Effects of selective and non-selective endothelin receptor blockade on ET-1-induced pressor response in the hamster.
In order to assess the physiological balance existing between vasoconstrictor and vasodilator endothelin-B receptor actions associated with their dual locations (i.e. on vascular smooth muscle and endothelial cells), we investigated the effects of selective and non-selective endothelin receptor antagonists on endothelin-1-induced increase in blood pressure. Atrasentan (a selective endothelin-A receptor antagonist; 6 mg/kg) and A-192621 (a selective endothelin-B receptor antagonist; 0.03, 0.3, or 30 mg/kg) were administered intravenously to anaesthetized Syrian Golden hamsters, alone or in combination, to induce respectively selective or non-selective receptor antagonism. Atrasentan partially blocked the blood pressure response induced by endothelin-1 (0.5 nmol/kg), whereas a selective endothelin-B receptor antagonism potentiated this response, independently of the dose of A-192621. Interestingly, combination of the very low dose of A-192621 (which selectively blocked putatively endothelium-located endothelin-B receptors) with atrasentan, suppressed the protective effect previously observed with atrasentan alone. Nevertheless, combination of atrasentan with the two highest doses of A-192621 tested, dose-dependently reduced the response triggered by endothelin-1. Our results suggest that endothelial endothelin-B receptors are important to control the vascular reactivity to endothelin-1. Furthermore, our data suggest that the efficacy of a non-selective endothelin-A/ endothelin-B receptor antagonist relies upon its potency to block endothelin-B receptors in the hamster.
Honoré
Jean-Claude
JC
Department of Pharmacology, Medical School Université de Sherbrooke, Sherbrooke, Canada.
Fecteau
Marie-Hélène
MH
Wessale
Jerry L
JL
D'Orléans-Juste
Pedro
P
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D016232:Endothelins / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D008647:Mesocricetus; D010446:Peptide Fragments / Q000494:pharmacology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism
C120508:A 192621; D065130:Endothelin A Receptor Antagonists; 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