Altered Endothelin Receptor Expression and Affinity in Spontaneously Hypertensive Rat Cerebral and Coronary Arteries

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Abstract

Background

Hypertension is associated with arterial hyperreactivity, and endothelin (ET) receptors are involved in vascular pathogenesis. The present study was performed to examine the hypothesis that ET receptors were altered in cerebral and coronary arteries of spontaneously hypertensive rats (SHR).

Methodology/Principal Findings

Cerebral and coronary arteries were removed from SHR. Vascular contraction was recorded using a sensitive myograph system. Real-time PCR and Western blotting were used to quantify mRNA and protein expression of receptors and essential MAPK pathway molecules. The results demonstrated that both ET _A and ET _B receptor-mediated contractile responses in SHR cerebral arteries were shifted to the left in a nonparallel manner with increased maximum contraction compared with Wistar-Kyoto (WKY) rats. In SHR coronary arteries, the ET _A receptor-mediated contraction curve was shifted to the left in parallel with an increased pEC ₅₀ compared with the arteries in WKY rats. There was no significant increase in ET _B receptor-mediated contraction in SHR coronary arteries. ET _A receptor mRNA and protein expression was increased in SHR cerebral arteries compared with the arteries in WKY rats. However, ET _A receptor mRNA and protein levels in coronary arteries and ET _B receptor protein levels in cerebral and coronary arteries remained unchanged in SHR compared with WKY rats. Meanwhile, phosphorylated ERK1/2 protein was significantly increased in SHR brain and heart vessels.

Conclusions/Significance

In SHR cerebral arteries, ET _A receptor expression was upregulated. ET _A receptor affinity was increased in coronary arteries, and ET _B receptor affinity was increased in cerebral arteries. The ERK1/2 activation may be involved in the receptor alterations.

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Most cited references 42

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Cloning and expression of a cDNA encoding an endothelin receptor.

H. Arai, Yusuke Hori, I Aramori … (2015)

Endothelins are a newly described peptide family consisting of three peptides (ET-1, ET-2 and ET-3) which are the most potent vasoconstrictive peptides known. They are crucial in the regulation of vascular smooth muscle tone. The diverse functions of endothelins are thought to be mediated by interaction with many different receptors coupled to the inositol phosphate/calcium ion messenger pathway. However, because of the structural resemblance of the three peptides, the presence and nature of multiple endothelin receptors remain to be elucidated. We report here the cloning of a complementary DNA encoding a bovine endothelin receptor, which has a transmembrane topology similar to that of other G protein-coupled receptors and shows specific binding, with the highest selectivity to ET-1 in animal cells transfected with the cloned cDNA. This receptor messenger RNA is widely distributed in the central nervous system and peripheral tissues, particularly in the heart and lung. Our results support the view that there are other receptor subtypes.

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Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease.

Markus P. Schneider, David Pollock, Erika Boesen (2006)

First identified as a powerful vasoconstrictor, endothelin has an extremely diverse set of actions that influence homeostatic mechanisms throughout the body. Two receptor subtypes, ET(A) and ET(B), which usually have opposing actions, mediate the actions of endothelin. ET(A) receptors function to promote vasoconstriction, growth, and inflammation, whereas ET(B) receptors produce vasodilation, increases in sodium excretion, and inhibit growth and inflammation. Potent and selective receptor antagonists have been developed and have shown promising results in the treatment of cardiovascular diseases such as pulmonary arterial hypertension, acute and chronic heart failure, hypertension, renal failure, and atherosclerosis. However, results are often contradictory and complicated because of the tissue-specific vasoconstrictor actions of ET(B) receptors and the fact that endothelin is an autocrine and paracrine factor whose activity is difficult to measure in vivo. Considerable questions remain regarding whether ET(A)-selective or nonselective ET(A)/ET(B) receptor antagonists would be useful in a range of clinical settings.

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Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study.

B Psaty, C D Furberg, L Kuller … (2001)

Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events. Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure. In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination, and all subsequent cardiovascular events were ascertained and classified. At baseline, 1961 men and 2941 women were at risk for an incident myocardial infarction or stroke. During follow-up that averaged 6.7 years, 572 subjects had a coronary event, 385 had a stroke, and 896 died. After adjustment for potential confounders, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure were directly associated with the risk of incident myocardial infarction and stroke. Only SBP was associated with total mortality. Importantly, SBP was a better predictor of cardiovascular events than DBP or pulse pressure. In the adjusted model for myocardial infarction, a 1-SD change in SBP, DBP, and pulse pressure was associated with hazard ratios (95% confidence intervals) of 1.24 (1.15-1.35), 1.13 (1.04-1.22), and 1.21 (1.12-1.31), respectively; and adding pulse pressure or DBP to the model did not improve the fit. For stroke, the hazard ratios (95% confidence intervals) were 1.34 (1.21-1.47) with SBP, 1.29 (1.17-1.42) with DBP, and 1.21 (1.10-1.34) with pulse pressure. The association between blood pressure level and cardiovascular disease risk was generally linear; specifically, there was no evidence of a J-shaped relationship. In those with treated hypertension, the hazard ratios for the association of SBP with the risks for myocardial infarction and stroke were less pronounced than in those without treated hypertension. In this population-based study of older adults, although all measures of blood pressure were strongly and directly related to the risk of coronary and cerebrovascular events, SBP was the best single predictor of cardiovascular events.

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Author and article information

Contributors

Joseph Najbauer: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 2 September 2013

Volume: 8

Issue: 9

Electronic Location Identifier: e73761

Affiliations

[1 ]Division of Experimental Vascular Research, Institute of Clinical Sciences in Lund, Lund University, Sweden

[2 ]Department of Pharmacology, Xi’an Jiaotong University College of Medicine, Xi’an, Shaanxi, People’s Republic of China

[3 ]Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, Shaanxi, People’s Republic of China

University of Pécs Medical School, Hungary

Author notes

* E-mail: lei.cao@ 123456med.lu.se

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: LC YXC CBX LE. Performed the experiments: LC. Analyzed the data: LC. Contributed reagents/materials/analysis tools: YXC LE. Wrote the manuscript: LC YXC LE.

Article

Publisher ID: PONE-D-13-18604

DOI: 10.1371/journal.pone.0073761

PMC ID: 3759417

PubMed ID: 24023902

SO-VID: a20fb21e-18da-41e5-a104-7fa963e81528

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 7 May 2013

Date accepted : 23 July 2013

Funding

This study was supported by the Swedish Research Council (Grant 5958, http://www.vr.se); the Swedish Heart-Lund Foundation (Grant 20070273, http://www.hjart-lungfonden.se); and the National Natural Science Foundation of China (Grant 30772566, http://www.nsfc.gov.cn/e_nsfc/desktop/zn/0101.htm). The funders had no role in study plan, data collection and analysis, decision to publish, or preparation of the manuscript.

Altered Endothelin Receptor Expression and Affinity in Spontaneously Hypertensive Rat Cerebral and Coronary Arteries

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Abstract

Background

Methodology/Principal Findings

Conclusions/Significance

Related collections

PLOS Climate

Most cited references 42

Cloning and expression of a cDNA encoding an endothelin receptor.

Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease.

Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study.

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Contributors

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History

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