Coronary vasoconstriction by endothelin-1 in anesthetized goats: role of endothelin receptors, nitric oxide and prostanoids.
The role of endothelin ETA and ETB receptors as well as of nitric oxide (NO) and prostanoids in the effects of endothelin-1 on the coronary circulation was studied in anesthetized goats. Where blood flow in the left circumflex coronary artery (coronary blood flow) (electromagnetically measured), systemic arterial pressure, left ventricle pressure and d P/dt, and heart rate were recorded. Endothelin-1 (0.01-0.3 nmol), intracoronarily injected, produced marked, dose-dependent reductions in basal coronary blood flow, ranging from 5% for 0.01 nmol to 75% for 0.3 nmol; 0.1 and 0.3 nmol endothelin-1 also reduced systolic ventricle pressure and dP/dt. The effects of endothelin-1 on coronary blood flow were diminished during intracoronary infusion of BQ-123 (cyclo-(D-Asp-Pro-D-Val-Leu-D-Trp). specific antagonist for endothelin ETA receptors. 2-16 nmol/min) in a dose-dependent way, but not during the infusion of BQ-788 (N-[N-[N-[(2.6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-1-leucyl]-1- (methoxycarbonyl)-D-tryptophyl]-D-norleucine monosodium, specific antagonist for endothelin ETB receptors. 2-4 nmol/min). IRL 1620 (Suc-[Glu9, Ala11.15]endothelin-1-(8-21), specific agonist for endothelin ETB receptors. 0.01-0.3 nmol), intracoronarily injected. slightly reduced basal coronary blood flow only when 0.1 and 0.3 nmol were applied (maximal reduction about 25%); 0.3 nmol IRL 1620 also reduced systolic ventricle pressure and dP/dt. The effects of IRL 1620 were not modified by BQ-123 or BQ-788. NG-nitro-1-arginine methyl ester (L-NAME, inhibitor of NO synthesis, 47 mg/kg by i.v. route) reduced resting coronary blood flow by 10% and increased mean systemic arterial pressure and systolic ventricle pressure by 22 and 20%. respectively, without changing systolic ventricle dP/dt and heart rate. With L-NAME, the reductions of coronary blood flow by endothelin-1 were potentiated (P < 0.05), and those by IRL 1620 were not changed (P > 0.05). Meclofenamate (cyclooxygenase inhibitor, 4-6 mg/kg by i.v. route) modified neither the basal values of hemodynamic variables nor the coronary effects of endothelin-1 and IRL 1620. Therefore, endothelin-1 produces marked coronary vasoconstriction, which may be mediated by endothelin ETA receptors, with no participation of endothelin ETB receptors. NO, but not prostanoids, may produce a basal coronary vasodilator tone and may inhibit endothelin-1-induced coronary vasoconstriction. Also, it is suggested that the coronary vasoconstriction by endothelin-1 may impair cardiac performance due to heart ischemia.
García
J L
JL
Deparatmento de Fisiología, Facultad de Medicina, Universidad Autónoma, Madrid, Spain.
Fernández
N
N
García-Villalón
A L
AL
Monge
L
L
Gómez
B
B
Diéguez
G
G
D000771:Anesthesia, Intravenous; D000778:Anesthetics, Dissociative; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D019332:Endothelin-1 / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology; D005260:Female; D006041:Goats; D006439:Hemodynamics / Q000187:drug effects; D007649:Ketamine; D009569:Nitric Oxide / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology*; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*
D000778:Anesthetics, Dissociative; D019332:Endothelin-1; D016232:Endothelins; D009842:Oligopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010880:Piperidines; D011453:Prostaglandins; D017466:Receptors, Endothelin; C074308:sovateltide; D009569:Nitric Oxide; C086539:BQ 788; D007649:Ketamine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)