Dual cardiovascular effects of endothelin-1 dissociated by BQ-153, a novel ETA receptor antagonist.
Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor peptide that elicited both vasodilator and vasoconstrictor responses in anesthetized pigs. Within 1.0 min after the first injection of ET-1 (0.4 nmol/kg, intravenously, i.v.) there was a transient decrease in mean arterial pressure (MAP 82 +/- 4 to 64 +/- 5 mm Hg; p < or = 0.01). The vasodepressor response was accompanied by reductions in left ventricular (LV) + dp/dtmax (1,834 +/- 104 to 1,493 +/- 87 mm Hg/s, p < or = 0.001), LV - dp/dt (2,600 +/- 149 to 1,865 +/- 136 mm Hg/s; p < or = 0.001) and cardiac output (CO 2.6 +/- 0.1 to 2.0 +/- 0.1 L/min, p < or = 0.001). The short (< 3.0 min) vasodilatory phase was followed by a prolonged (> 15 min) vasopressor response in which MAP (82 +/- 4 to 103 +/- 5 mm Hg; p < or = 0.001) and pulmonary arterial pressure (PAP 11 +/- 1 to 15 +/- 1 mm Hg; p < or = 0.01) increased. With each subsequent dose (0.4 nmol/kg i.v.) of ET-1, the initial vasodilatory component diminished progressively, only a monophasic vasoconstrictor response was observed after the fourth dose. The reductions in CO progressively decreased from 2.6 to 0.1 to 1.7 +/- 0.1 L/min (p < or = 0.001) by the end of the experiment. In contrast to the systemic circulation effects, ET-1 produced consistent and reproducible reductions in renal blood flow (RBF 105 +/- 16 to 21 +/- 6 mm Hg; p < or = 0.004) that lasted approximately 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Cirino
M
M
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada.
Battistini
B
B
Yano
M
M
Rodger
I W
IW
D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C072485:cyclo(sulfoalanyl-prolyl-valyl-leucyl-tryptophyl)