Effect of endothelin antagonists on the responses to prostanoid endothelium-derived contracting factor.
1. The effect of endothelin antagonists on endothelium-dependent contractions was studied in conditions of stimulated endothelium-derived contracting factor (EDCF) release and with exogenous activation of thromboxane A2-endoperoxide receptors in the rat aorta. 2. The incubation of aortic rings with N omega-nitro-L-arginine methyl ester (L-NAME) led to EDCF-mediated contraction upon stimulation with acetylcholine (24 +/- 3% of KCl contraction). When vessels were preincubated with bosentan, an endothelinA- and endothelinB-receptor antagonist, in addition to L-NAME, acetylcholine-induced contraction was reduced to 8 +/- 2% (P < 0.01) of KCl contractions. PD147953, a selective endothelinA-receptor antagonist, reduced the contraction to 14 +/- 4% (P < 0.05) of KCl contractions. 3. Bosentan preincubation produced a significant parallel rightward shift of the contractions to U46619, a selective thromboxane A2 receptor agonist. In contrast, PD147953 failed to exhibit any inhibitory effect on U46619 contractions. 4. These results suggest that endothelin antagonists inhibit EDCF-mediated contractions by blocking endothelinA receptors and that, in addition, bosentan antagonizes the direct stimulation of thromboxane A2 receptors.
Moreau
P
P
University Hospital, Bern, Switzerland.
Takase
H
H
Lüscher
T F
TF
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors*; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D017466:Receptors, Endothelin; D017482:Receptors, Thromboxane / Q000819:agonists; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; C091892:PD 147953; D011450:Prostaglandin Endoperoxides, Synthetic; D011453:Prostaglandins; D017466:Receptors, Endothelin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000077300:Bosentan