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Su H, Li M, Li N, Zhang Y, He Y, Zhang Z, Zhang Y, Gao Q, Xu Z, Tang J. Endothelin-1 potentiated constriction in preeclampsia placental veins: Role of ETAR/ETBR/CaV1.2/CALD1. Placenta 2024; 158:165-174. [PMID: 39476475 DOI: 10.1016/j.placenta.2024.10.011] [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: 05/22/2024] [Revised: 10/11/2024] [Accepted: 10/20/2024] [Indexed: 12/11/2024]
Abstract
BACKGROUND Placenta plays a vital role in preeclampsia. The present study investigated the role of endothelin-1 (ET-1) and its receptors in preeclampsia placenta. METHOD Placenta samples were collected from normal and preeclampsia pregnancies, with one single fetus. Placental chorionic plate vessel tone was measured with DMT using vasoactive agents with or without antagonists. Role of L-type voltage-dependent calcium channels (CaV1.2) in single smooth muscle cell was detected using whole-cell patch clamp. PCR, Western blot, and ELISA was used to detect molecule expressions. Placental vessel explants and human umbilical vein smooth muscle cell (HUVSMC) were exposed to ET-1 treatment with or without antagonists. Human umbilical vein endothelial cell (HUVEC) and pregnant sheep was exposed to hypoxic condition, simulating preeclampsia. RESULTS ET-1 and IRL1620 mediated stronger contractions in preeclampsia placental veins, despite unchanged ETAR and decreased ETBR expression. Comparing with control, there was higher ET-1 in umbilical plasma, maternal plasma, and placental vessels from preeclampsia. In utero hypoxia increased plasma ET-1 in fetal lambs and ewes. Hypoxia promoted ET-1 production in HUVEC. Role and expression of CaV1.2 was decreased in preeclampsia placental vessels, while high-molecular-weight caldesmon (CALD1), the marker of contractile phenotype of smooth muscle cells, was significantly increased. ET-1 treatment increased CALD1 in placental explants and in HUVSMC via ETAR/ETBR. CONCLUSION The present study firstly demonstrated ET-1 induced greater contraction in preeclampsia placental chorionic plate veins via ETAR/ETBR, instead of via weaker CaV1.2. In utero hypoxia promoted plasma ET-1 in fetal lambs and ewe, similar to that in preeclampsia. ET-1, binding with ETAR/ETBR increased CALD1, which was associated with stronger contraction in preeclampsia. The data provided important information in preeclampsia onset.
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Affiliation(s)
- Hongyu Su
- Institute for Fetology, The First Affiliated Hospital of Soochow University, China
| | - Min Li
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Soochow University, China
| | - Na Li
- Perinatology Laboratory, Maternity and Child Health Care Hospital of Wuxi, China
| | - Yingying Zhang
- Perinatology Laboratory, Maternity and Child Health Care Hospital of Wuxi, China
| | - Yun He
- Department of Gynecology and Obstetrics, Taixing People's Hospital, China
| | - Ze Zhang
- Department of Gynecology and Obstetrics, Taixing People's Hospital, China
| | - Yumeng Zhang
- Institute for Fetology, The First Affiliated Hospital of Soochow University, China
| | - Qinqin Gao
- Institute for Fetology, The First Affiliated Hospital of Soochow University, China
| | - Zhice Xu
- Institute for Fetology, The First Affiliated Hospital of Soochow University, China; Perinatology Laboratory, Maternity and Child Health Care Hospital of Wuxi, China
| | - Jiaqi Tang
- Institute for Fetology, The First Affiliated Hospital of Soochow University, China.
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Jain A, Bozovicar K, Mehrotra V, Bratkovic T, Johnson MH, Jha I. Investigating the specificity of endothelin-traps as a potential therapeutic tool for endothelin-1 related disorders. World J Diabetes 2022; 13:434-441. [PMID: 35800412 PMCID: PMC9210543 DOI: 10.4239/wjd.v13.i6.434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/24/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Endothelin (ET)-traps are Fc-fusion proteins with a design based on the physiological receptors of ET-1. Previous work has shown that use of the selected ET-traps potently and significantly reduces different markers of diabetes pathology back to normal, non-disease levels.
AIM To demonstrate the selected ET-traps potently and significantly bind to ET-1.
METHODS We performed phage display experiments to test different constructs of ET-traps, and conducted bio-layer interferometry binding assays to verify that the selected ET-traps bind specifically to ET-1 and display binding affinity in the double-digit picomolar range (an average of 73.8 rM, n = 6).
RESULTS These experiments have confirmed our choice of the final ET-traps and provided proof-of-concept for the potential use of constructs as effective biologics for diseases associated with pathologically elevated ET-1.
CONCLUSION There is increased need for such therapeutics as they could help save millions of lives around the world.
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Affiliation(s)
- Arjun Jain
- ET-Traps Limited, Cambridge CB3 0JE, United Kingdom
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom
- Accelerate Cambridge, Judge Business School, University of Cambridge, Cambridge CB2 1AG, United Kingdom
| | - Kristof Bozovicar
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Slovenia 1000, Slovenia
| | - Vidhi Mehrotra
- ET-Traps Limited, Cambridge CB3 0JE, United Kingdom
- Accelerate Cambridge, Judge Business School, University of Cambridge, Cambridge CB2 1AG, United Kingdom
| | - Tomaz Bratkovic
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Slovenia 1000, Slovenia
| | - Martin H Johnson
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom
| | - Ira Jha
- ET-Traps Limited, Cambridge CB3 0JE, United Kingdom
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Nabeh OA, Matter LM, Khattab MA, Esraa Menshawey. "The possible implication of endothelin in the pathology of COVID-19-induced pulmonary hypertension". Pulm Pharmacol Ther 2021; 71:102082. [PMID: 34601121 PMCID: PMC8483983 DOI: 10.1016/j.pupt.2021.102082] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/23/2021] [Accepted: 09/23/2021] [Indexed: 12/21/2022]
Abstract
COVID-19 pandemic has changed the world dramatically since was first reported in Wuhan city, China [1]. Not only as a respiratory illness that could lead to fatal respiratory failure, but also some evidences suggest that it can propagate as a chronic disease associated with a variety of persistent post COVID-19 pathologies that affect patients' life [2,3]. Pulmonary hypertension (PH) is one of the challenging diseases that may develop as a consequence of SARS-COV-2 infection in some COVID-19 survivors [4,5]. The vasopressor, proliferative, proinflammatory, and prothrombotic actions of endothelin [6] may be encountered in the COVID-19-induced PH pathology. And so, endothelin blockers may have an important role to restrict the development of serious PH outcomes with special precautions considering patients with significant hypoxemia.
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Affiliation(s)
- Omnia Azmy Nabeh
- M.Sc/ Assistant Lecturer, Department of Medical Pharmacology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt; M.Sc, Cardiovascular Medicine, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Lamiaa Mohammed Matter
- MD/Lecturer, Department of Medical Pharmacology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt; Professional Diploma of Family Medicine, Arab Institute for Continuing Professional Development, Arab Medical Union, Egypt.
| | - Mahmoud Ahmed Khattab
- M.Sc/ Assistant Lecturer, Department of Medical Pharmacology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt; M.Sc Internal Medicine, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Esraa Menshawey
- Medical Student, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt.
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Jain A, Coffey C, Mehrotra V, Flammer J. Endothelin-1 traps as a potential therapeutic tool: from diabetes to beyond? Drug Discov Today 2019; 24:1937-1942. [PMID: 31394173 DOI: 10.1016/j.drudis.2019.07.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 06/27/2019] [Accepted: 07/26/2019] [Indexed: 12/16/2022]
Abstract
There is substantial research on the vasoactive peptide endothelin (ET)-1 in physiology, as well as in pathology. In fact, pathologically elevated levels of ET-1 have been found in several disease states, such as various cardiovascular diseases, different cancers, some neurodegenerative disorders, as well as in diabetes. Here, we describe and discuss ET-1, its importance in different diseases, and the potential therapeutic effects of ET-traps in the treatment of these diseases. Previous in vitro and in vivo research (in the diabetes disease space) demonstrated that ET-traps potently and significantly prevent the induction of different markers of diabetes-related pathology. This included induction of extracellular matrix (ECM) proteins (collagen 4α1 and fibronectin), which are pathologically elevated in diabetes. The ET-traps prevented induction of these and brought a significant return to non-diabetic levels. We also discuss the merits of using ET-traps over the currently used endothelin receptor antagonists (ERAs) and previously used therapeutic antibodies.
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Affiliation(s)
- Arjun Jain
- Accelerate Cambridge, Judge Business School, University of Cambridge, Cambridge, UK.
| | | | - Vidhi Mehrotra
- Accelerate Cambridge, Judge Business School, University of Cambridge, Cambridge, UK
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Cipolla MJ, Liebeskind DS, Chan SL. The importance of comorbidities in ischemic stroke: Impact of hypertension on the cerebral circulation. J Cereb Blood Flow Metab 2018; 38:2129-2149. [PMID: 30198826 PMCID: PMC6282213 DOI: 10.1177/0271678x18800589] [Citation(s) in RCA: 228] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Comorbidities are a hallmark of stroke that both increase the incidence of stroke and worsen outcome. Hypertension is prevalent in the stroke population and the most important modifiable risk factor for stroke. Hypertensive disorders promote stroke through increased shear stress, endothelial dysfunction, and large artery stiffness that transmits pulsatile flow to the cerebral microcirculation. Hypertension also promotes cerebral small vessel disease through several mechanisms, including hypoperfusion, diminished autoregulatory capacity and localized increase in blood-brain barrier permeability. Preeclampsia, a hypertensive disorder of pregnancy, also increases the risk of stroke 4-5-fold compared to normal pregnancy that predisposes women to early-onset cognitive impairment. In this review, we highlight how comorbidities and concomitant disorders are not only risk factors for ischemic stroke, but alter the response to acute ischemia. We focus on hypertension as a comorbidity and its effects on the cerebral circulation that alters the pathophysiology of ischemic stroke and should be considered in guiding future therapeutic strategies.
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Affiliation(s)
- Marilyn J Cipolla
- 1 Department of Neurological Sciences, University of Vermont Larner College of Medicine, Burlington, VT, USA
| | - David S Liebeskind
- 2 Neurovascular Imaging Research Core and Stroke Center, Department of Neurology, University of California at Los Angeles, Los Angeles, CA, USA
| | - Siu-Lung Chan
- 1 Department of Neurological Sciences, University of Vermont Larner College of Medicine, Burlington, VT, USA
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Lin C, Wu X, Zhou Y, Shao B, Niu X, Zhang W, Lin Y. Maternal high-fat diet programs cerebrovascular remodeling in adult rat offspring. J Cereb Blood Flow Metab 2018; 38:1954-1967. [PMID: 28914129 PMCID: PMC6259319 DOI: 10.1177/0271678x17731956] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Maternal environmental factors such as diet have consequences on later health of the offspring. We found that maternal high-fat diet (HFD) exposure renders adult offspring brain more susceptible to ischemic injury. The present study was further to investigate whether HFD consumption during rat pregnancy and lactation influences the cerebral vasculature in adult male offspring. Besides the endothelial damage observed in the transmission electron microscopy, the MCAs of offspring from fat-fed dams fed with control diet (HFD/C) also displayed increased wall thickness and media/lumen ratio, suggesting that cerebrovascular hypertrophy or hyperplasia occurs. Moreover, smaller lumen diameter and elevated myogenic tone of the MCAs over a range of intralumenal pressures indicate inward cerebrovascular remodeling in HFD/C rats, with a concomitant increase in vessel stiffness. More importantly, both wire and pressure myography demonstrated that maternal HFD intake also enhanced the MCAs contractility to ET-1, accompanied by increases in ET types A receptor (ETAR) but not B (ETBR) density in the arteries. Furthermore, ETAR antagonism but not ETBR antagonism restored maternal HFD-induced cerebrovascular dysfunction in adult offspring. Taken together, maternal diet can substantially influence adult offspring cerebrovascular health, through remodeling of both structure and function, at least partially in an ET-1 manner.
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Affiliation(s)
- ChengCheng Lin
- 1 Department of Surgery Laboratory, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - XiaoYun Wu
- 2 Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - YuLei Zhou
- 2 Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Bei Shao
- 2 Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - XiaoTing Niu
- 2 Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - WanLi Zhang
- 2 Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - YuanShao Lin
- 2 Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Hardigan T, Abdul Y, Ergul A. Linagliptin reduces effects of ET-1 and TLR2-mediated cerebrovascular hyperreactivity in diabetes. Life Sci 2016; 159:90-96. [PMID: 26898123 PMCID: PMC4988948 DOI: 10.1016/j.lfs.2016.02.067] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 02/12/2016] [Accepted: 02/16/2016] [Indexed: 12/12/2022]
Abstract
AIMS The anti-hyperglycemic agent linagliptin, a dipeptidyl peptidase-4 inhibitor, has been shown to reduce inflammation and improve endothelial cell function. In this study, we hypothesized that DPP-IV inhibition with linagliptin would improve impaired cerebral blood flow in diabetic rats through improved insulin-induced cerebrovascular relaxation and reversal of pathological cerebrovascular remodeling that subsequently leads to improvement of cognitive function. MAIN METHODS Male type-2 diabetic Goto-Kakizaki (GK) and nondiabetic Wistar rats were treated with linagliptin, and ET-1 plasma levels and dose response curves to ET-1 (0.1-100nM) in basilar arteries were assessed. The impact of TLR2 antagonism on ET-1 mediated basilar contraction and endothelium-dependent relaxation to acetylcholine (ACh, 1nM-1M) in diabetic GK rats was examined with antibody directed against the TLR2 receptor (Santa Cruz, 5μg/mL). The expression of TLR2 in middle cerebral arteries (MCAs) from treated rats and in brain microvascular endothelial cells (BMVEC) treated with 100nM linagliptin was assessed. KEY FINDINGS Linagliptin lowered plasma ET-1 levels in diabetes, and reduced ET-1-induced vascular contraction. TLR2 antagonism in diabetic basilar arteries reduced ET-1-mediated cerebrovascular dysfunction and improved endothelium-dependent vasorelaxation. Linagliptin treatment in the BMVEC was able to reduce TLR2 expression in cells from both diabetic and nondiabetic rats. CONCLUSIONS These results suggest that inhibition of DPPIV using linagliptin improves the ET-1-mediated cerebrovascular dysfunction observed in diabetes through a reduction in ET-1 plasma levels and reduced cerebrovascular hyperreactivity. This effect is potentially a result of linagliptin causing a decrease in endothelial TLR2 expression and a subsequent increase in NO bioavailability.
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Affiliation(s)
- Trevor Hardigan
- Department of Physiology, Augusta University, Augusta, GA, United States
| | - Yasir Abdul
- Department of Physiology, Augusta University, Augusta, GA, United States
| | - Adviye Ergul
- Department of Physiology, Augusta University, Augusta, GA, United States; Charlie Norwood Veterans Administration Medical Center, Augusta, GA, United States.
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Salazar J, Luzardo E, Mejías JC, Rojas J, Ferreira A, Rivas-Ríos JR, Bermúdez V. Epicardial Fat: Physiological, Pathological, and Therapeutic Implications. Cardiol Res Pract 2016; 2016:1291537. [PMID: 27213076 PMCID: PMC4861775 DOI: 10.1155/2016/1291537] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 03/02/2016] [Accepted: 04/03/2016] [Indexed: 12/20/2022] Open
Abstract
Epicardial fat is closely related to blood supply vessels, both anatomically and functionally, which is why any change in this adipose tissue's behavior is considered a potential risk factor for cardiovascular disease development. When proinflammatory adipokines are released from the epicardial fat, this can lead to a decrease in insulin sensitivity, low adiponectin production, and an increased proliferation of vascular smooth muscle cells. These adipokines move from one compartment to another by either transcellular passing or diffusion, thus having the ability to regulate cardiac muscle activity, a phenomenon called vasocrine regulation. The participation of these adipokines generates a state of persistent vasoconstriction, increased stiffness, and weakening of the coronary wall, consequently contributing to the formation of atherosclerotic plaques. Therefore, epicardial adipose tissue thickening should be considered a risk factor in the development of cardiovascular disease, a potential therapeutic target for cardiovascular pathology and a molecular point of contact for "endocrine-cardiology."
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Affiliation(s)
- Juan Salazar
- Endocrine and Metabolic Diseases Research Center, University of Zulia, Maracaibo 4004, Venezuela
| | - Eliana Luzardo
- Endocrine and Metabolic Diseases Research Center, University of Zulia, Maracaibo 4004, Venezuela
| | - José Carlos Mejías
- Endocrine and Metabolic Diseases Research Center, University of Zulia, Maracaibo 4004, Venezuela
| | - Joselyn Rojas
- Endocrine and Metabolic Diseases Research Center, University of Zulia, Maracaibo 4004, Venezuela
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Antonio Ferreira
- Endocrine and Metabolic Diseases Research Center, University of Zulia, Maracaibo 4004, Venezuela
- Internal Medicine Service, “Dr. Manuel Noriega Trigo” Hospital, San Francisco 4004, Venezuela
| | - José Ramón Rivas-Ríos
- Endocrine and Metabolic Diseases Research Center, University of Zulia, Maracaibo 4004, Venezuela
| | - Valmore Bermúdez
- Endocrine and Metabolic Diseases Research Center, University of Zulia, Maracaibo 4004, Venezuela
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The Association of Endothelin-1 with Markers of Arterial Stiffness in Black South African Women: The SABPA Study. JOURNAL OF AMINO ACIDS 2015; 2015:481517. [PMID: 26823980 PMCID: PMC4707353 DOI: 10.1155/2015/481517] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 11/26/2015] [Accepted: 12/01/2015] [Indexed: 12/20/2022]
Abstract
Background. Limited data exist regarding endothelin-1 (ET-1), a vasoactive contributor in vascular tone, in a population subjected to early vascular deterioration. We compared ET-1 levels and explored its association with markers of arterial stiffness in black and white South Africans. Methodology. This cross-sectional substudy included 195 black (men: n = 99; women: n = 95) and 197 white (men: n = 99; women: n = 98) South Africans. Serum ET-1 levels were measured as well as markers of arterial stiffness (blood pressure, pulse wave velocity, and arterial compliance). ET-1 levels were higher in black men and white women compared to their counterparts after adjusting for C-reactive protein. In both single and partial (adjusting for body mass index and gamma glutamyl transferase) regression analyses ET-1 correlated with age, interleukin-6, high density lipoprotein cholesterol, systolic blood pressure, pulse pressure, and pulse wave velocity in black women. In multivariate regression analyses the independent association of ET-1 with systolic blood pressure (Adj. R2 = 0.13; β = 0.28, p < 0.01) and pulse pressure (Adj. R2 = 0.11; β = 0.27, p < 0.01) was confirmed in black women only. ET-1 additionally associated with interleukin-6 in black women (p < 0.01). Conclusion. Our result suggests that ET-1 and its link with subclinical arteriosclerosis are potentially driven by low-grade inflammation as depicted by the association with interleukin-6 in the black female cohort.
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Unić D, Barić D, Brkić K, Planinc M, Jonjić D, Rudež I, Sutlić Ž. Off-pump myocardial revascularization attenuates endothelin-1 expression in systemic, pulmonary, and coronary circulation. Wien Klin Wochenschr 2014; 126:710-7. [PMID: 25398294 DOI: 10.1007/s00508-014-0664-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2013] [Accepted: 10/22/2014] [Indexed: 01/23/2023]
Abstract
OBJECTIVE The objective of this study was to evaluate the influence of cardiopulmonary bypass (CPB) on endothelin-1 (ET-1) expression in various circulation compartments in patients undergoing myocardial revascularization. METHODS A total of 30 patients were randomized to undergo myocardial revascularization with (CABG, n = 15) or without (OPCAB, n = 15) CPB. Samples were taken preoperatively, after establishing CPB and after CPB (CABG group), prior to and after revascularization (OPCAB group), and 6 and 24 h postoperatively. Values of ET-1 were compared between groups at all time points and correlated with postoperative cardioselective enzyme values and clinical parameters. RESULTS In OPCAB group, ET-1 levels did not significantly vary between time points. In CABG group, ET-1 levels were significantly elevated vs. baseline in arterial: ART-T2 vs. ART-T0 (1.83 ± 1.81 vs. 0.76 ± 1.07 fmol/mL, p = 0.05), pulmonary: SG-T2 vs. SG-T0 (2.70 ± 2.75 vs. 0.39 ± 0.28 fmol/mL, p < 0.001) and SG-T3 vs. SG-T0 (1.56 ± 0.28 vs. 0.39 ± 0.28 fmol/mL, p < 0.001), and coronary circulation CS-T2 vs. CS-T1 (1.12 ± 0.49 vs. 0.27 ± 0.09 fmol/mL, p = 0.01). ET-1 levels were significantly higher in CABG group in all vascular compartments: ART-T2 (1.83 ± 1.81 vs. 0.17 ± 0.16 fmol/mL, p = 0.02), ART-T4 (0.99 ± 0.56 vs. 0.24 ± 0.12 fmol/mL, p = 0.01), SG-T1 (0.59 ± 0.15 vs. 0.25 ± 0.13 fmol/mL, p = 0.01), SG-T2 (2.70 ± 2.75 vs. 0.30 ± 0.24 fmol/mL, p = 0.004), SG-T3 (1.56 ± 0.28 vs. 0.35 ± 0.31 fmol/mL, p < 0.001), SG-T4 (1.34 ± 0.11 vs. 0.34 ± 0.16 fmol/mL, p < 0.001), and CS-T2 (1.12 ± 0.49 vs. 0.12 ± 0.12 fmol/mL, p = 0.004). Coronary sinus ET-1 level after CPB (CS-T2) in CABG group correlated positively with troponin-I level 24 h postoperatively (r(2) = 0.802, p = 0.02) CONCLUSION: Off-pump myocardial revascularization attenuates ET-1 expression in all investigated vascular compartments. Elevated coronary ET-1 levels after CPB in CABG group correlate with troponin-I levels 24 h postoperatively.
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Affiliation(s)
- Daniel Unić
- Department of Cardiac and Transplant Surgery, Dubrava University Hospital, Av. G. Šuška 6, HR-10 000, Zagreb, Croatia,
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Cipolla MJ, Sweet JG, Gokina NI, White SL, Nelson MT. Mechanisms of enhanced basal tone of brain parenchymal arterioles during early postischemic reperfusion: role of ET-1-induced peroxynitrite generation. J Cereb Blood Flow Metab 2013; 33:1486-92. [PMID: 23778163 PMCID: PMC3790940 DOI: 10.1038/jcbfm.2013.99] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 04/30/2013] [Accepted: 05/10/2013] [Indexed: 12/14/2022]
Abstract
The contributions of vasoconstrictors (endothelin-1 (ET-1), peroxynitrite) and endothelium-dependent vasodilatory mechanisms to basal tone were investigated in parenchymal arterioles (PAs) after early postischemic reperfusion. Transient middle cerebral artery occlusion (tMCAO) was induced for 2 hours with 30 minutes reperfusion in male Wistar rats and compared with ischemia alone (permanent MCAO (pMCAO); 2.5 hours) or sham controls. Changes in lumen diameter of isolated and pressurized PAs were compared. Quantitative PCR was used to measure endothelin type B (ETB) receptors. Constriction to intravascular pressure ('basal tone') was not affected by tMCAO or pMCAO. However, constriction to inhibitors of endothelial cell, small- (SK) and intermediate- (IK) conductance, Ca(2+)-sensitive K(+) channels (apamin and TRAM-34, respectively) were significantly enhanced in PAs from tMCAO compared with pMCAO or sham. Addition of the ETB agonist sarafotoxin caused constriction in PAs from tMCAO but not from sham animals (21 ± 4% versus 3 ± 3% at 1 nmol/L; P<0.01) that was inhibited by the peroxynitrite scavenger FeTMPyP (5,10,15,20-tetrakis (N-methyl-4'-pyridyl) porphinato iron (III) chloride) (100 μmol/L). Expression of ETB receptors was not found on PA smooth muscle, suggesting that constriction to sarafotoxin after tMCAO was due to peroxynitrite and not ETB receptor expression. The maintenance of basal tone in PAs after tMCAO may restrict flow to the ischemic region and contribute to infarct expansion.
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Affiliation(s)
- Marilyn J Cipolla
- 1] Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont College of Medicine, Burlington, Vermont, USA [3] Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont, USA
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Coucha M, Li W, Ergul A. The effect of endothelin receptor A antagonism on basilar artery endothelium-dependent relaxation after ischemic stroke. Life Sci 2012; 91:676-80. [PMID: 22365958 DOI: 10.1016/j.lfs.2012.01.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2011] [Revised: 12/27/2011] [Accepted: 01/26/2012] [Indexed: 01/01/2023]
Abstract
AIMS Endothelin (ET) receptor A antagonism decreases neuronal damage in experimental models of stroke. Since large arteries like basilar artery contribute significantly to total cerebrovascular resistance and are major determinants of microvascular pressure, dysregulation of basilar artery function may worsen stroke injury. ET-1 is involved in the regulation of basilar constriction. However, whether stroke influences vasoreactivity of basilar artery and to what extent ET-1 contributes to basilar vascular dysfunction after stroke remained unknown. The goal of this study was to test the hypothesis that ET-1 impairs basilar artery vasorelaxation after ischemia/reperfusion (I/R) injury via activation of ET(A) receptor. MAIN METHODS Male Wistar rats were subjected to 3h middle cerebral artery occlusion (MCAO) and 21 h reperfusion. One group received ET(A) receptor antagonist atrasentan (5 mg/kg, i.p.) at reperfusion. At 24h, basilar arteries were isolated from control non-stroked, stroked and stroked+atrasentan-treated animals for vascular reactivity measurements using pressurized arteriograph. KEY FINDINGS Acetylcholine (Ach)-induced maximum relaxation (R(max)) was decreased in stroked animals as compared to non-stroked group and ET(A) antagonism partially restored it. There was also a trend for decreased EC(50) value for the antagonist treatment group indicating improved Ach sensitivity. SIGNIFICANCE These findings suggest that I/R not only affects vessels distal to the occlusion but also impairs relaxation of proximal large vessels. ET-1-mediated basilar artery dysfunction may contribute to neurovascular damage after stroke and early restoration of vascular function by ET receptor antagonism after I/R injury may offer a therapeutic strategy.
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Affiliation(s)
- Maha Coucha
- Department of Physiology, Georgia Health Sciences University, Augusta, GA 30912, United States
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Celebi H, Catakoglu AB, Kurtoglu H, Sener M, Hanavdelogullari R, Demiroglu C, Aytekin V, Aytekin S. The relation between coronary flow rate, plasma endothelin-1 concentrations, and clinical characteristics in patients with normal coronary arteries. CARDIOVASCULAR REVASCULARIZATION MEDICINE 2008; 9:144-8. [PMID: 18606377 DOI: 10.1016/j.carrev.2007.11.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2007] [Revised: 10/31/2007] [Accepted: 11/02/2007] [Indexed: 01/29/2023]
Abstract
BACKGROUND Coronary slow flow (CSF) is characterized by delayed opacification of epicardial arteries in the absence of occlusive disease. In the present study, we aimed to investigate the relation between coronary flow rate, plasma endothelin-1 (ET-1) concentrations, and clinical characteristics in patients with normal coronary arteries. METHODS The study population included 77 patients with angiographically normal coronary arteries who underwent coronary angiography on suspicion of ischemic heart disease due to typical chest pain or ischemic findings on treadmill exercise test or myocardial scintigraphy. Based on the Thrombolysis In Myocardial Infarction frame count (TFC), patients were grouped into those with normal coronary flow and those with slow coronary flow. RESULTS Forty-eight (61.5%) patients were found to have CSF. Plasma ET-1 concentrations were significantly higher with the presence of CSF (P=.03). There were significant differences between plasma ET-1 concentrations, and mean TFC, TFC for left anterior descending coronary artery (LAD), TFC for left circumflex coronary artery (CX), and TFC for right coronary artery separately in patients with and without CSF (P=.033, P<.001, P<.001, P<.001, and P<.001, respectively). Mean TFC, TFC for LAD, and TFC for CX, and ET-1 concentrations were significantly higher in smokers than in nonsmokers (P<.001, P<.001, P=.004, and P=.033, respectively). However, logistic regression analysis suggested that ET-1 concentration was not an independent determinant of CSF. CONCLUSIONS Although there is a significant relation between ET-1 concentrations and coronary flow rate, ET-1 concentrations are not sufficient to determine the presence of CSF. Smoking is strongly associated with CSF, TFC, and increased ET-1 concentrations.
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Affiliation(s)
- Huseyin Celebi
- Department of Cardiology, Florence Nightingale Hospital, Istanbul, Turkey
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14
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Yamaguchi O, Kaneshiro T, Saitoh SI, Ishibashi T, Maruyama Y, Takeishi Y. Regulation of coronary vascular tone via redox modulation in the alpha1-adrenergic-angiotensin-endothelin axis of the myocardium. Am J Physiol Heart Circ Physiol 2008; 296:H226-32. [PMID: 19028798 DOI: 10.1152/ajpheart.00480.2008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
We hypothesized that alpha(1)-adrenoceptor stimulation of cardiac myocytes results in the production of an endothelin (ET)-releasing factor that stimulates the coronary vasculature to release ET and, by manipulating the redox state of cardiac and vascular cells, may influence the extent of alpha(1)-adrenergic-ET-1 vasoconstriction. Dihydroethidium (DHE) and dichlorodihydrofluorescein (DCF) intensities were increased by phenylephrine stimulation in isolated rat cardiac myocytes, which were enhanced by the mitochondrial electron transport chain complex I inhibitor rotenone (DHE: 20.4 +/- 1.2-fold and DCF: 25.2 +/- 0.9-fold, n = 8, P < 0.01, respectively) but not by the NADPH oxidase inhibitor apocynin. Olmesartan, an angiotensin II type 1 receptor antagonist, and enalaprilate did not change DHE and DCF intensities by phenylephrine. Next, we measured the vasoconstriction of isolated, pressurized rat coronary arterioles (diameter: 74 +/- 8 microm) in response to supernatant collected from isolated cardiac myocytes. The addition of supernatant from phenylephrine-stimulated myocytes to a 2-ml vessel bath (n = 8 each) caused volume-dependent vasoconstriction (500 microl: -14.8 +/- 2.2%). Olmesartan and TA0201, an ET type A receptor antagonist, converted vasoconstriction into vasodilation (8.5 +/- 1.2% and 10.5 +/- 0.5%, P < 0.01, respectively) in response to supernatant from phenylephrine-stimulated myocytes, which was eliminated with catalase. Vasoconstriction was weakened using supernatant from phenylephrine with rotenone-treated myocytes. Treatment of arterioles with apocynin to myocyte supernatant converted vasoconstriction into vasodilation (7.8 +/- 0.8%, P < 0.01). These results suggest that alpha(1)-adrenergic stimulation in cardiac myocytes produces angiotensin I and H(2)O(2) and that angiotensin releases ET-1 through NADPH oxidase in coronary arterioles. Thus, coronary vasoconstriction via the alpha-adrenergic-angiotensin-ET axis appears to require redox-mediated signaling in cardiac and vascular cells.
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Affiliation(s)
- Osamu Yamaguchi
- First Dept. of Internal Medicine, Fukushima Medical Univ., 1 Hikarigaoka, Fukushima 960-1295, Japan
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15
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Chao HH, Liu JC, Lin JW, Chen CH, Wu CH, Cheng TH. Uric acid stimulates endothelin-1 gene expression associated with NADPH oxidase in human aortic smooth muscle cells. Acta Pharmacol Sin 2008; 29:1301-1312. [PMID: 18954524 DOI: 10.1111/j.1745-7254.2008.00877.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
AIM Recent experimental and human studies have shown that hyperuricemia is associated with hypertension and cardiovascular diseases. Elevated levels of endothelin-1 (ET-1) has been regarded as one of the most powerful independent predictors of cardiovascular diseases. For investigating whether uric acidinduced vascular diseases are related to ET-1, the uric acid-induced ET-1 expression in human aortic smooth muscle cells (HASMC) was examined. METHODS Cultured HASMC treated with uric acid, cell proliferation and ET-1 expression were examined. Antioxidant pretreatments on uric acid-induced extracellular signal-regulated kinases (ERK) phosphorylation were carried out to elucidate the redox-sensitive pathway in proliferation and ET-1 gene expression. RESULTS Uric acid was found to increase HASMC proliferation, ET-1 expression and reactive oxygen species production. The ability of both N-acetylcysteine and apocynin (1-[4-hydroxy-3-methoxyphenyl]ethanone, a NADPH oxidase inhibitor) to inhibit uric acid-induced ET-1 secretion and cell proliferation suggested the involvement of intracellular redox pathways. Furthermore, apocynin, and p47phox small interfering RNA knockdown inhibited ET-1 secretion and cell proliferation induced by uric acid. Inhibition of ERK by U0126 (1,4-diamino-2,3-dicyano- 1,4-bis[2-aminophenylthio]butadiene) significantly suppressed uric acid-induced ET-1 expression, implicating this pathway in the response to uric acid. In addition, uric acid increased the transcription factor activator protein-1 (AP-1) mediated reporter activity, as well as the ERK phosphorylation. Mutational analysis of the ET-1 gene promoter showed that the AP-1 binding site was an important cis-element in uric acid-induced ET-1 gene expression. CONCLUSION This is the first observation of ET-1 regulation by uric acid in HASMC, which implicates the important role of uric acid in the vascular changes associated with hypertension and vascular diseases.
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Allanore Y, Kahan A. Atteinte myocardique primitive de la sclérodermie systémique. Rev Med Interne 2007. [DOI: 10.1016/s0248-8663(07)80024-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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17
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Parrilli G, Manguso F, Orsini L, Coccoli P, Vecchione R, Terracciano L, De Luca N, Cirillo N, Abazia C, Budillon G, Marchesini G. Essential hypertension and chronic viral hepatitis. Dig Liver Dis 2007; 39:466-472. [PMID: 17369113 DOI: 10.1016/j.dld.2007.01.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2006] [Revised: 12/04/2006] [Accepted: 01/03/2007] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Both arterial hypertension and chronic hepatitis are common disorders. The relationship between arterial pressure and liver cirrhosis has been extensively studied, but no studies are available in chronic hepatitis (CH). Recently, a few studies have reported that treatment with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs), commonly used in arterial hypertension, reduce hepatic fibrosis in patients with viral CH and in nonalcoholic steatohepatitis. This study was aimed at comparing the evolution of post-viral CH in patients with/without concomitant essential hypertension. METHODS Two sets of observations were carried out: (a) a cross-sectional cohort study of 95 patients with viral CH, to compare the severity of histological and biochemical data at diagnosis, in relation to pharmacologically treated essential hypertension, and (b) a retrospective study with the observation of 254 patients with CH of viral etiology, followed up from 2 to 20 years, to establish the natural history of viral CH in relation to treated essential hypertension. RESULTS In the cross-sectional analysis, patients with treated hypertension had a significantly older age at diagnosis of CH (51.4 +/- 8.4 years vs. 46.2 +/- 12.2 in normotensive; P < 0.001) and histological evidence of less severe necro-inflammatory liver damage. ALT levels were also lower (109.8 +/- 62.5 U/L vs. 166.0+/-169.5 in normotensive; P < 0.001) as were endothelin-1 levels (0.74 +/- 0.97 vs. 1.77 +/- 1.51 fmol/mL; P < 0.001). The retrospective study confirmed an older age at diagnosis in patients with treated hypertension (48.7 +/- 9.8 vs. 41.9 +/- 11.8 years; P < 0.001) and lower death rates (2.2% vs. 11%; P < 0.05). CONCLUSIONS The evolution of post-viral CH seems to be less severe in subjects with essential hypertension, possibly in relation to treatment with antihypertensive drugs.
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Affiliation(s)
- G Parrilli
- Department of Clinical Medicine, Naples, Italy.
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Fahmy Elnoamany M, Abdelraouf Dawood A. Right Ventricular Myocardial Isovolumic Relaxation Time as Novel Method for Evaluation of Pulmonary Hypertension: Correlation with Endothelin-1 Levels. J Am Soc Echocardiogr 2007; 20:462-9. [DOI: 10.1016/j.echo.2006.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2006] [Indexed: 01/29/2023]
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Singh AD, Amit S, Kumar OS, Rajan M, Mukesh N. Cardioprotective effects of bosentan, a mixed endothelin type A and B receptor antagonist, during myocardial ischaemia and reperfusion in rats. Basic Clin Pharmacol Toxicol 2006; 98:604-10. [PMID: 16700825 DOI: 10.1111/j.1742-7843.2006.pto_405.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The present study evaluated the cardioprotective potential of bosentan, a mixed endothelin type A and B receptor antagonist, in the myocardial ischaemia-reperfusion model of myocardial infarction. Adult male wistar rats (175-225 g) were divided into three groups: sham operated, non-myocardial ischaemia-reperfusion (SHAM); saline-treated myocardial ischaemia-reperfusion control (CON); bosentan-treated myocardial ischaemia-reperfusion (BOS). All animals were anaesthetized and subjected to 40 min. occlusion of left anterior descending coronary artery followed by 120 min. of reperfusion. Saline or drug was administered to the CON or BOS group, respectively, 20 min. after the left anterior descending coronary artery occlusion. Haemodynamic parameters viz. systolic arterial pressure, diastolic arterial pressure and heart rate were recorded throughout the experimental period. Hearts were subsequently excised and processed for histopathological and infarct size evaluation and for biochemical estimation of cardiac specific enzyme creatine kinase-MB (CK-MB) and myocardial malondialdehyde, a lipid peroxidation marker. Myocardial ischaemic reperfusion resulted in severe myocardial injury, depression of haemodynamic function, significant increase in malondialdehyde levels and decline in CK-MB isoenzyme activity in the heart tissue. Administration of bosentan (3 mg/kg, intravenously) slightly improved haemodynamic effects, decreased myocardial oxygen consumption, significantly (P<0.01) attenuated the rise in malondialdehyde levels and loss of myocardial CK-MB isoenzyme activity compared to the CON group, whereas bosentan administration significantly reduced the percentage area of fiber loss and infarct area. It is therefore concluded that endothelin-1 may mediate myocardial damage produced by ischaemia and reperfusion and that dual blockade of endothelinA and endothelinB receptors may have potential as a mode of therapy for myocardial infarction.
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Affiliation(s)
- Arya Dharamvir Singh
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi-110 029, India.
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20
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Cheng MF, Yu HM, Ko BW, Chang Y, Chen MY, Ho TI, Tsai YM, Fang JM. Practical synthesis of potential endothelin receptor antagonists of 1,4-benzodiazepine-2,5-dione derivatives bearing substituents at the C3-, N1- and N4-positions. Org Biomol Chem 2006; 4:510-8. [PMID: 16446809 DOI: 10.1039/b514937a] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The expedient synthesis of various 1,4-benzodiazepine-2,5-dione compounds, particularly those having substituents at the C3-, N1- and N4-positions is achieved. The important features in these synthetic strategies include: (i) using the coupling reaction of isatoic anhydride with alpha-amino ester for direct construction of the core structure of 1,4-benzodiazepine-2,5-dione; (ii) using potassium carbonate as the base of choice for selective alkylation at the N1-site, while using lithiated 2-ethylacetanilide as the required base to furnish the N4-alkylation; and (iii) using 2-nitrobenzoyl chloride as a synthetic equivalent of anthranilic acid to facilitate the polyethylene resin-bound liquid-phase combinatorial synthesis. The prepared 1,4-benzodiazepine-2,5-dione compounds are evaluated for endothelin receptor antagonism by a functional assay that measures the inhibitory activity against the change of intramolecular calcium ion concentration induced by endothelin-1. The preliminary results indicate that 1,4-benzodiazepine-2,5-diones bearing two flanked aryl substituents at the N1- and N4-sites show better inhibitory activity than the corresponding unalkylated and N-monoalkylated compounds. A promising candidate, 1-benzyl-7-chloro-3-isopropyl-4-(3-methoxybenzyl)-1,4-benzodiazepine-2,5-dione (17b), exhibits an IC50 value in low nM range.
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Affiliation(s)
- Ming-Fu Cheng
- Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan
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21
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Merkus D, Brzezinska AK, Zhang C, Saito S, Chilian WM. Cardiac myocytes control release of endothelin-1 in coronary vasculature. Am J Physiol Heart Circ Physiol 2005; 288:H2088-92. [PMID: 15637126 DOI: 10.1152/ajpheart.00522.2003] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Alpha-adrenergic vasoconstriction in the coronary circulation is mediated through alpha-adrenoceptors on cardiac myocytes and subsequent release of endothelin, a very potent, long-lasting vasoconstrictor. Recent studies found that adult cardiac myocytes do not express the preproendothelin gene. Thus we hypothesized that alpha-adrenoceptor stimulation on the cardiac myocytes results in the production of an endothelin-releasing factor, which stimulates the coronary vasculature to produce endothelin. We tested this hypothesis by using an in vitro model in which isolated adult rat cardiac myocytes can be stimulated with an alpha-adrenoceptor agonist (phenylephrine). Their bathing fluid is then transferred to isolated coronary arterioles, and vasoactive responses are measured. To identify the source of endothelin, the endothelin-converting enzyme inhibitor phosphoramidon was added to either the myocytes or the isolated arterioles. Phenylephrine enhanced the vasoconstrictor properties of the myocyte bathing fluid. Administration of phosphoramidon (in either the presence or the absence of phenylephrine) to the myocytes had no effect on the vasoactive properties of the bathing fluid. In contrast, administration of phosphoramidon to the isolated arteriole before administration of the bathing fluid converted vasoconstriction to vasodilation, similar to the effect of the endothelin A receptor antagonist JKC-301, indicating that the endothelin is indeed produced by the coronary vasculature. Administration of the angiotensin type 1 receptor antagonist losartan to the vessel bath enhanced vasodilation to the bathing fluid of the phenylephrine-treated but not control myocytes. In conclusion, during alpha-adrenergic activation cardiac myocytes release a factor, probably angiotensin II, that stimulates the vascular production of endothelin. Although the physiological implications of this mechanism are not obvious, this may represent a protective mechanism that integrates neuronal vasoconstrictor mechanisms with myocardial metabolism, which minimizes periods of both coronary underperfusion and overperfusion.
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Affiliation(s)
- Daphne Merkus
- Experimental Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
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Abstract
BACKGROUND AND OBJECTIVES Pulmonary arterial hypertension (PHT) is a potentially fatal disease. The purpose of this article is to review the current knowledge of the role played by endothelin (ET) in PHT and the relevant drug regimens used in the treatment of this condition. METHODS A detailed search via MEDLINE (PubMed) was performed by using PHT and ET as the key terms. RESULTS PHT could be a primary or a secondary diagnosis associated with various heart and lung diseases. PHT appears during the late stage of systemic sclerosis and may complicate other systemic diseases such as systemic lupus erythematosus. The vascular endothelium and activation of various mediators and growth factors such as the ET system are thought to play a crucial role in the development of this condition. The pathologic process progresses very rapidly from vasoconstriction to widespread pulmonary vascular obstruction. The use of high doses of calcium channel blockers is of limited value. Life-long anticoagulant therapy is recommended for the treatment of PHT. Currently, the drug being used in PHT therapy is continuous central-venous prostacyclin infusion. Prostacyclin is a strong vasodilator with antiaggregate and antifibrotic properties and has the potential to reduce endothelial injury and to induce vasculature remodeling. This treatment results in improved functional status and increased life span. Unfortunately, its use is accompanied by various side effects, technical difficulties, and high cost. The role of other therapeutic modalities (inhaled prostacyclin, subcutaneous treprostinil, oral beraprost, sildenafil) in vascular remodeling, and the improvement in functional capacity and survival of patients with PHT, are currently under investigation. Bosentan, administered orally, is a recently developed active ET receptor antagonist. It is a promising new therapeutic tool in the treatment of PHT because of its potent vasodilator, antiproliferative, and vascular remodeling activity. CONCLUSIONS The revolutionary conceptual shift in understanding the pathogenesis of PHT from a vasoconstrictive process to a vasoproliferative one, has led to a modification in the treatment of this disease from the use of vasodilators to the use of drugs with antiproliferative and vascular remodeling activity. Until now, prostacyclin was the only drug of this type available for the treatment of PHT. ET blockade seems to be a reasonable and potential therapeutic option.
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Matz RL, Andriantsitohaina R. Age-related endothelial dysfunction : potential implications for pharmacotherapy. Drugs Aging 2003; 20:527-50. [PMID: 12749750 DOI: 10.2165/00002512-200320070-00005] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Aging per se is associated with abnormalities of the vascular wall linked to both structural and functional changes that can take place at the level of the extracellular matrix, the vascular smooth muscle and the endothelium of blood vessels. Endothelial dysfunction is generally defined as a decrease in the capacity of the endothelium to dilate blood vessels in response to physical and chemical stimuli. It is one of the characteristic changes that occur with age, independently of other known cardiovascular risk factors. This may account in part for the increased incidence of cardiovascular events in elderly people that can be reversed by restoring endothelial function. A better understanding of the mechanisms involved and the aetiopathogenesis of this process will help in the search for new therapeutic agents.Age-dependent alteration of endothelium-dependent relaxation seems to be a widespread phenomenon both in conductance and resistance arteries from several species. In the course of aging, there is an alteration in the equilibrium between relaxing and contracting factors released by the endothelium. Hence, there is a progressive reduction in the participation of nitric oxide and endothelium-derived hyperpolarising factor associated with increased participation of oxygen-derived free radicals and cyclo-oxygenase-derived prostanoids. Also, the endothelin-1 and angiotensin II pathways may play a role in age-related endothelial dysfunction. The use of drugs acting at different levels of these signalling cascades, including antioxidant therapy, lipid-lowering drugs and estrogens, seems to be promising.
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Affiliation(s)
- Rachel L Matz
- Biochemisches Institut, Fachbereich Humanmedizin, Justus Liebig Universität, Giessen, Germany
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24
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Wilasrusmee C, Ondocin P, Bruch D, Shah G, Kittur S, Wilasrusmee S, Kittur DS. Amelioration of cyclosporin A effect on microvasculature by endothelin inhibitor. Surgery 2003; 134:384-9. [PMID: 12947345 DOI: 10.1067/msy.2003.233] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND We have previously shown that endothelial injury by cyclosporin A (CyA) is associated with an increased endothelin-1 (ET-1) release. We now sought to determine, in an animal model of angiogenesis, if inhibiting the effect of ET-1 on endothelial cells (ECs) would reverse the CyA-mediated endothelial injury in an animal model of angiogenesis. METHODS An angiogenic mixture of Matrigel (0.5 ml), fibroblast growth factor (1 ng/ml), vascular endothelial growth factor (100 ng/ml), and heparin (64 unit/ml) was injected as a subcutaneous plug in the flank of C3H mice (n = 5). In experimental groups CyA (20 mg/ml), CyA, and BQ 123 (ET-A receptor antagonist), CyA and PD 142893 (ET-A and ET-B receptor antagonist), or CyA and ET-1 antibody were added to the angiogenic mixture. Angiogenesis in the mixture was quantified by modified planimetric point counting method in skin/Matrigel cross-sections stained with factor VIII to highlight endothelial neocapillaries. Mean +/- SD of angiogenic area was analyzed with analysis of variance and Bonferroni test. The survival curves obtained by Kaplan-Meier analysis were compared between the groups, and the statistical significance of survival and mortality rates was computed by log rank's and Fisher's exact test, respectively. RESULTS The mean +/- SD of angiogenic area in control animals (without CyA in the angiogenic mixture) was 56.76 +/- 4.2. CyA inhibited angiogenesis in the subcutaneous angiogenic plug. Adding CyA to the angiogenic mixture significantly reduced angiogenic area (5.33 +/- 1.4, P <.001) while vehicle for CyA had no such effect (56.33 +/- 3.8, P =.10). Polyclonal ET-1 antibody or PD 142893 ameliorated the effect of CyA, whereas BQ 123 did not. The mean angiogenic areas in animals with ET-1 antibody, PD 142893, or BQ 123 in the angiogenic mixture were 57.20 +/- 7.5 (P =.06), 46.00 +/- 11.5 (P = 1.0), 8.60 +/- 2.9 (P <.001), respectively. CONCLUSIONS Our data show that blocking ET-B receptors specifically ameliorates the microvascular injury to the neocapillaries in angiogenesis caused by CyA. Antiendothelin-1 antibody and ETR antagonist (PD 142893) could, therefore, reduce the ill effects of CyA on microvascular endothelium.
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Affiliation(s)
- Chumpon Wilasrusmee
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY 13210, USA
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Kenyon KW, Nappi JM. Bosentan for the treatment of pulmonary arterial hypertension. Ann Pharmacother 2003; 37:1055-62. [PMID: 12841819 DOI: 10.1345/aph.1c256] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE To describe the pharmacology, pharmacokinetics, efficacy, and safety of bosentan in the treatment of pulmonary arterial hypertension (PAH). DATA SOURCES A MEDLINE and Current Contents search (1966-June 2002) of the English-language literature was conducted to identify published dose-ranging, pharmacokinetic, pivotal efficacy trials and review articles of bosentan and endothelin antagonists. Additional references were identified from the bibliographies of the retrieved articles. DATA SYNTHESIS Bosentan is the first orally active, nonpeptide endothelin receptor antagonist approved by the Food and Drug Administration for use in patients with World Health Organization (WHO) functional class III and IV PAH. Titrated to a dose of 125 mg twice daily, bosentan produces pulmonary vasodilation, improving cardiopulmonary hemodynamics leading to better outcomes for patients. It is metabolized primarily by the hepatic system via the cytochrome P450 enzyme pathway and eliminated by biliary excretion. Bosentan is an inducer of the isoenzymes CYP3A4 and 2C9. It possesses a unique pharmacokinetic profile with a terminal elimination half-life of approximately 5 hours, yet steady-state plasma concentrations are not achieved for 3-5 days as a result of enhanced drug clearance and autoinduction following multiple daily dosing. The major adverse effects of bosentan are the potential for birth defects and hepatotoxicity. CONCLUSIONS The use of bosentan in patients with WHO functional class III and IV PAH is associated with improved exercise tolerance, cardiopulmonary hemodynamics, and increased time to clinical worsening when compared with placebo. It offers significant advantage in ease of administration and quality of life compared with epoprostenol therapy, with similar efficacy.
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Affiliation(s)
- Kenneth W Kenyon
- College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425-0132, USA
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26
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Chong AY, Blann AD, Lip GYH. Assessment of endothelial damage and dysfunction: observations in relation to heart failure. QJM 2003; 96:253-67. [PMID: 12651970 DOI: 10.1093/qjmed/hcg037] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Affiliation(s)
- A-Y Chong
- Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK
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