanidipine produces a sustained blood pressure-lowering activity with a high rate of responder/normalized patients, associated with a favorable tolerability profile.
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Affiliation(s)
- Guido Grassi
- Clinica Medica of the University of Milano-Bicocca and IRCCS Multimedica, Milan, Italy
| | | | - Gino Seravalle
- San Luca Hospital, Italian Auxological Institute, Milan, Italy
| | - Francesco Fici
- Clinica Medica of the University of Milano-Bicocca and IRCCS Multimedica, Milan, Italy
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10
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Robles NR, Fici F, Grassi G. Dihydropyridine calcium channel blockers and renal disease. Hypertens Res 2017; 40:21-28. [PMID: 27412800 DOI: 10.1038/hr.2016.85] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/23/2016] [Accepted: 05/27/2016] [Indexed: 01/10/2023]
Abstract
Although blood pressure control is considered the main mechanism for preventing the progression of chronic kidney disease (CKD), angiotensin-converting enzyme inhibitors and angiotensin receptors blockers have an additional organ-protective role. The effects of calcium channel blockers (CCBs) in renal disease are not so clearly defined. CCBs have pleiotropic effects that might contribute to protection of the kidney, such as attenuating the mesangial entrapment of macromolecules, countervailing the mitogenic effect of platelet-derived growth factors and platelet-activating factors and suppressing mesangial cell proliferation. Some evidence has accumulated in recent years demonstrating that the new dihydropyridinic CCBs (such as lercanidipine or efonidipine) may affect both postglomerular and preglomerular vessels, resulting in a decreased filtration fraction and nephroprotective effect. Increasing clinical and experimental evidence supports this view and the use of CCBs in CKD hypertensive patients.
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Affiliation(s)
- Nicolás R Robles
- Cátedra de Riesgo Cardiovascular, Facultad de Medicina, Universidad de Salamanca, Salamanca, Spain
| | | | - Guido Grassi
- Clinica Medica, Università Milano-Bicocca, Monza, Italy
- IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
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11
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Bhattacharjee N, Barma S, Konwar N, Dewanjee S, Manna P. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: An update. Eur J Pharmacol 2016; 791:8-24. [PMID: 27568833 DOI: 10.1016/j.ejphar.2016.08.022] [Citation(s) in RCA: 192] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 08/03/2016] [Accepted: 08/24/2016] [Indexed: 02/09/2023]
Abstract
Diabetic nephropathy (DN), a chronic complication of diabetes, is charecterized by glomerular hypertrophy, proteinuria, decreased glomerular filtration, and renal fibrosis resulting in the loss of renal function. Although the exact cause of DN remains unclear, several mechanisms have been postulated, such as hyperglycemia-induced renal hyper filtration and renal injury, AGEs-induced increased oxidative stress, activated PKC-induced increased production of cytokines, chemokines, and different inflammatory and apoptotic signals. Among various factors, oxidative stress has been suggested to play a major role underlying the onset and propagation of DN. It triggers several signaling pathways involved in DN, like AGEs, PKC cascade, JAK/STAT signaling, MAPK, mTOR, and SMAD. Oxidative stress-induced activation of both inflammatory and apoptotic signals are two major problems in the pathogenesis of DN. The FDA approved pharmacotherapeutic agents affecting against polyol pathway principally include anti-oxidants, like α-lipoic acid, vitamin E, and vitamin C. Kremezin and benfotiamine are the FDA approved AGEs inhibitors, another therapeutic target against DN. Ruboxistaurin, telmizartan, rapamycin, fenofibrate, aliskiren, and manidipine are some FDA approved pharmacotherapeutics effective against DN via diverse mechanisms. Beside this, some therapeutic agents are still waiting for FDA approval and few drugs without FDA approval are also prescribed in some countries for the management of DN. Despite the medications available in the market to treat DN, the involvement of multiple mechanisms makes it difficult to choose an optimum therapeutic agent. Therefore, much research is required to find out new therapeutic agent/strategies for an adequate pharmacotherapy of DN.
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Affiliation(s)
- Niloy Bhattacharjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Raja S C Mullick Road, Kolkata 700032, India
| | - Sujata Barma
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Raja S C Mullick Road, Kolkata 700032, India
| | - Nandita Konwar
- Biological Science and Technology Division, CSIR-NEIST, Jorhat, Assam 785006, India
| | - Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Raja S C Mullick Road, Kolkata 700032, India.
| | - Prasenjit Manna
- Biological Science and Technology Division, CSIR-NEIST, Jorhat, Assam 785006, India.
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12
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Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure. Sci Rep 2016; 6:27192. [PMID: 27273361 PMCID: PMC4895143 DOI: 10.1038/srep27192] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 05/16/2016] [Indexed: 12/14/2022] Open
Abstract
Pharmacological blockade of the N- and L-type calcium channel lessens renal injury in kidney disease patients. The significance of specific blockade of α1 subunit of N-type calcium channel, Cav2.2, in diabetic nephropathy, however, remains to be clarified. To examine functional roles, we mated Cav2.2−/− mice with db/db (diabetic) mice on the C57BLKS background. Cav2.2 was localized in glomeruli including podocytes and in distal tubular cells. Diabetic Cav2.2−/− mice significantly reduced urinary albumin excretion, glomerular hyperfiltration, blood glucose levels, histological deterioration and systolic blood pressure (SBP) with decreased urinary catecholamine compared to diabetic Cav2.2+/+ mice. Interestingly, diabetic heterozygous Cav2.2+/− mice also decreased albuminuria, although they exhibited comparable systolic blood pressure, sympathetic nerve activity and creatinine clearance to diabetic Cav2.2+/+ mice. Consistently, diabetic mice with cilnidipine, an N-/L-type calcium channel blocker, showed a reduction in albuminuria and improvement of glomerular changes compared to diabetic mice with nitrendipine. In cultured podocytes, depolarization-dependent calcium responses were decreased by ω-conotoxin, a Cav2.2-specific inhibitor. Furthermore, reduction of nephrin by transforming growth factor-β (TGF-β) in podocytes was abolished with ω-conotoxin, cilnidipine or mitogen-activated protein kinase kinase inhibitor. In conclusion, Cav2.2 inhibition exerts renoprotective effects against the progression of diabetic nephropathy, partly by protecting podocytes.
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13
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Sato N, Saijo Y, Sasagawa Y, Morimoto H, Takeuchi T, Sano H, Koyama S, Takehara N, Morita K, Sumitomo K, Maruyama J, Kikuchi K, Hasebe N. Visit-to-visit variability and seasonal variation in blood pressure: Combination of Antihypertensive Therapy in the Elderly, Multicenter Investigation (CAMUI) Trial subanalysis. Clin Exp Hypertens 2015; 37:411-9. [DOI: 10.3109/10641963.2014.995802] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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14
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Nagasawa K, Takahashi K, Matsuura N, Takatsu M, Hattori T, Watanabe S, Harada E, Niinuma K, Murohara T, Nagata K. Comparative effects of valsartan in combination with cilnidipine or amlodipine on cardiac remodeling and diastolic dysfunction in Dahl salt-sensitive rats. Hypertens Res 2014; 38:39-47. [DOI: 10.1038/hr.2014.136] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 07/30/2014] [Accepted: 08/12/2014] [Indexed: 11/09/2022]
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15
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Coca A, Mazón P, Aranda P, Redón J, Divisón JA, Martínez J, Calvo C, Galcerán JM, Barrios V, Coll ARCI. Role of dihydropyridinic calcium channel blockers in the management of hypertension. Expert Rev Cardiovasc Ther 2014; 11:91-105. [DOI: 10.1586/erc.12.155] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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16
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Coca A. Manidipine plus delapril in patients with Type 2 diabetes and hypertension: reducing cardiovascular risk and end-organ damage. Expert Rev Cardiovasc Ther 2014; 5:147-59. [PMID: 17338661 DOI: 10.1586/14779072.5.2.147] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
In patients with hypertension and diabetes, atherothrombosis is a leading cause of morbidity and mortality, and there is now compelling evidence demonstrating that lowering elevated blood pressure (BP) is one of the most beneficial aims of therapy in this high-risk population. Indeed, major international guidelines have set a target BP goal of 130/80 mmHg in high-risk patients and recommend combination treatment with two or more drug classes to help achieve this objective. Manidipine plus delapril is a fixed-dose combination of a third-generation dihydropyridine calcium antagonist and an angiotensin-converting enzyme inhibitor, which is effective in mild-to-moderately hypertensive patients with an inadequate response to monotherapy. It is also effective in the long-term (50 weeks) management of essential hypertension. Comparative studies have demonstrated that manidipine plus delapril is as effective as enalapril plus hydrochlorothiazide (HCTZ) in patients with hypertension that is unresponsive to monotherapy, and as effective as ramipril plus HCTZ, valsartan plus HCTZ, irbesartan plus HCTZ and olmesartan plus HCTZ in patients with essential hypertension and Type 2 diabetes. In addition, manidipine plus delapril exhibited renoprotective effects in normotensive Type 2 diabetic patients, and improved fibrinolytic function (significantly more than irbesartan plus HCTZ) in hypertensive patients with Type 2 diabetes. Manidipine 10 mg plus delapril 30 mg once daily was generally well tolerated, with no unexpected adverse effects and evidence of a low incidence of ankle edema. Thus, manidipine plus delapril is a fixed-dose combination treatment that significantly reduces elevated BP with once-daily administration. It is well tolerated and has ancillary properties, such as nephroprotective activity and improvement of fibrinolytic balance, which may help reduce cardiovascular morbidity and mortality, particularly in high-risk patients, such as those with Type 2 diabetes mellitus.
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Affiliation(s)
- Antonio Coca
- Institute of Medicine & Dermatology Hospital Clinic, Villarroel 170.08036, Barcelona, Spain.
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17
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Tikhonoff V, Mazza A, Casiglia E, Pessina AC. Role of manidipine in the management of patients with hypertension. Expert Rev Cardiovasc Ther 2014; 2:815-27. [PMID: 15500427 DOI: 10.1586/14779072.2.6.815] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Manidipine is a third-generation dihydropyridine calcium antagonist, which causes systemic vasodilation by inhibiting the voltage-dependent calcium inward currents in smooth muscle cells. In clinical studies, manidipine has been shown to significantly lower office and 24-h blood pressure compared with placebo in patients with essential hypertension. The resulting reduction in blood pressure is maintained over 24 h, with preservation of the circadian blood pressure pattern; its blood pressure-lowering capacity appears to be similar to that of other calcium antagonists. In elderly patients with mild-to-moderate essential hypertension, manidipine is able to significantly decrease blood pressure compared with placebo for up to 3 years of treatment. The drug also significantly lowers blood pressure in patients with hypertension and concomitant Type 2 diabetes mellitus or renal impairment, and is devoid of adverse metabolic effects. It is well-tolerated with few untoward adverse effects related to vasodilation. In particular, manidipine appears to have less potential for pedal edema than other calcium channel blockers.
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Affiliation(s)
- Valérie Tikhonoff
- University of Padova, Department of Clinical and Experimental Medicine, Via Giustiniani No. 2, I-35128 Padova, Italy.
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18
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Reboldi G, Gentile G, Angeli F, Verdecchia P. Exploring the optimal combination therapy in hypertensive patients with diabetes mellitus. Expert Rev Cardiovasc Ther 2014; 7:1349-61. [DOI: 10.1586/erc.09.133] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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19
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Ott C, Schneider MP, Raff U, Ritt M, Striepe K, Alberici M, Schmieder RE. Effects of manidipine vs. amlodipine on intrarenal haemodynamics in patients with arterial hypertension. Br J Clin Pharmacol 2013; 75:129-35. [PMID: 23240643 DOI: 10.1111/j.1365-2125.2012.04336.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
AIMS Intraglomerular pressure is one of the main drivers of progression of renal failure. Experimental data suggest that there are important differences between calcium channel blockers (CCBs) in their renal haemodynamic effects: manidipine reduces, whereas amlodipine increases intraglomerular pressure. The aim of this study was to investigate the effects of manidipine and amlodipine treatment on intragomerular pressure (P(glom)) in patients with mild to moderate essential hypertension. METHODS In this randomized, double-blind, parallel group study, hypertensive patients were randomly assigned to receive manidipine 20 mg (n = 54) or amlodipine 10 mg (n = 50) for 4 weeks. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined by constant-infusion input-clearance technique with p-aminohippurate (PAH) and inulin. P(glom) and resistances of the afferent (R(A)) and efferent (R(E)) arterioles were calculated according to the model established by Gomez. RESULTS P(glom) did not change in the manidipine group (P = 0.951), whereas a significant increase occurred in the amlodipine group (P = 0.009). There was a significant difference in the change of P(glom) by 1.2 mmHg between the manidipine and amlodipine group (P = 0.042). In both treatment arms, R(A) was reduced (manidipine P = 0.018; amlodipine P < 0.001). The reduction of R(A) was significantly more pronounced with amlodipine compared with manidipine treatment (P < 0.001). R(E) increased in both treatment arms (manidipine P = 0.012; amlodipine P = 0.002), with no difference between the treatment arms. Both CCBs significantly reduced systolic and diastolic blood pressure (BP) (both P < 0.001). However, amlodipine treatment resulted in a significantly greater decrease of BP compared with manidipine (P < 0.001). CONCLUSIONS In accordance with experimental data after antihypertensive treatment of 4 weeks, intraglomerular pressure was significantly lower with the CCB manidipine than with amlodipine, resulting and explaining their disparate effects on albuminuria.
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Affiliation(s)
- Christian Ott
- Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Germany
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20
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Abe M, Okada K, Suzuki H, Yoshida Y, Soma M. T/L-type calcium channel blocker reduces the composite ranking of relative risk according to new KDIGO guidelines in patients with chronic kidney disease. BMC Nephrol 2013; 14:135. [PMID: 23815742 PMCID: PMC3703301 DOI: 10.1186/1471-2369-14-135] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 06/04/2013] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) group recommended that patients with chronic kidney disease (CKD) be assigned according to stage and composite relative risk on the basis of glomerular filtration rate (GFR) and albuminuria criteria. The aim of this post-hoc analysis was to investigate the effects of add-on therapy with calcium channel blockers (CCBs) on changes in the composite ranking of relative risk according to KDIGO guidelines. Benidipine, an L- and T-type CCB, and amlodipine, an L-type CCB to angiotensin II receptor blocker (ARB), were examined. METHODS Patients with blood pressure (BP) > 130/80 mmHg, an estimated GFR (eGFR) of 30-90 mL/min/1.73 m2, and albuminuria > 30 mg/gCr, despite treatment with the maximum recommended dose of ARB, were randomly assigned to two groups. Each group received one of two treatments: 2 mg benidipine daily, increased to 8 mg daily (n = 52), or 2.5 mg amlodipine daily, increased to 10 mg daily (n = 52). RESULTS After 6 months of treatment, a significant and comparable reduction in systolic and diastolic BP was observed in both groups. The eGFR was significantly decreased in the amlodipine group, but there was no significant change in the benidipine group. The decrease in albuminuria in the benidipine group was significantly lower than in the amlodipine group. The composite ranking of relative risk according to the new KDIGO guidelines was significantly improved in the benidipine group; however, no significant change was noted in the amlodipine group. Moreover, significantly fewer cases in the benidipine group than the amlodipine group showed a reduced risk category score. CONCLUSION The present post-hoc analysis showed that compared to amlodipine benidipine results in a greater reduction in albuminuria accompanied by an improved composite ranking of relative risk according to the KDIGO CKD severity classification. TRIAL REGISTRATION TRIAL REGISTRATION NUMBER UMIN000002644.
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Affiliation(s)
- Masanori Abe
- Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Kazuyoshi Okada
- Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Hiroko Suzuki
- Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Yoshinori Yoshida
- Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Masayoshi Soma
- Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
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21
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Sato N, Saijo Y, Sasagawa Y, Morimoto H, Takeuchi T, Sano H, Koyama S, Takehara N, Morita K, Sumitomo K, Maruyama J, Kikuchi K, Hasebe N. Combination of antihypertensive therapy in the elderly, multicenter investigation (CAMUI) trial: results after 1 year. J Hypertens 2013; 31:1245-55. [PMID: 23492647 DOI: 10.1097/hjh.0b013e32835fdf60] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Combination therapy with angiotensin receptor blockers (ARBs) and calcium channel blockers or diuretics is common for hypertensive patients. This study aimed to determine which combination is better for elderly hypertensive patients. METHODS In this prospective, randomized, open-label trial, hypertensive outpatients aged at least 65 years who had not achieved their target blood pressure (BP) with standard ARB dosages were randomly assigned to receive either a fixed-dose combination of losartan (50 mg) and hydrochlorothiazide (12.5 mg) (ARB+D; n = 72) or a combination of amlodipine (5 mg) and the typical dosage of ARBs (ARB+C; n = 68) to evaluate the change in the BP, laboratory values and cognitive function. RESULTS At 3 months, the SBP/DBP was found to have significantly decreased from 156/83 ± 15/11 mmHg to 139/76 ± 14/10 mmHg in the ARB+D group and 155/83 ± 11/10 mmHg to 132/72 ± 14/10 mmHg in the ARB+C group. The BP reduction efficacy was greater in the ARB+C group than in the ARB+D group. At 6 months, the SBP/DBP reached the same level in both groups. At 12 months, the urine albumin/creatinine ratio was significantly decreased from the geometric mean of 17.1 to 9.6 mg/g in the ARB+D group, whereas it was increased from 19.8 to 23.7 mg/g in the ARB+C group. Conversely, the estimated glomerular filtration rate tended to show a decrease in the ARB+D group. There was no significant difference in mini-mental state examination after 1 year. CONCLUSION ARB+amlodipine (5 mg) yielded a greater BP reduction, whereas ARB+HCTZ (12.5 mg) resulted in a greater reduction in the albuminuria, suggesting that each combination therapy is advantageous in a different manner for elderly hypertensive patients.
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Affiliation(s)
- Nobuyuki Sato
- Department of Cardiology, Asahikawa Medical University, Hokkaido 078–8510, Japan.
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22
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Abstract
The calcium channel antagonists (CCAs) were originally introduced as vasodilators for the treatment of coronary heart disease, but are now also noted for their clinical efficacy in the management of hypertension. Data from large clinical studies have shown that CCAs are not associated with the undesirable metabolic effects (e.g. worsening of dyslipidemia and reduction of insulin sensitivity) seen with older agents such as thiazide diuretics and beta-adrenoceptor antagonists (beta-blockers) that are used to treat hypertension. Indeed, reductions in cardiovascular risk and rates of onset of new cases of diabetes mellitus have been reported in trials in patients with hypertension treated with CCAs. These beneficial effects extend beyond those expected to accompany reductions in BP. Until recently, the biochemical effects underlying these metabolic changes were only poorly understood, but pharmacologic studies have now started to shed more light on these issues. Of particular interest are studies with manidipine, some of which suggest that this agent may be associated with greater improvements in insulin sensitivity and may have better renal protective properties than other CCAs. Confirmation of potential differences among CCAs in terms of the relative magnitude of any beneficial metabolic effects requires further study. Ongoing research is expected to clarify further the action of these agents at the cellular level and to assist with the optimization of antihypertensive therapy, particularly in patients with elevated cardiovascular risk profiles.
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Affiliation(s)
- Luca Cavalieri
- Promedica Srl, Parma, Italy; Medical Department, Chiesi Famaceutici SpA, Parma, Italy
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23
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Tishina EV, Mychka VB, Saidova MA. Moxonidine-based combination antihypertensive therapy in patients with metabolic syndrome. КАРДИОВАСКУЛЯРНАЯ ТЕРАПИЯ И ПРОФИЛАКТИКА 2012. [DOI: 10.15829/1728-8800-2012-3-36-46] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Aim.To assess the effects of moxonidine-based combination therapy on clinical status, laboratory parameters, and target organs in patients with metabolic syndrome (MS).Material and methods.In total, 60 MS patients with Stage 1-2 arterial hypertension (AH) were randomised into 3 groups. Group I was administered moxonidine (0,2-0,4 mg/d) and amlodipine (5-10 mg/d); Group II received moxonidine (0,2-0,4 mg/d) and hydrochlorothiazide (12,5 mg/d); Group III was treated with moxonidine (0,2-0,4 mg/d) and enalapril (10-20 mg/d). At baseline and after 24 weeks of treatment, the following characteristics were assessed: waist circumference (WC), body mass index (BMI), 24-hour blood pressure monitoring (BMP) parameters, left ventricular myocardial mass index (LVMMI), E/A ratio, isovolumetric relaxation time (IVRT), deceleration time (DT) of early diastolic velocity, peak Em velocity at interventricular septum and lateral wall levels, E/Em ratio (myocardial tissue Doppler echocardiography), pulse wave velocity (PWV) between descending aorta and aortic bifurcation levels (ultrasound method), and stiffness index β of ascending aorta. In addition, lipid, carbohydrate, and purine metabolism parameters were assessed; glomerular filtration rate (GFR) was calculated (MDRD method); and urine albumin levels were measured.Results.In Group I (moxonidine + amlodipine), target blood pressure (BP) levels were achieved in 70% of the patients. Systolic BP (SBP) levels, LVMMI, and DT decreased by 19,3±11,4 mm Hg, 4,4 g/m2 (p=0,09), and 10,6 ms (p<0,05), respectively. The increase in E/A ratio and Em annular velocity (Em av) reached 0,4 (p<0,05) and 1,4 cm/s (p<0,05), respectively, while E/Em av ratio decreased by 0,8 (p<0,05), and PWV decreased by 1,6 ms (p<0,05). The BMI decrease reached 0,7 kg/m2 (p<0,05). In Group II (moxonidine + hydrochlorothiazide), target BP levels were achieved in 40% of the participants, with a decrease in SBP levels by 14,7 mm Hg (p<0,05). DT was reduced by 9,4 ms (p<0,05), E/A ratio increased by 0,1 (p<0,05), while PWV, BMI, and GFR decreased by 1,3 m/s (p<0,05), 0,8 kg/m2 (p<0,05), and 5,6 ml/min/1,73 m2 (p<0,05), respectively. In Group III (moxonidine + enalapril), 60% of the patients achieved target BP levels, and SBP levels were reduced by 21,1 mm Hg (p<0,05). LVMMI decreased by 5,1 g/m2 (p<0,05), Em av increased by 0,3 cm/s (p<0,05), while the respective reduction in PWV, WC, and BMI reached 1,1 m/s (p<0,05), 1,8 cm (p<0,05), and 0,5 kg/m2 (p<0,05). All three groups demonstrated a significant reduction in urine albumin levels.Conclusion.The moxonidine-based combination therapy effectively reduced the levels of BP and urine albumin. The combination of moxonidine with amlodipine or enalapril improved cardiac structure and function, as well as renal excretory function. The combination of moxonidine and hydrochlorothiazide, however, negatively affected renal excretion. All three variants of combination therapy were metabolically neutral and demonstrated beneficial effects on visceral obesity.
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Affiliation(s)
- E. V. Tishina
- A. L. Myasnikov Research Institute of Clinical Cardiology, Russian Cardiology Scientific and Clinical Complex, Moscow
| | - V. B. Mychka
- A. L. Myasnikov Research Institute of Clinical Cardiology, Russian Cardiology Scientific and Clinical Complex, Moscow
| | - M. A. Saidova
- A. L. Myasnikov Research Institute of Clinical Cardiology, Russian Cardiology Scientific and Clinical Complex, Moscow
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Dooley R, Harvey BJ, Thomas W. Non-genomic actions of aldosterone: from receptors and signals to membrane targets. Mol Cell Endocrinol 2012; 350:223-34. [PMID: 21801805 DOI: 10.1016/j.mce.2011.07.019] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Revised: 07/05/2011] [Accepted: 07/09/2011] [Indexed: 10/17/2022]
Abstract
In tissues which express the mineralocorticoid receptor (MR), aldosterone modulates the expression of membrane targets such as the subunits of the epithelial Na(+) channel, in combination with important signalling intermediates such as serum and glucocorticoid-regulated kinase-1. In addition, the rapid 'non-genomic' activation of protein kinases and secondary messenger signalling cascades has also been detected in aldosterone-sensitive tissues of the nephron, distal colon and cardiovascular system. These rapid actions are variously described as being coupled to MR or to an as yet unidentified, membrane-associated aldosterone receptor. The rapidly activated signalling cascades add a level of fine-tuning to the activity of aldosterone-responsive membrane transporters and also modulate the aldosterone-induced changes in gene expression through receptor and transcription factor phosphorylation.
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Affiliation(s)
- Ruth Dooley
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland
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25
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Choi HK, Soriano LC, Zhang Y, Rodríguez LAG. Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study. BMJ 2012; 344:d8190. [PMID: 22240117 PMCID: PMC3257215 DOI: 10.1136/bmj.d8190] [Citation(s) in RCA: 172] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/04/2011] [Indexed: 11/21/2022]
Abstract
OBJECTIVE To determine the independent associations of antihypertensive drugs with the risk of incident gout among people with hypertension. DESIGN Nested case-control study. SETTING UK general practice database, 2000-7. PARTICIPANTS All incident cases of gout (n = 24,768) among adults aged 20-79 and a random sample of 50,000 matched controls. MAIN OUTCOME MEASURE Relative risk of incident gout associated with use of antihypertensive drugs. RESULTS After adjusting for age, sex, body mass index, visits to the general practitioner, alcohol intake, and pertinent drugs and comorbidities, the multivariate relative risks of incident gout associated with current use of antihypertensive drugs among those with hypertension (n = 29,138) were 0.87 (95% confidence interval 0.82 to 0.93) for calcium channel blockers, 0.81 (0.70 to 0.94) for losartan, 2.36 (2.21 to 2.52) for diuretics, 1.48 (1.40 to 1.57) for β blockers, 1.24 (1.17 to 1.32) for angiotensin converting enzyme inhibitors, and 1.29 (1.16 to 1.43) for non-losartan angiotensin II receptor blockers. Similar results were obtained among those without hypertension. The multivariate relative risks for the duration of use of calcium channel blockers among those with hypertension were 1.02 for less than one year, 0.88 for 1-1.9 years, and 0.75 for two or more years and for use of losartan they were 0.98, 0.87, and 0.71, respectively (both P<0.05 for trend). CONCLUSIONS Compatible with their urate lowering properties, calcium channel blockers and losartan are associated with a lower risk of incident gout among people with hypertension. By contrast, diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout.
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Affiliation(s)
- Hyon K Choi
- Section of Rheumatology and the Clinical Epidemiology Unit, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118, USA.
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Abstract
Blood pressure (BP) plays an important role in the development and progression of cardiovascular disease. Moreover, hypertensive patients often have additional cardiovascular risk factors. Despite the abundance of antihypertensive drug categories, satisfactory BP regulation is often difficult to achieve. A major cause of this difficulty to properly manage BP is the less than optimal adherence of subjects to treatment. This is often due to the various adverse effects of the antihypertensive drugs. Calcium channel blockers (CCB) have an established efficacy for reducing BP. However, their side effect of peripheral edema is often a cause for the discontinuation of treatment. Manidipine holds some unique properties differentiating it from the rest of the CCB class. It has a better safety profile with a lower incidence of peripheral edema. Moreover, there are indications that manidipine holds additional beneficial attributes, such as improvement of renal function and decrease of insulin resistance.
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Ruggenenti P, Lauria G, Iliev IP, Fassi A, Ilieva AP, Rota S, Chiurchiu C, Barlovic DP, Sghirlanzoni A, Lombardi R, Penza P, Cavaletti G, Piatti ML, Frigeni B, Filipponi M, Rubis N, Noris G, Motterlini N, Ene-Iordache B, Gaspari F, Perna A, Zaletel J, Bossi A, Dodesini AR, Trevisan R, Remuzzi G. Effects of Manidipine and Delapril in Hypertensive Patients With Type 2 Diabetes Mellitus. Hypertension 2011; 58:776-83. [DOI: 10.1161/hypertensionaha.111.174474] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m
2
(IQR: 0.16–0.50 mL/min per 1.73 m
2
) on combined therapy, 0.36 mL/min per 1.73 m
2
(IQR: 0.18–0.53 mL/min per 1.73 m
2
) on delapril, and 0.30 mL/min per 1.73 m
2
(IQR: 0.12–0.50 mL/min per 1.73 m
2
) on placebo (
P
=0.87 and
P
=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04–0.78;
P
=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07–0.99;
P
=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24–0.87;
P
=0.017) and 0.52 (0.27–0.99;
P
=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (
P
=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.
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Affiliation(s)
- Piero Ruggenenti
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Giuseppe Lauria
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Ilian Petrov Iliev
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Anna Fassi
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Aneliya Parvanova Ilieva
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Stefano Rota
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Carlos Chiurchiu
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Drazenka Pongrac Barlovic
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Angelo Sghirlanzoni
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Raffaella Lombardi
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Paola Penza
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Guido Cavaletti
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Maria Luisa Piatti
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Barbara Frigeni
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Marco Filipponi
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Nadia Rubis
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Greta Noris
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Nicola Motterlini
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Bogdan Ene-Iordache
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Flavio Gaspari
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Annalisa Perna
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Jelka Zaletel
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Antonio Bossi
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Alessandro Roberto Dodesini
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Roberto Trevisan
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
| | - Giuseppe Remuzzi
- From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation “Carlo Besta” Neurological Institute, Milan,
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Fogari R, Mugellini A, Circelli M, Cremonesi G. Combination delapril/manidipine as antihypertensive therapy in high-risk patients. Clin Drug Investig 2011; 31:439-53. [PMID: 21627336 DOI: 10.2165/11589000-000000000-00000] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The majority of patients with hypertension, and in particular high-risk patients or those with diabetes mellitus or renal dysfunction, are likely to require combination therapy with at least two antihypertensive agents (from different classes) to achieve their blood pressure (BP) target. The delapril/manidipine fixed-dose combination consists of two antihypertensive agents with different, yet complementary, mechanisms of action. Delapril/manidipine has demonstrated short- and long-term antihypertensive efficacy in a number of clinical studies in patients with hypertension with an inadequate response to monotherapy. Comparative studies have demonstrated that delapril/manidipine is as effective as enalapril/hydrochlorothiazide (HCTZ) in patients with hypertension with an inadequate response to monotherapy, and as effective as irbesartan/HCTZ, losartan/HCTZ, olmesartan medoxomil/HCTZ, ramipril/HCTZ and valsartan/HCTZ in reducing BP in patients with hypertension and diabetes, or in obese patients with hypertension. Therapy with delapril/manidipine also appears to exert beneficial effects that extend beyond a reduction in BP, including nephroprotective activity and an improvement in fibrinolytic balance, supporting its value as a treatment option in these patient populations at high or very high cardiovascular risk because of the presence of organ damage, diabetes or renal disease.
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Affiliation(s)
- Roberto Fogari
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
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30
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Martell-Claros N, de la Cruz JJ. Manidipine for hypertension not controlled by dual therapy in patients with diabetes mellitus: a non-comparative, open-label study. Clin Drug Investig 2011; 31:427-34. [PMID: 21528940 DOI: 10.2165/11587400-000000000-00000] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
BACKGROUND AND OBJECTIVE Little is known about the effects of the calcium channel antagonist manidipine when it is added as a third drug in non-controlled hypertensive patients with diabetes mellitus receiving dual antihypertensive therapy. The aim of this study was to evaluate the response in terms of blood pressure (BP) and microalbuminuria when manidipine is administered to patients with type 2 diabetes and uncontrolled hypertension who are already being treated with a combination of a low-dose diuretic plus an ACE inhibitor or an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]). We also evaluated the effects of addition of manidipine on plasma fasting glucose, glycosylated haemoglobin (HbA(1c)), serum uric acid, the lipid profile, serum creatinine and creatinine clearance. METHODS This was a non-comparative, open-label study of hypertensive diabetic patients with systolic/diastolic BP >130/80 mmHg. All patients had been receiving treatment for ≥3 months with stable doses of a diuretic plus an ACE inhibitor or ARB. Manidipine 10 mg/day was added, increasing to 20 mg/day if the target BP was not reached after 3 months' treatment. The follow-up period was 6 months. Patient compliance was verified by tablet count. The doses of statins being taken by patients prior to commencement of the trial were not modified during the study. All patients were treated with oral antihyperglycaemic agents only; patients receiving insulin were excluded from the study. RESULTS 136 patients were enrolled in the trial and completed the study; 41.9% of the patients were males, the mean ± SD age of the study population was 64.4 ± 12.3 years, and the mean ± SD body mass index was 30.2 ± 4.9 kg/m(2). The mean ± SD BP at baseline was 158.6 ± 15.6/86.7 ± 11.2 mmHg compared with 136.8 ± 12.0/78.0 ± 11.2 (-21.8/-8.7, respectively) mmHg at the end of the study period (p < 0.001). A total of 63.6% of the patients attained a BP of <140/90 mmHg and 20.9% attained a BP of <130/80 mmHg. The mean ± SD heart rate decreased from 75.1 ± 11.2 at baseline to 72.8 ± 11.2 beats/min at the end of the study (p = 0.06; not significant). Fifty percent (95% CI 41.6, 58.4) of the patients had microalbuminuria at baseline compared with 31.3% (95% CI 23.0, 39.6) at study end (p = 0.006). Reductions in mean ± SD fasting glucose levels (-10.2 ± 50.3 mg/dL; p < 0.05), HbA(1c) (-0.19 ± 0.97%; p = 0.05), total cholesterol (-11.9 ± 35.2 mg/dL; 95% CI -18.1, -5.8; p < 0.005), triglycerides (-10.8 ± 51.1 mg/dL; 95% CI -19.7, -1.8; p = 0.018) and low-density lipoprotein-cholesterol (-8.1 ± 27.7 mg/dL; 95% CI -13.2, -2.9; p = 0.002) were observed. No patients dropped out of the study because of adverse effects. The most frequent adverse effect encountered was malleolar oedema (9%). CONCLUSION Manidipine added as the third drug to a renin-angiotensin system inhibitor plus a low dose of diuretic significantly reduces BP, improves renal function, has favourable effects on the lipid and glucose profiles, and reduces microalbuminuria in uncontrolled hypertensive patients with type 2 diabetes. Long-term trials are necessary to evaluate time-related effects.
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31
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Lambertucci L, Di Serio C, Castellani S, Torrini M, Lotti E, Cristofari C, Masotti G, Marchionni N, Ungar A. Trandolapril, but not verapamil nor their association, restores the physiological renal hemodynamic response to adrenergic activation in essential hypertension. Transl Res 2011; 157:348-56. [PMID: 21575919 DOI: 10.1016/j.trsl.2010.12.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2010] [Revised: 12/22/2010] [Accepted: 12/28/2010] [Indexed: 10/18/2022]
Abstract
The purpose of this study was to evaluate the effects of antihypertensive drugs on renal hemodynamics in hypertensive patients during an adrenergic activation by mental stress (MS), which induces renal vasoconstriction in healthy subjects. Renal hemodynamics was assessed twice in 30 middle-aged essential hypertensive patients (57±6 years)-after 15 days of pharmacological wash-out and after 15 days of treatment with Trandolapril (T, 4 mg, n=10), Verapamil (V, 240 mg, n=10), or both (T 2 mg+V 180 mg, n=10). Each experiment consisted of 4 30-min periods (baseline, MS, recovery I and II). Renal hemodynamics was evaluated with effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) from plasminogen activator inhibitor and inulin clearance, respectively. MS increased blood pressure (BP) to a similar extent before and after each treatment. Before treatment, the increasing BP was not associated with any modification of ERPF in the 3 groups. Renal vascular resistances (RVR) markedly increased during MS (+23% in the T group, +21.6% in the V group, and +32.9% in the T+V group); GFR remained constant during the whole experiment. After treatment, ERPF decreased significantly during MS in the T group (-15%, P<0.05) and in the V group (-11.7%, p<0.01); in the T+V group, ERPF modifications were not statistically significant (P=0.07). In the T group, ERPF reverted to baseline values at the end of the stimulus, whereas in the V group, renal vasoconstriction was more prolonged. Only in hypertensive patients treated with 4 mg of T, RVR reverted to baseline during the recovery I, whereas in the V group, RVR remained elevated for the whole experiment. No modifications of GFR were observed in all groups. The kidney of hypertensive patients cannot react to a sympathetic stimulus with the physiological vasoconstriction. A short-term antihypertensive treatment with 4 mg of T restores the physiological renal response to adrenergic activation.
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Affiliation(s)
- Lorella Lambertucci
- Unit of Geriatric Medicine and Cardiology, Department of Clinical Care Medicine and Surgery, University of Florence and Azienda Ospedaliero Universitaria Careggi, Florence, Italy
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Aritomi S, Niinuma K, Ogawa T, Konda T, Nitta K. Effects of an N-type calcium antagonist on angiotensin II-renin feedback. Am J Nephrol 2011; 33:168-75. [PMID: 21293118 DOI: 10.1159/000323969] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2010] [Accepted: 01/01/2011] [Indexed: 11/19/2022]
Abstract
BACKGROUND Interrupting the renin-angiotensin system (RAS) with an angiotensin II receptor blocker (ARB) has been found to induce RAS overactivation. In this study, we investigated the effect of 2 calcium channel blockers (CCBs), cilnidipine (L-/N-type CCB) and amlodipine (L-type CCB), on the RAS activation induced by an ARB in a strain of spontaneously hypertensive rats (SHR/Izm, 10 weeks of age). METHODS Rats intravenously catheterized for blood collection were randomly divided into groups that were administered the vehicle, the ARB valsartan or valsartan combined with one of the 2 CCBs. Their blood and kidneys were collected 270 min after administration. RESULTS Valsartan increased the plasma angiotensin II (Ang II) level in a dose-dependent manner. Cilnidipine suppressed the increase in plasma renin activity and plasma Ang II levels induced by valsartan, but amlodipine did not. Combined administration of cilnidipine, but not amlodipine, and valsartan significantly reduced the noradrenaline content in the renal cortex. CONCLUSIONS The results of this study suggest that the suppressive effect of cilnidipine on the valsartan-induced increase in RAS activity can be partly explained by its sympatholytic action mediated by N-type calcium channel blockade, and that combined administration of cilnidipine and valsartan might provide a synergistic therapeutic effect.
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Affiliation(s)
- Shizuka Aritomi
- Pharmaceutical Research Laboratories, Ajinomoto Co., Inc., Kawasaki, Japan
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33
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Impact of renal function on cardiovascular events in elderly hypertensive patients treated with efonidipine. Hypertens Res 2010; 33:1211-20. [PMID: 20844543 DOI: 10.1038/hr.2010.162] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
This study evaluated the impact of renal function on cardiovascular outcomes in elderly hypertensive patients enrolled in the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive patients. The patients were randomly assigned to either a strict-treatment group (target systolic blood pressure (BP) <140 mm Hg, n=2212) or a mild-treatment group (target systolic BP, 140 to <160 mm Hg, n=2206), each with efonidipine (a T/L-type Ca channel blocker)-based regimens. Cardiovascular events (stroke, cardiovascular disease and renal disease) were evaluated during the 2-year follow-up period following the prospective randomized open-blinded end-point method. Estimated glomerular filtration rate (eGFR) was elevated throughout the trial period in both the strict-treatment (59.4-62 ml min⁻¹ per 1.73 m²) and the mild-treatment group (58.8-61.4 ml min⁻¹ per 1.73 m²). This tendency was also observed in diabetic patients and patients aged ≥75 years, with baseline eGFR<60 ml min⁻¹ per 1.73 m². Baseline eGFR (<60 vs. ≥60 ml min⁻¹ per 1.73 m²) had no definite relationship with the incidence of cardiovascular events, nor did the level of BP control. Proteinuria at the time of entry into the study, however, was significantly correlated with cardiovascular event rates (7.1%), an association that was more apparent in patients with eGFR<60 ml min⁻¹ per 1.73 m² (8.2%). Furthermore, the event rate was more elevated in patients with greater declines in eGFR and was amplified when the baseline eGFR was <60 ml min⁻¹ per 1.73 m². In conclusion, the rates of decline of renal function and proteinuria constitute critical risk factors for cardiovascular events in elderly hypertensive patients, trends that are enhanced when baseline eGFR is diminished. Furthermore, the fact that efonidipine-based regimens ameliorate renal function in elderly hypertensive patients with chronic kidney disease may offer novel information on the mechanisms of cardiovascular protection.
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Kralova I, Winsö O, Olivecrona M, Naredi S. Non-traumatic subarachnoid hemorrhage is associated with subnormal blood creatinine levels. Scandinavian Journal of Clinical and Laboratory Investigation 2010; 70:438-46. [PMID: 20704519 DOI: 10.3109/00365513.2010.506925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE The aim of this study was to examine the hypothesis that patients with non-traumatic subarachnoid hemorrhage (SAH) have statistically significant subnormal creatinine levels and that the creatinine levels are associated with severity of disease. MATERIALS AND METHODS This was a retrospective observational study over 2 years (2005-2006) in which the SAH patients were divided into patients with severe symptoms and patients with mild/moderate symptoms, and were compared to patients with; traumatic brain injury, trauma without brain injury and patients undergoing elective knee surgery. Blood creatinine levels (day 1-3, and day 7) were recorded. RESULTS Compared to a normal distribution, SAH patients had statistically significant subnormal creatinine levels day one through seven. SAH patients with severe symptoms had statistically significant subnormal creatinine levels already on day one, in contrast to patients with mild/moderate symptoms. Women with severe symptoms had statistically significant subnormal creatinine levels throughout the study period in contrast to men with severe symptoms who had a normal distribution of creatinine at admission. Women with mild/moderate symptoms had a normal distribution of creatinine only at admission in contrast to men who had a normal distribution of creatinine throughout the study period. Male patients with traumatic brain injury, all trauma patients without brain injury and all patients undergoing elective knee surgery had a normal distribution of creatinine on all studied days. CONCLUSIONS SAH is associated with subnormal serum creatinine levels. This finding is more pronounced in patients with severe symptoms and in women.
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Affiliation(s)
- Ivana Kralova
- Department of Anaesthesia and Intensive Care, Institute of Surgical and Perioperative Sciences, Medical Faculty, Umeå University, Umeå, Sweden.
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35
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Kosaka H, Hirayama K, Yoda N, Sasaki K, Kitayama T, Kusaka H, Matsubara M. The L-, N-, and T-type triple calcium channel blocker benidipine acts as an antagonist of mineralocorticoid receptor, a member of nuclear receptor family. Eur J Pharmacol 2010; 635:49-55. [PMID: 20307534 DOI: 10.1016/j.ejphar.2010.03.018] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2009] [Revised: 02/17/2010] [Accepted: 03/04/2010] [Indexed: 12/01/2022]
Abstract
Aldosterone-induced activation of mineralocorticoid receptor, a member of the nuclear receptor family, results in increased tissue damage such as vascular inflammation and cardiac and perivascular fibrosis. Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for hypertension and angina. Benidipine exhibits pleiotropic pharmacological features such as renoprotective and cardioprotective effects through triple blockade of L-, N-, and T-type calcium channels. However, the mechanism of additional beneficial effects on end-organ damage is poorly understood. Here, we examined the effects of benidipine and other calcium channel blockers on aldosterone-induced mineralocorticoid receptor activation using luciferase reporter assay system. Benidipine showed more potent activity than efonidipine, amlodipine, or azelnidipine. Benidipine depressed the response to higher concentrations of aldosterone, whereas pretreatment of eplerenone, a steroidal mineralocorticoid receptor antagonist, did not. Binding studies using [(3)H] aldosterone indicated that benidipine and other calcium channel blockers competed for binding to mineralocorticoid receptor. Benidipine and other calcium channel blockers showed antagonistic activity on Ser810 to Leu mutant mineralocorticoid receptor, which is identified in patients with early-onset hypertension. On the other hand, eplerenone partially activated the mutant. Results of analysis using optical isomers of benidipine indicated that inhibitory effect of aldosterone-induced mineralocorticoid receptor activation was independent of its primary blockade of calcium channels. These results suggested that benidipine directly inhibits aldosterone-induced mineralocorticoid receptor activation, and the antagonistic activity might contribute to the drug's pleiotropic pharmacological features.
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Affiliation(s)
- Hiromichi Kosaka
- Drug Discovery Research Laboratories, Kyowa Hakko Kirin Co., Ltd., Sunto-gun, Shizuoka, Japan
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36
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Fujimoto S, Satoh M, Nagasu H, Horike H, Sasaki T, Kashihara N. Azelnidipine exerts renoprotective effects by improvement of renal microcirculation in angiotensin II infusion rats. Nephrol Dial Transplant 2009; 24:3651-8. [DOI: 10.1093/ndt/gfp407] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Omae K, Ogawa T, Nitta K. Influence of T-calcium channel blocker treatment on deterioration of renal function in chronic kidney disease. Heart Vessels 2009; 24:301-7. [PMID: 19626404 DOI: 10.1007/s00380-008-1125-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2008] [Accepted: 10/24/2008] [Indexed: 01/13/2023]
Abstract
Some calcium channel blockers (CCBs) have renoprotective effects. Our aim was to compare the effects of different subclasses of CCBs on the deterioration of renal function in chronic kidney disease (CKD). This is a prospective, observational cohort study in a single center. The subjects were 107 nondiabetic CKD patients. The rate of deterioration of estimated glomerular filtration rate (DeltaeGFR) was calculated by [last visit eGFR - baseline eGFR/follow-up duration]. Multivariate analysis was performed using the change in urinary protein (DeltaUP) and DeltaeGFR during follow-up as response variables. CCB subclasses were L-type in 76 patients, T- and L-type in 28 patients, and nondihydropyridines in 6 patients. Multiregression analysis indicated that higher baseline proteinuria (UP) and the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers were associated with the decrease of UP, while the use of L-type CCBs, prednisolone, and probucol was associated with the increase of UP. The use of T- and L-type CCBs, ACEIs and diuretics was associated with a good outcome in terms of DeltaeGFR, whereas chronic glomerulonephritis, polycystic kidney disease, and higher baseline eGFR and UP were associated with a poor outcome. It is suggested that the use of T- and L-type CCB among other subclasses may improve the outcome of patients with nondiabetic CKD in terms of renal function.
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Affiliation(s)
- Kiyotsugu Omae
- Internal Medicine Department, Yoshikawa Hospital, Tokyo, [corrected] Japan
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38
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Abstract
Excretion of albumin with urine (UAE) in small amounts, i.e. microalbuminuria (MAU), also referred to as "incipient nephropathy", has long been considered a marker of early nephropathy and increased cardiovascular risk in the specific setting of diabetes mellitus. However, numerous clinical studies found an association between MAU and other cardiovascular risk factors, target organ damage and risk of cardiovascular disease in clinical contexts different from diabetes and including arterial hypertension. The present article reviews the available evidence on the clinical value of MAU in subjects with primary hypertension. In these subjects, prevalence of MAU varied from about 4% to 46% across different studies and these differences may be explained by the huge intra-individual variability in UAE, discrepancies in the technique of measurement and different definitions of MAU. A direct and continuous association between UAE and blood pressure (BP) has been found in many studies. A continuous association between UAE and left ventricular mass has also been found in most studies. In contrast, it is not yet clear whether the association between UAE and other factors including age, gender, smoking, ethnicity, insulin resistance, lipids and obesity is independent or mediated by confounders, particularly BP. From a prognostic standpoint, several longitudinal studies showed an association between MAU and the risk of future cardiovascular disease. Of particular note, in some of these studies the incidence of major cardiovascular events progressively increased with UAE starting below the conventional MAU thresholds. Thus, besides being a direct risk factor for progressive renal damage, MAU can be considered a marker, which integrates and reflects the long-term level of activity of several other detrimental factors on cardiovascular system. Antihypertensive treatment reduces UAE and such effect may be detected after just a few days of treatment. Among available antihypertensive drugs, angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonists seem to be superior to other antihypertensive drugs in reducing UAE. The dual blockade of the renin-angiotensin system with an ACE inhibitor and an angiotensin II receptor antagonist is a new and promising approach to control UAE in hypertensive patients. Determination of MAU is recommended in the initial work-up of subjects with primary hypertension.
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Affiliation(s)
- Paolo Verdecchia
- Department of Cardiovascular Disease, Hospital R. Silvestrini, Perugia, Italy.
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Reboldi G, Gentile G, Angeli F, Verdecchia P. Choice of ACE inhibitor combinations in hypertensive patients with type 2 diabetes: update after recent clinical trials. Vasc Health Risk Manag 2009; 5:411-27. [PMID: 19475778 PMCID: PMC2686259 DOI: 10.2147/vhrm.s4235] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The diabetes epidemic continues to grow unabated, with a staggering toll in micro- and macrovascular complications, disability, and death. Diabetes causes a two- to fourfold increase in the risk of cardiovascular disease, and represents the first cause of dialysis treatment both in the UK and the US. Concomitant hypertension doubles total mortality and stroke risk, triples the risk of coronary heart disease and significantly hastens the progression of microvascular complications, including diabetic nephropathy. Therefore, blood pressure reduction is of particular importance in preventing cardiovascular and renal outcomes. Successful antihypertensive treatment will often require a combination therapy, either with separate drugs or with fixed-dose combinations. Angiotensin converting enzyme (ACE) inhibitor plus diuretic combination therapy improves blood pressure control, counterbalances renin-angiotensin system activation due to diuretic therapy and reduces the risk of electrolyte alterations, obtaining at the same time synergistic antiproteinuric effects. ACE inhibitor plus calcium channel blocker provides a significant additive effect on blood pressure reduction, may have favorable metabolic effects and synergistically reduce proteinuria and the rate of decline in glomerular filtration rate, as evidenced by the GUARD trial. Finally, the recently published ACCOMPLISH trial showed that an ACE inhibitor/calcium channel blocker combination may be particularly useful in reducing cardiovascular outcomes in high-risk patients. The present review will focus on different ACE inhibitor combinations in the treatment of patients with type 2 diabetes mellitus and hypertension, in the light of recent clinical trials, including GUARD and ACCOMPLISH.
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Affiliation(s)
- Gianpaolo Reboldi
- 1Department of internal Medicine. University of Perugia, Perugia, Italy.
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40
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Ohashi N, Mitamura H, Ogawa S. Development of newer calcium channel antagonists: therapeutic potential of efonidipine in preventing electrical remodelling during atrial fibrillation. Drugs 2009; 69:21-30. [PMID: 19192934 DOI: 10.2165/00003495-200969010-00002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Calcium channel antagonists are most frequently prescribed for the treatment of hypertension and the majority specifically inhibit the L-type Ca2+ channel. In order to prevent reflex sympathetic over activity caused by L-type calcium channel antagonists (calcium channel blockers [CCBs]), increasing attention has focused on the blockade of the T-type Ca2+ channel. The T-type Ca2+ channel is found in the kidney and can also appear in the ventricle of the heart when in failure. Therefore, the T-type Ca2+ channel is a possible new target for the treatment of nephropathy and heart failure. In clinical trials, the efficacy and safety of T-type CCBs in hypertension and chronic renal disease have been reported. It is well known that the T-type Ca2+ channel is present in the adult atrium and plays a role in the cardiac pacemaker, but recent experimental studies suggest that this current also promotes electrical remodelling of the atrium. Using efonidipine, a dual L- and T-type CCB, it has been demonstrated that atrial electrical remodelling can be diminished in dogs. Furthermore, the T-type Ca2+ channel has recently been found in the pulmonary veins, contributing to the pulmonary vein pacemaker activity and triggered activity. A variety of drugs having T-type CCB effects have been shown to be effective in the management of atrial fibrillation, suggesting that this channel may be a novel therapeutic target.
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Affiliation(s)
- Narutaka Ohashi
- Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
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41
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Pruijm MT, Maillard MP, Burnier M. Patient adherence and the choice of antihypertensive drugs: focus on lercanidipine. Vasc Health Risk Manag 2009; 4:1159-66. [PMID: 19337529 PMCID: PMC2663443 DOI: 10.2147/vhrm.s3510] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Despite the development of many effective antihypertensive drugs, target blood pressures are reached in only a minority of patients in clinical practice. Poor adherence to drug therapy and the occurrence of side effects are among the main reasons commonly reported by patients and physicians to explain the poor results of actual antihypertensive therapies. The development of new effective antihypertensive agents with an improved tolerability profile might help to partly overcome these problems. Lercanidipine is an effective dihydropyridine calcium channel blocker of the third generation characterized by a long half-life and its lipophylicity. In contrast to first-generation dihydropyridines, lercanidipine does not induce reflex tachycardia and induces peripheral edema with a lower incidence. Recent data suggest that in addition to lowering blood pressure, lercanidipine might have some renal protective properties. In this review we shall discuss the problems of drug adherence in the management of hypertension with a special emphasis on lercanidipine.
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Affiliation(s)
- Menno T Pruijm
- Service of Nephrology and Hypertension, Department of Medicine, University Hospital, Rue du Bugnon 17, Lausanne, Switzerland
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42
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Navar LG, Arendshorst WJ, Pallone TL, Inscho EW, Imig JD, Bell PD. The Renal Microcirculation. Compr Physiol 2008. [DOI: 10.1002/cphy.cp020413] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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43
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Abstract
Calcium antagonists are a heterogeneous group of drugs that affect not only different channels but different parts of the same channel. These differences translate into different renal hemodynamic effects. This Commentary discusses the implications of these differences for surrogate markers of outcome.
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Affiliation(s)
- P Hart
- 1Department of Medicine, Division of Nephrology and Hypertension, Cook County Hospital, Chicago, Illinois, USA
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44
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Richard S, Virsolvy A, Fort A. [Molecular effects of new calcium antagonists: is the principle of parcimony out of place?]. Ann Cardiol Angeiol (Paris) 2008; 57:166-73. [PMID: 18565491 DOI: 10.1016/j.ancard.2008.02.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2008] [Accepted: 02/28/2008] [Indexed: 11/17/2022]
Abstract
The calcium (Ca2+) channel antagonists (CCA) are used successfully in the treatment of hypertension and angina pectoris. Their mode of action is to decrease Ca2+ entry in the vascular smooth muscle cells. Their molecular targets are voltage activated Ca2+ channels (VACC), especially the L-type (VACC-L). This review examines the role of the VACC-L and of the T-type (VACC-T) in vascular physiology and hypertension. The molecular mechanisms at the base of the vascular selectivity of CCA are presented with, in filigree, the concern of trying to understand the effect of recently developed molecules. In particular, we will examine the ideas having recently emerged concerning the mode of action of last generation dihydropyridines (DHPs) stripped of some of the undesirable effects of prototypes AC considered as highly specific of the VACC-L. These properties could result, in particular, from their effects on the VACC-T, which could occur in addition to those classically observed on the VACC-L.
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MESH Headings
- Animal Experimentation
- Animals
- Antihypertensive Agents/pharmacology
- Antihypertensive Agents/therapeutic use
- Calcium Channel Blockers/pharmacology
- Calcium Channel Blockers/therapeutic use
- Calcium Channels, L-Type/drug effects
- Calcium Channels, L-Type/genetics
- Calcium Channels, L-Type/metabolism
- Calcium Channels, L-Type/physiology
- Calcium Channels, T-Type/drug effects
- Calcium Channels, T-Type/genetics
- Calcium Channels, T-Type/metabolism
- Calcium Channels, T-Type/physiology
- Cells, Cultured
- Dihydropyridines/pharmacology
- Electrophysiology
- Humans
- Hypertension/drug therapy
- Hypertension/physiopathology
- Hypertension, Renal/drug therapy
- Kidney Glomerulus
- Mice
- Muscle Cells/drug effects
- Muscle Cells/metabolism
- Muscle Cells/physiology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Patch-Clamp Techniques
- Rats
- Vasoconstriction/physiology
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Affiliation(s)
- S Richard
- Inserm U637, physiopathologie cardiovasculaire, CHU Arnaud-de-Villeneuve, 371, avenue du Doyen-Faston-Giraud, 34295 Montpellier cedex 5, France.
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45
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Simonetti GD, Santoro L, Ferrarini A, Crosazzo-Franscini L, Fossali E, Bianchetti MG. Systemic hypertension and proteinuria in childhood chronic renal parenchymal disease: role of antihypertensive drug management. Paediatr Drugs 2008; 9:413-8. [PMID: 18052411 DOI: 10.2165/00148581-200709060-00008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
A variety of chronic kidney diseases tend to progress towards end-stage kidney disease. Progression is largely due to factors unrelated to the initial disease, including systemic hypertension and proteinuria. Drugs that block the renin-angiotensin II-aldosterone system, either ACE inhibitors or angiotensin II receptor antagonists, reduce both BP and proteinuria and appear superior to a more conventional antihypertensive treatment regimen in preventing progression to end-stage kidney disease. The most recent recommendations state that the BP goal in children with chronic kidney disease is the corresponding 90th centile for body height, age, and gender. Since satisfactory BP control is often not achieved, the mnemonic acronym DELTAREPROSI was generated to recall the following tips for the practical management of hypertension and proteinuria in childhood chronic renal parenchymal disease: DEfinition of hypertension and Low blood pressure TArget in REnal disease (90th centile calculated by means of simple formulas), potential of drugs inhibiting the REnin-angiotensin II-aldosterone system in hypertension and PROteinuria, advantages of SImplified treatment regimens and escalating the doses every SIx weeks.
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Akizuki O, Inayoshi A, Kitayama T, Yao K, Shirakura S, Sasaki K, Kusaka H, Matsubara M. Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295R. Eur J Pharmacol 2008; 584:424-34. [PMID: 18331727 DOI: 10.1016/j.ejphar.2008.02.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2007] [Revised: 01/25/2008] [Accepted: 02/06/2008] [Indexed: 11/16/2022]
Abstract
Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca2+ channels. More recently, it has been demonstrated that benidipine inhibits T-type Ca2+ channels in addition to L-type Ca2+ channels. Therefore, effect of calcium channel blockers, including benidipine, on aldosterone production and T-type Ca2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCl-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that benidipine concentration-dependently inhibited T-type Ca2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCl-induced upregulation of 11-beta-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-induced Ca2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca2+ influx inhibitory activities of benidipine for aldosterone production. T-type Ca2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca2+ channels.
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Affiliation(s)
- Osamu Akizuki
- Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., Shizuoka 411-8731, Japan
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T-type calcium channel blockade as a therapeutic strategy against renal injury in rats with subtotal nephrectomy. Kidney Int 2008; 73:826-34. [PMID: 18200001 DOI: 10.1038/sj.ki.5002793] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
T-type calcium channel blockers have been previously shown to protect glomeruli from hypertension by regulating renal arteriolar tone. To examine whether blockade of these channels has a role in protection against tubulointerstitial damage, we used a stereo-selective T-type calcium channel blocker R(-)-efonidipine and studied its effect on the progression of this type of renal injury in spontaneously hypertensive rats that had undergone subtotal nephrectomy. Treatment with racemic efonidipine for 7 weeks significantly reduced systolic blood pressure and proteinuria. The R(-)-enantiomer, however, had no effect on blood pressure but significantly reduced proteinuria compared to vehicle-treated rats. Both agents blunted the increase in tubulointerstitial fibrosis, renal expression of alpha-smooth muscle actin and vimentin along with transforming growth factor-beta (TGF-beta)-induced renal Rho-kinase activity seen in the control group. Subtotal nephrectomy enhanced renal T-type calcium channel alpha1G subunit expression mimicked in angiotensin II-stimulated mesangial cells or TGF-beta-stimulated proximal tubular cells. Our study shows that T-type calcium channel blockade has renal protective actions that depend not only on hemodynamic effects but also pertain to Rho-kinase activity, tubulointerstitial fibrosis, and epithelial-mesenchymal transitions.
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48
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49
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Abstract
Although tighter blood pressure control is considered the main mechanism for preventing the progression of chronic renal failure, angiotensin-converting enzyme inhibitors and angiotensin receptors blockers seem to have an additional organ protective role. The effects of calcium antagonists in renal disease are not so clearly defined. Calcium antagonists have pleiotropic effects that might contribute to protect the kidney, such as attenuating mesangial entrapment of macromolecules, countervailing the mitogenic effect of platelet-derived growth factors and platelet-activating factors, and suppressing mesangial cell proliferation. They could also act as free radical scavengers and inhibit the renal effects of endothelin. Some evidence has been accumulated demonstrating that certain new dihydropyridinic calcium antagonists may affect postglomerular as well as preglomerular vessels, resulting in decreased filtration fraction and nephroprotective effect as renin-angiotensin axis-blocking drugs. Though there are few reports on the clinical renal effects of new calcium antagonists, they have rendered promising results. Manidipine does not increase proteinuria as do some classic calcium antagonists, and lercanidipine combined with renin-angiotensin axis-blocking drugs reduce proteinuria. Both drugs have been shown to decrease microalbuminuria when administered alone.
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50
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Ruilope LM, Kirwan BA, de Brouwer S, Danchin N, Fox KAA, Wagener G, Segura J, Poole-Wilson PA, Lubsen J. Uric acid and other renal function parameters in patients with stable angina pectoris participating in the ACTION trial: impact of nifedipine GITS (gastro-intestinal therapeutic system) and relation to outcome. J Hypertens 2007; 25:1711-8. [PMID: 17620970 DOI: 10.1097/hjh.0b013e3281c49d93] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Little data is available concerning the prognostic implications of renal function abnormalities, their evolution over time and the effects of nifedipine on such abnormalities in patients with stable angina pectoris. METHODS The previously published ACTION trial compared long-acting nifedipine GITS 60 mg once daily to placebo among 7,665 patients. Standard laboratory tests including creatinine and uric acid were assessed at baseline, after 6 months, 2 and 4 years, and at the end of follow-up. We assessed the impact of nifedipine on markers of renal dysfunction and determined whether evidence of renal failure alters the impact of nifedipine on the clinical outcome of patients with stable angina. RESULTS Uric acid was not while creatinine level and estimated creatinine clearance were potent conditionally independent predictors of total mortality and of cardiovascular clinical events. Relative to placebo, nifedipine reduced 6-month uric acid levels by 3% (P < 0.001) of the baseline value. This difference was maintained during long-term follow-up, was present both in normotensives and in hypertensives, and was not explained by differences in diuretic therapy or allopurinol use. Nifedipine had no effect on the occurrence of clinical renal failure. Relative to placebo, the effects of nifedipine on cardiovascular death or myocardial infarction [hazard ratio (HR) = 1.01, 95% confidence interval (CI) 0.88-1.17], any stroke or transient ischaemic attack (HR = 0.73, 95% CI 0.60-0.88), new overt heart failure (HR = 0.72, 95% CI 0.55-0.95), and the need for any coronary procedure (HR = 0.81, 95% CI 0.75-0.88) were consistent across strata of markers of renal dysfunction. CONCLUSIONS We conclude that, in patients with stable angina, nifedipine reduces uric acid levels and does not affect other markers of renal dysfunction. Renal dysfunction does not alter the effects of nifedipine on clinical outcome.
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Affiliation(s)
- Luis M Ruilope
- Hypertension Unit, Hospital 12 de Octubre. Madrid, Spain.
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