Studies with Endothelin-3 and Endothelin-1 on Rat Blood Pressure and Isolated Tissues

Spokes, R.A.; Ghatei, Mohammad A.; Bloom, Stephen R.

doi:10.1097/00005344-198900135-00053

Cited by 51 publications

(16 citation statements)

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“…Indeed, the antagonism observed in vivo with 10 mg kg-' ( ± )-SB 209670 is indistinguishable from that observed with the same dose of (+)-SB 209670 endothelin-1 in hypertensive strains of rat w may be involved in the abnormal elevation o resistance (Douglas et al, 1992;19! 1994a (Spokes et al, 1989;Douglas & Hiley, 1991;Ohlstein & Douglas, 1993 are inhibited selectively by BQ-123 over a dose-range which does not attenuate the depressor actions of endothelin-l (Douglas et al, 1992). However, such a classification is now recognized as being an oversimplification.…”

Section: Resultsmentioning

confidence: 99%

In vivo pharmacological characterization of the non‐peptide endothelin receptor antagonist SB 209670

Douglas

Edwards

Elliott

et al. 1995

British J Pharmacology

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The aim of the present study was to assess the ability of SB 209670, a high affinity non‐peptide endothelin receptor antagonist (0.4 and 18 nm Kis at human cloned ETA and ETB receptors, respectively), to inhibit the haemodynamic actions of endothelin‐1 in vivo. Systemic administration of (±)‐SB 209670, given either as a bolus i.v. injection or as a continuous i.v. infusion, did not alter basal haemodynamic parameters in the anaesthetized rat. Infusion of (±)‐SB 209670 (10 μg kg−1 min−1) selectively inhibited the depressor and carotid vasodilator response to exogenous endothelin‐1: 100 μg kg−1 min−1 was required to inhibit significantly the biphasic haemodynamic actions of endothelin‐1. The haemodynamic actions of angiotensin II and calcitonin gene‐related peptide were unaltered by 100 μg kg−1 min−1 (±)‐SB 209670. Bolus i.v. administration of (±)‐SB 209670 (1 mg kg−1) selectively inhibited the depressor and carotid vasodilator actions of endothelin‐1: 10 mg kg−1 (±)‐SB 209670 was required to inhibit the secondary vasoconstrictor actions of endothelin‐1. (±)‐SB 209670 (10 mg kg−1) was also effective at antagonizing the pressor actions of endothelin‐1 in the conscious rat for up to 3 h after intraduodenal administration thereby demonstrating that the antagonist was bioavailable upon enteric administration. This dose of (±)‐SB 209670 did not alter basal haemodynamic parameters in the conscious rat. Thus, (±)‐SB 209670 is an effective endothelin receptor antagonist in vivo. Using the doses defined in this study, SB 209670 may, therefore, serve as a useful tool for understanding the role of endogenous endothelin‐1 in the control of cardiovascular function under both physiological and pathophysiological conditions.

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Section: Resultsmentioning

confidence: 99%

In vivo pharmacological characterization of the non‐peptide endothelin receptor antagonist SB 209670

Douglas

Edwards

Elliott

et al. 1995

British J Pharmacology

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“…These peptides also differ functionally, as vascular smooth muscle is responsive to ET-1 and ET-2 (6) but is 20-55 times less responsive to 10,11). In cells derived from other tissues, such as the kidney and brain, 13).…”

Section: Introductionmentioning

confidence: 99%

“…ET-1 and ET-2 differ from each other only at two amino acid positions, whereas ET-3 is different from both ET-1 and ET-2 at six positions (6). These peptides also differ functionally, as vascular smooth muscle is responsive to ET-1 and ET-2 (6) but is 20-55 times less responsive to ET-3 (8,10,11). In cells derived from other tissues, such as the kidney and brain, ET-1 and ET-3 are equipotent in their effects (12,13).…”

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confidence: 99%

Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor.

Lin

Kaji

Winkel

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

314

127

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By screening a cDNA library derived from the A10 rat vascular smooth muscle cell line for functional expression in COS cells, we have isolated a high-affinity receptor for endothelin 1 (Kd = 476 pM) and endothelin 2. The affinity of the cloned endothelin receptor for endothelin 3 is >100 times less in A10 cells and in a CHO cell line stably transformed by the endothelin receptor cDNA. The 426-amino acid receptor polypeptide has seven putative hydrophobic transmembrane domains and is presumed to be a member of the family of guanine nucleotide-binding regulatory (G) protein-coupled receptors. Microinjection of in vitro transcripts of the cloned cDNA into CHO cells confers a transient increase in intracellular calcium in response to endothelin 1, indicating that the receptor is functional and couples to the appropriate G protein(s). RNA analysis reveals high expression in rat lung and heart, tissues known to exhibit binding to iodinated endothelin 1.total number of such subtypes and their tissue distribution is unknown.ET binding is followed by an increase in intracellular Ca2+, which is preceded by an increase in inositol phosphates (for review, see refs. 14 and 15). Some work suggests that the actions of ET are sensitive to pertussis toxin and may be mediated by a guanine nucleotide-binding regulatory (G) protein (14, 16), whereas other work indicates that the response to ET is insensitive to pertussis toxin (17-19). Identification and characterization of ET-1 receptors should give insights into the details of signal transduction by ET-1.We report here the cloning, sequencing, ¶ and functional expression of a vascular smooth muscle receptor for ET-1. We establish definitively that it is a subtype that distinguishes ET-1 and ET-2 from ET-3, that it is a seven-transmembranedomain receptor of the G-protein-coupled family, and that it acts through increases in cell Ca2".Endothelin 1 (ET-1), a 21-amino acid peptide secreted by vascular endothelial cells, is one of the most potent vasoconstrictors yet discovered (1). In rats, injection of ET-1 causes prolonged increased mean arterial pressure (2, 3). A correlation has been shown between increased serum ET-1 levels and blood pressure in hypertensive patients (4, 5). These results suggest a possible pathologic role for circulating ET-1 in the etiology of essential hypertension and the potential therapeutic benefits of endothelin (ET) antagonists for the treatment of this disease.ET-1, endothelin 2 (ET-2), endothelin 3 (ET-3), and vasoactive intestinal contractor (or endothelin-,3) are members of a family of related mammalian peptides (6)(7)(8). The structures of these peptides are unique among hormones produced by mammalian species. All are 21-amino acid peptides with two disulfide bridges. The mammalian ETs closely resemble the sarafotoxin class of snake venoms, which produce coronary vasoconstriction (9). They also exhibit homology to a-scorpion toxin, one of a family of toxins known to bind to and activate the voltage-gated Na' channel. This similarity to inse...

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“…In vascular smooth muscle cells, both receptors are expressed 11,12 and mediate vasoconstriction. [11][12][13][14] Only the ET B receptors are found on endothelial cells, where these cause vasodilatation through the release of endothelium-derived vasodilators, such as nitric oxide (NO). 15 ET-1-induced vasoconstriction is predominantly mediated by the ET A receptor, but ET B receptors may contribute under some circumstances.…”

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confidence: 99%

Altered Peripheral Vascular Responses to Exogenous and Endogenous Endothelin–1 in Patients With Well–Compensated Cirrhosis

Helmy¹,

Jalan²,

Newby

et al. 2001

Hepatology

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Plasma endothelin concentrations are elevated in cirrhosis and correlate with disease severity. This study assessed forearm vascular responses to exogenous endothelin-1 (ET-1), and evaluated the contribution of endogenous ET-1 to the maintenance of basal peripheral vascular tone in patients with well-compensated cirrhosis (n ‫؍‬ 11) and matched healthy controls (n ‫؍‬ 8). Bilateral forearm blood flow (FBF) was measured at baseline and following unilateral, subsystemic, intrabrachial artery infusions of ET-1 (2 and 6 pmol/min); BQ-123, a selective ET A receptor antagonist (3 and 10 nmol/min); and BQ-788, a selective ET B receptor antagonist (0.3 and 1 nmol/min) using venous occlusion plethysmography. Baseline systemic hemodynamics and plasma ET-1 and big ET-1 concentrations were measured using electrical bioimpedance and radioimmunoassay, respectively. Patients and controls had similar baseline FBF, systemic hemodynamics, and plasma ET-1 and big ET-1 concentrations. In both groups, ET-1 and BQ-788 caused significant vasoconstriction (P < .001) and BQ-123 caused significant vasodilatation (P < .001). Compared with controls, cirrhotic patients had attenuated ET-1 responses (P < A hyperdynamic circulation characterized by low arterial pressure, high cardiac output, and low systemic vascular resistance is a feature of patients with advanced cirrhosis and portal hypertension. [1][2][3] This hyperdynamic circulation worsens with disease progression [4][5][6] and is accompanied by a reduced reactivity to vasopressor systems including the reninangiotensin and sympathetic nervous systems. These hemodynamic changes play a crucial role in the pathogenesis of portal hypertension and its complications, including variceal hemorrhage, ascites, and the hepatorenal syndrome. 7,8 Endothelin-1 (ET-1) is the most potent vasoconstrictor known, belonging to a 21-amino acid peptide family with a range of biological effects. 9-11 ET-1 was originally identified in the culture medium of porcine aortic endothelial cells 9,10 and is derived from a larger pre-pro-endothelin-1 (212 amino acids), which is cleaved by endopeptidases to produce big ET-1 (38 amino acids), which is then converted to ET-1 by specific endothelin-converting enzymes. [9][10] Molecular studies have, so far, identified 2 endothelin receptor subtypes in mammalian species: endothelin-A (ET A ) and endothelin-B (ET B ). In vascular smooth muscle cells, both receptors are expressed 11,12 and mediate vasoconstriction. [11][12][13][14] Only the ET B receptors are found on endothelial cells, where these cause vasodilatation through the release of endothelium-derived vasodilators, such as nitric oxide (NO). 15 ET-1-induced vasoconstriction is predominantly mediated by the ET A receptor, but ET B receptors may contribute under some circumstances. 16 Since 1991, many studies have reported increased plasma concentrations of ET-1 in patients with cirrhosis. [17][18][19][20][21][22][23][24][25][26] The mechanisms underlying the elevated ET-1 concentrations are unclear and do not appe...

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Studies with Endothelin-3 and Endothelin-1 on Rat Blood Pressure and Isolated Tissues

Cited by 51 publications

References 0 publications

In vivo pharmacological characterization of the non‐peptide endothelin receptor antagonist SB 209670

In vivo pharmacological characterization of the non‐peptide endothelin receptor antagonist SB 209670

Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor.

Altered Peripheral Vascular Responses to Exogenous and Endogenous Endothelin–1 in Patients With Well–Compensated Cirrhosis

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