Mechanisms of the biphasic responses to endothelin-3 in dog coronary arteries.
1. Endothelin-3 (ET-3) elicited relaxations at low concentrations (up to 10(-8) M) and contractions at higher concentrations in dog isolated coronary arteries precontracted with prostaglandin F2 alpha (PGF2 alpha). The relaxation by ET-3 was not affected by endothelium denudation nor treatment with NG-nitro-L-arginine, but was abolished or reversed to a contraction by treatment with indomethacin and markedly suppressed by tranylcypromine, a PGI2 synthetase inhibitor, or diphloretin phosphate, a prostaglandin receptor antagonist. ET-1 produced only concentration-dependent contractions. 2. BQ-123, a new selective ETA receptor antagonist, caused relaxation of the strips contracted with ET-3 in a dose-dependent manner and prevented the ET-3-induced contraction but did not affect the contraction produced by PGF2 alpha. The relaxation caused by ET-3 was enhanced by treatment with BQ-123. 3. It is concluded that the relaxations elicited by ET-3 in dog coronary arteries are mediated via liberation of PGI2 by activation of non-ETA receptors, located in subendothelial tissues, possibly smooth muscle cells, whereas the peptide-induced contractions are mediated via ETA receptors.
Okamura
T
T
Department of Pharmacology, Shiga University of Medical Sciences, Ohtsu, Japan.
Matsumoto
T
T
Ikemoto
F
F
Toda
N
N
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D011464:Epoprostenol / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019335:Nitroarginine; D010456:Peptides, Cyclic / Q000494:pharmacology; D011121:Polyphloretin Phosphate / Q000494:pharmacology; D014191:Tranylcypromine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
D016232:Endothelins; D010456:Peptides, Cyclic; D019335:Nitroarginine; C013509:diphloretin phosphate; D014191:Tranylcypromine; D011121:Polyphloretin Phosphate; D001120:Arginine; D015237:Dinoprost; D011464:Epoprostenol; C072247:cyclo(Trp-Asp-Pro-Val-Leu)