ETA receptors mediate vasoconstriction, whereas ETB receptors clear endothelin-1 in the splanchnic and renal circulation of healthy men

Böhm, Felix; Pernow, John; Lindstrøm, Jonas Christoffer; Ahlborg, Gunvor

doi:10.1042/cs20020192

Cited by 30 publications

(21 citation statements)

References 14 publications

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“…4B). These results altogether indicate that ET A , but not ET B , is the predominant vasoconstrictor ET receptor in the mouse abdominal aorta, which concurs with reports on several rat as well as human vessels (5,8,12,21,22,25).…”

Section: Discussionsupporting

confidence: 93%

“…While ET B receptors present in the smooth muscle mediate vasoconstriction (13,14,24), those in the endothelial cell cause vasodilation via the release of endothelium-dependent relaxing factors, such as nitric oxide (NO) (12,17,23). However, it has been recently found that part of the depressor effect of ET B receptor may be related to the clearance of ET-1 in the plasma (3,5). In addition, ET A receptor has also been suggested to be functional in the endothelial cells (11,18,19).…”

mentioning

confidence: 97%

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Endothelin-1-induced responses in isolated mouse vessels: the expression and function of receptor types

Zhou¹,

Dirksen²,

Zweíer³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Mice have been increasingly used as models for investigating cardiovascular diseases. However, the responsiveness of mouse vasculature to endothelin (ET)-1 has not been clearly established. The goal of this study was to determine the role of ET receptors (ET(A) and ET(B)) in mouse vessels using isometric force measurements. Results showed that in the abdominal aorta ET-1 induced a concentration-dependent contraction (EC(50): 1.4 nM) with maximum reaching 89.5 +/- 4.9% (10 nM) of that induced by 60 mM K(+) [with nitric oxide synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME)]. However, in the thoracic aorta or the carotid artery, ET-1 was poorly effective. RT-PCR revealed that in the endothelium-denuded abdominal aorta, the PCR product for ET(B) receptors was very low compared with ET(A). Similarly in tissues treated with l-NAME, the ET(B) receptor-specific agonist sarafotoxin 6c (S6c; 100 nM) induced only a minimal contraction (<5%). Meanwhile, the ET(A) antagonist BQ-123 (1 microM) completely inhibited the maximum ET-1 (10 nM) contractile response. Furthermore, we found that in the abdominal aorta that had not been treated with l-NAME, ET-1-induced contraction significantly decreased. However, in such specimens, S6c was unable to induce any relaxation on phenylephrine-induced contraction. These results indicate that the role of ET receptors differs considerably among mouse vessels. In the abdominal aorta, ET(A) receptor mediates a potent vasoconstrictor response, whereas ET(B) has, if any, only a minimal functional presence. Also, our data suggest that ET-1 might involve a NOS-dependent vasodilation in the abdominal aorta, which remains to be further defined.

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 97%

Endothelin-1-induced responses in isolated mouse vessels: the expression and function of receptor types

Zhou¹,

Dirksen²,

Zweíer³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…The ET A receptor antagonist BQ‐123 was demonstrated to lower blood pressure acutely in CIH‐treated, but not sham, rats and to prevent CIH‐induced increases in arterial pressure . Together, these results indicate that the ET A receptor is the predominant receptor mediating ET‐induced vasoconstriction, which is consistent with reports from human vessels …”

Section: Introductionsupporting

confidence: 87%

Endothelin receptors in augmented vasoconstrictor responses to endothelin‐1 in chronic intermittent hypoxia

Guo

Tian

Wang

et al. 2013

Clin Exp Pharma Physio

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Chronic intermittent hypoxia (CIH) contributes to the development of cardiovascular diseases in patients with obstructive sleep apnoea. Many studies have shown an association between increased circulating endothelin (ET)-1 levels and CIH. The aim of the present study was to determine the role of ET receptors in altered aortic function in an animal model of CIH. Rats were subjected to CIH (Fi o2 9% for 1 min, repeated every 2 min for 8 h/day, 7 days/week) for 3 weeks. After 3 weeks, the rats were killed and their aortas retrieved for use in in vitro experiments (isometric force measurement), histological analysis, immunohistochemistry and western blotting. Aortas from rats subjected to CIH exhibited marked endothelial dysfunction and increased responsiveness to ET-1. Furthermore, CIH induced increased ET-1 and ETA receptor expression, whereas ETB receptor expression was decreased. Aortic contractile responses to ET-1 were inhibited by the ETA and ETB receptor antagonists BQ-123 and BQ-788, respectively. Acetylcholine-induced relaxation responses were significantly attenuated in aortas from rats subjected to CIH, whereas CIH had no significant effect on aortic responses to sodium nitroprusside. The results of the present study suggest that increased expression of ETA receptors, which mediate a potent vasoconstrictor response, plays an important role in the pathogenesis of CIH. In addition, decreased endothelial ETB receptor expression, which is associated with the functional decline of endothelium-dependent vasodilation, also contributes to the pathogenesis of CIH. It appears that the ETB receptor-induced buffering of ET-1 responsiveness is mediated via a nitric oxide-dependent mechanism.

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“…This receptor does not modulate the haemodynamic properties of Big ET‐2 as it is poorly converted in the pulmonary or systemic circulation in anaesthetized rabbits. This is supported by human in vivo studies done by Bohm et al . (2003), which showed that ET B functions as a clearance receptor and may modulate ET A ‐mediated vasoconstriction by altering the plasma concentration of ET‐1.…”

Section: Does Et‐2 Have a Separate Synthesis From Other Et Peptides?supporting

confidence: 78%

Endothelin‐2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer

Ling

Maguire

Davenport

2012

British J Pharmacology

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Endothelin-2 [ET-2; also known as vasoactive intestinal contractor (VIC), in rodents] differs from endothelin-1 (ET-1) by only two amino acids, and unlike the third isoform, endothelin-3 (ET-3), it has the same affinity as ET-1 for both ETA and ETB receptors. It is often assumed that ET-2 would mimic the actions of the more abundant ET-1 and current pharmacological interventions used to inhibit the ET system would also block the actions of ET-2. These assumptions have focused research on ET-1 with ET-2 studied in much less detail. Recent research suggests that our understanding of the ET family requires re-evaluation. Although ET-2 is very similar in structure as well as pharmacology to ET-1, and may co-exist in the same tissue compartments, there is converging evidence for an important and distinct ET-2 pathway. Specifically is has been demonstrated that ET-2 has a key role in ovarian physiology, with ET-2-mediated contraction proposed as a final signal facilitating ovulation. Furthermore, ET-2 may also have a pathophysiological role in heart failure, immunology and cancer. Comparison of ET-2 versus ET-1 mRNA expression suggests this may be accomplished at the level of gene expression but differences may also exist in peptide synthesis by enzymes such as endothelin converting enzymes (ECEs) and chymase, which may allow the two pathways to be distinguished pharmacologically and become separate drug targets. LINKED ARTICLESThis article is part of a themed section on Endothelin. To view the other articles in this section visit http://dx.doi. org/ 10.1111/bph.2013.168.issue-2 Abbreviations ECE-1, endothelin converting enzyme 1; ECE-2, endothelin converting enzyme 2; ELISA, enzyme-linked immunosorbent assay; HIFs, hypoxia-inducible factors; MEK1/2, mitogen-activated protein kinase kinase; MMP-2, matrix metallopeptidase 2; MMP-9, matrix metallopeptidase 9; NEP, neutral endopeptidase; PRKO, progesterone receptor knockout; PMA, phorbol 12-myristate 13 acetate; VIC, vasoactive intestinal contractor IntroductionThe existence of a peptidic endothelium-derived constricting factor was originally proposed in 1985 by Hickey et al. (Hickey et al., 1985) but was identified and named endothelin (ET) by colleagues in 1988 (Yanagisawa et al., 1988). The peptide was renamed ET-1 to reflect the subsequent discovery a year later of human genes encoding two further members of the family, ET-2 and ET-3 (Inoue et al., 1989). The ET peptides act by activating two G-protein couples receptors, ETA and ETB. (Davenport, 2002;Alexander et al., 2011) ET-3 is the only endogenous isoform that distinguishes between the two receptors, having the same affinity at ETB as ET-1 and ET-2 but, at physiological concentrations, has much lower or little affinity for ETA. The established dogma is that ET-2 has the same affinity for both ETA and ETB receptors as ET-1. It is often assumed that ET-2 would mimic the actions of the more abundant peptide, and current pharmacological interventions used to inhibit the ET system would also block the actions o...

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ETA receptors mediate vasoconstriction, whereas ETB receptors clear endothelin-1 in the splanchnic and renal circulation of healthy men

Cited by 30 publications

References 14 publications

Endothelin-1-induced responses in isolated mouse vessels: the expression and function of receptor types

Endothelin-1-induced responses in isolated mouse vessels: the expression and function of receptor types

Endothelin receptors in augmented vasoconstrictor responses to endothelin‐1 in chronic intermittent hypoxia

Endothelin‐2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer

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