title: Roles of endothelin receptors in the regional and systemic vascular responses to ET-1 in the anaesthetized ganglion-blocked rat: use of selective antagonists.
abstract: 1. Endothelin-1 (ET-1) produces vasoconstriction, via activation of ETA and ETB receptors on vascular smooth muscle, and vasodilatation via ETB receptors on endothelial cells. Here we have used the ETA receptor-selective antagonist, BQ-123, the ETB receptor-selective antagonist, BQ-788 and the ETA/ETB receptor non-selective antagonist, PD 145065, to study the role of these receptors in mediating the haemodynamic changes induced by an infusion of ET-1 to the anesthetized ganglion-blocked rat. 2. Infusion of ET-1 (10 pmol kg-1 min-1) increased the mean arterial pressure (MAP) by 57.5 +/- 5.1 mmHg over 70 min. This pressor response was reduced by about 50% by coinfusion of BQ-123 (10 mmol kg-1 min-1), but was unaffected by either BQ-788 (10 nmol kg-1 min-1) or PD 145065 (10 nmol kg-1 min-1). 3. After infusion of ET-1 for 70 min the cardiac output had fallen from 102.6 +/- 11.3 to 55.7 +/- 7.6 ml min-1 and the total peripheral resistance had increased from 3.24 +/- 0.6 to 10.0 +/- 0.8 mmHg ml-1 min-1 (per 100g body weight). BQ-123 decreased the magnitudes of these changes whereas BQ-788 potentiated them. PD 145065 was without effect. 4. ET-1 increased the vascular resistances of all the organs studied except the brain and stomach. These changes were attenuated by BQ-123 in the kidneys, skin, adrenal glands and caecum and potentiated by BQ-788 in the kidneys, small intestine, large intestine and mesentery. PD 145065 had little effect on the individual tissues. 5. Thus, BQ-123, a selective ETA receptor antagonist, inhibits the pressor and vascular constrictor effects of ET-1 more actively than PD 145065. As BQ-788 potentiates some of the vasoconstrictor effects of ET-1 and increases the effects of ET-1 on total peripheral resistance, the predominant role of ETB receptors in the rat circulation is to limit the pressor effects of ET-1.
authors.affiliation: William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London.
authors.forename: G H
authors.initials: GH
authors.lastname: Allcock
authors.forename: T D
authors.initials: TD
authors.lastname: Warner
authors.forename: J R
authors.initials: JR
authors.lastname: Vane
mesh_terms: D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D005730:Ganglionic Blockers / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D018738:Hexamethonium / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008863:Microspheres; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D005730:Ganglionic Blockers; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D017466:Receptors, Endothelin; C082887:PD 145065; D018738:Hexamethonium; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)