Effects of the Endothelin (ET) Receptor Antagonist BQ 123 on Initial and Delayed Vascular Responses Induced by ET-1 in Conscious, Normotensive Rats

Je, Bird; Tl, Waldron; Cr, Dorso; Mm, Asaad

doi:10.1097/00005344-199307000-00012

Cited by 7 publications

(3 citation statements)

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“…As in anesthetized rats, BQ-123 attenuates the pressor effect of ET-1 in conscious rats (12,14,47,69). BQ-123 also inhibits the decrease in plasma volume associated with ET-1 injection in conscious rats (47).…”

Section: Hemodynamicsmentioning

confidence: 90%

BQ‐123, A Selective Endothelin ET_A Receptor Antagonist

Moreland

1994

Cardiovascular Drug Reviews

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Key Words: BQ-123-Endothelin-Endothelin receptor antagonist.Endothelin (ET) is the most potent naturally occurring vasoconstrictor discovered to date. Yanagisawa et al. (193) introduced ET in a remarkably comprehensive manuscript which covered information from the molecular biology of the peptide to its activity in vivo. As is the case with many physiologically important peptides, ET is a proteolytic fragment of a larger protein. Repro-ET, a 203 amino acid precursor, is cleaved to big ET which also must undergo proteolysis to release the active 21 amino acid peptide, ET. ET, subsequently renamed ET-1, was quickly recognized as a member of a family of structurally and functionally similar peptides including the sarafotoxins (90). Two other members of the ET family, ET-2 and ET-3 were predicted from the isolation of genes related to ET-1 (71). All peptides in the ET family are composed of 21 amino acids with two intrachain disulfide bonds between the Cys residues at positions 1 and 15 and the Cys residues at positions 3 and 11 (Fig. 1).The ET isopeptides mediate their biological effects by binding to cell surface receptors. Two mammalian ET receptor isoforms have been cloned to date, ETA and ET,. Both receptor subtypes are G-protein coupled and contain seven membrane-spanning domains. The ETA receptor selectively binds ET-1 over ET-3 (4), whereas the ETB receptor binds ET-1 and ET-3 with similar affinity (150). A number of selective ETA and mixed ETA/ ET, receptor antagonists have been discovered that will be useful in elucidating the physiological and pathophysiological roles for ET (49,121). This review will be limited to describing the known effects of the first widely used selective ETA receptor antagonist, BQ-123. CHEMISTRYScreening natural products, including those in fermentation broths of microorganisms, is a method commonly used in the pharmaceutical industry to discover novel compounds

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Section: Hemodynamicsmentioning

confidence: 90%

BQ‐123, A Selective Endothelin ET_A Receptor Antagonist

Moreland

1994

Cardiovascular Drug Reviews

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“…for 20 min prior to and 30 min after sham surgery or clampingof the left renal artery for 30 min with an atraumatic vascular clamp. This dose of phosphoramidon inhibited renal and pressor effects of big ET-1 in anesthetized rats [16], This infusion rate of BQ-123 maximally inhibited an ET-l-induced pressor response in conscious, normotensive rats, but had no effect on the depressor response to ET-I [ 17], The total dose of BMS-182874 administered prior to ischemia (100 pmol/kg) and during reflow (150 pmol/kg) was greater than or equal to the dose (100 pmol/kg i.v.) nec essary to maximally inhibit the ET-l-induced pressor response in conscious, normotensive rats.…”

Section: Renal Function Studies 2 H Reflowmentioning

confidence: 82%

Comparison of a Novel ET<sub>A </sub>Receptor Antagonist and Phosphoramidon in Renal Ischemia

Bird¹,

Webb²,

Wasserman

et al. 1995

Pharmacology

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Infusion (0.46 µmol/kg/min) of the endothelin (ET)-converting-enzyme inhibitor, phosphoramidon (P), protected function and structure after 30 min renal ischemia in rats more than treatment (5 µmol/kg/min) with the ET_A receptor antagonist, BMS-182874 (B). The glomerular filtration rate (GFR; 0.7 ± 0.12 ml/min) and renal plasma flow (RPF) decreased approximately 40% at 2h reflow versus controls (C: 1.2 ± 0.12). B weakly protected the GFR (0.8 ± 0.07 ml/min); P restored it (1.1 ± 0.05). Both compounds reduced tubular injury at 2 h reflow; P ameliorated glomerular changes. At 24 h the GFR (0.6 ± 0.06 ml/min) and RPF decreased 67% versus C (1.8 ± 0.08). B did not protect the GFR and RPF. P partially protected the GFR (0.9 ± 0.07 ml/min) but not RPF, and reduced tubular injury. The results suggest that both ET_Aand non-ET_A receptors mediate ET-induced changes in ischemic renal failure.

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“…This was quickly countered by ET activation of ET A Rs, which mediate strong and long-lasting vessel constriction. An increase in vascular resistance without a concurrent decrease in cardiac output can set the stage for hypertension by increasing MAP, and thus systemic BP (Bird, Waldron, et al, 1993;Gasic, Wagner, et al, 1992;Haynes, Clarke, et al, 1991;Haynes, Ferro, et al, 1996;McMahon, Palomo, et al, 1991;Veniant, Clozel, et al, 1994). Interestingly, human pulmonary hypertension is one of the few diseases in which ETR pharmacological agents have improved clinical outcomes.…”

Section: Hypertension-mentioning

confidence: 99%

The heart as an extravascular target of endothelin-1 in particulate matter-induced cardiac dysfunction

Chan

Buckley

Farraj

et al. 2016

Pharmacology & Therapeutics

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Exposure to particulate matter air pollution has been causally linked to cardiovascular disease in humans. Several broad and overlapping hypotheses describing the biological mechanisms by which particulate matter exposure leads to cardiovascular disease have been explored, although linkage with specific factors or genes remains limited. These hypotheses may or may not also lead to particulate matter-induced cardiac dysfunction. Evidence pointing to autocrine/paracrine signaling systems as modulators of cardiac dysfunction has increased interest in the emerging role of endothelins as mediators of cardiac function following particulate matter exposure. Endothelin-1, a well-described small peptide expressed in the pulmonary and cardiovascular systems, is best known for its ability to constrict blood vessels, although it can also induce extravascular effects. Research on the role of endothelins in the context of air pollution has largely focused on vascular effects, with limited investigation of responses resulting from the direct effects of endothelins on cardiac tissue. This represents a significant knowledge gap in air pollution health effects research, given the abundance of endothelin receptors found on cardiac tissue and the ability of endothelin-1 to modulate cardiac contractility, heart rate, and rhythm. The plausibility of endothelin-1 as a mediator of particulate matter-induced cardiac dysfunction is further supported by the therapeutic utility of certain endothelin receptor antagonists. The present review examines the possibility that endothelin-1 release caused by exposure to PM directly modulates extravascular effects on the heart, deleteriously altering cardiac function.

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Effects of the Endothelin (ET) Receptor Antagonist BQ 123 on Initial and Delayed Vascular Responses Induced by ET-1 in Conscious, Normotensive Rats

Cited by 7 publications

References 0 publications

BQ‐123, A Selective Endothelin ET_A Receptor Antagonist

BQ‐123, A Selective Endothelin ET_A Receptor Antagonist

Comparison of a Novel ET<sub>A </sub>Receptor Antagonist and Phosphoramidon in Renal Ischemia

The heart as an extravascular target of endothelin-1 in particulate matter-induced cardiac dysfunction

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Effects of the Endothelin (ET) Receptor Antagonist BQ 123 on Initial and Delayed Vascular Responses Induced by ET-1 in Conscious, Normotensive Rats

Cited by 7 publications

References 0 publications

BQ‐123, A Selective Endothelin ETA Receptor Antagonist

BQ‐123, A Selective Endothelin ETA Receptor Antagonist

Comparison of a Novel ET<sub>A </sub>Receptor Antagonist and Phosphoramidon in Renal Ischemia

The heart as an extravascular target of endothelin-1 in particulate matter-induced cardiac dysfunction

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BQ‐123, A Selective Endothelin ET_A Receptor Antagonist

BQ‐123, A Selective Endothelin ET_A Receptor Antagonist