Concomitant antagonism of endothelial and vascular smooth muscle cell ETB receptors for endothelin induces hypertension in the hamster.
In the vascular system, endothelin (ET) type B (ET(B)) receptors for ET-1 are located on endothelial and on venous and arterial smooth muscle cells. In the present study, we investigated the hemodynamic effects of chronic ET(B) receptor blockade at low and high doses in the Syrian Golden hamster. After 16 days of gavage with A-192621 (0.5 or 30 mg.kg(-1).day(-1)), a selective ET(B) receptor antagonist, hamsters were anesthetized with a mixture of ketamine and xylazine (87 and 13 mg/kg im, respectively), and basal mean arterial blood pressure (MAP) and pressor responses to exogenous ET-1 were evaluated. The lower dose of A-192621 (0.5 mg.kg(-1).day(-1)) did not modify basal MAP, whereas the higher dose (30 mg.kg(-1).day(-1)) increased MAP and plasma ET levels. Radio-telemetry recordings confirmed the increase in MAP induced by the higher dose of A-192621 in conscious hamsters. On the other hand, although the lower dose of A-192621 was devoid of intrinsic pressor effects, it markedly reduced the transient hypotensive phase induced by intravenously injected IRL-1620, a selective ET(B) receptor agonist. Finally, A-192621 (0.5 mg.kg(-1).day(-1)) alone or A-192621 (30 mg.kg(-1).day(-1)) + atrasentan (6 mg.kg(-1).day(-1)), a selective ET(A) receptor antagonist, potentiated the pressor response to exogenous ET-1. Our results suggest that, in the hamster, ET(B) receptors on vascular smooth muscle cells are importantly involved in the clearance of endogenous ET-1, whereas the same receptor type on the endothelium is solely involved in the vasodilatory responses to the pressor peptide. Blockade of endothelial and vascular smooth muscle cell ET(B) receptors triggers a marked potentiation of ET(A)-dependent increases in systemic resistance.
Honoré
Jean-Claude
JC
Department of Pharmacology, Faculty of Medicine and Health Sciences. Université de Sherbrooke, 3001 12th Ave. North, Sherbrooke, PQ, Canada J1H 5N4.
Fecteau
Marie-Hélène
MH
Brochu
Isabelle
I
Labonté
Julie
J
Bkaily
Ghassan
G
D'Orleans-Juste
Pedro
P
D000758:Anesthesia; D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D003243:Consciousness; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism
C120508:A 192621; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C074308:sovateltide; D000077868:Atrasentan