Evidence for vasoconstriction mediated by the endothelin-B receptor in domestic swine

Endothelin-1 (ET-1), a potent vasoactive and mitogenic peptide, has been im plicated in a number of cardiovascular diseases. including congestive heart failure, neointimal hyperplasia associated with restenosis, and hypertensi on. The vasoconstriction induced by ET-1 is thought to be mediated mainly b y its action on ETA receptors on vascular smooth muscle cells. Recent studi es have indicated that vasoconstriction also may be mediated by stimulation of an ETB-receptor subtype. Increased use of the pig as a cardiovascular m odel prompted us to examine the receptor profile in this species using ABT- 627, a potent, nonpeptide antagonist of thr ETA receptor. The precursor to ET-1, big ET-1 (0.02 nmol/kg/min), was infused intravenously in domestic sw ine, resulting in a sustained increase in mean blood pressure of 38 +/- 3 m m Hg. After stabilization of the pressor response, ABT-627 (0.1-10 mu g/kg/ min) or vehicle was infused for 30 min. Whereas vehicle infusion had no app reciable effect, a dose-related reversal of the presser response to big ET- 1 (11-100%) was observed by the end of the ABT-627 infusion. Blood samples were assayed for plasma concentrations of ABT-627; peak levels ranged from 9 +/- 2 to 937 +/- 168 ng/ml. In a separate group of pigs, the highest dose of ABT-627 produced only a modest reversal of the hypertensive response to an infusion of angiotensin II (300 ng/kg/min). Additional results indicate that the vasoconstrictor effects produced by sarafotoxin 6C (0.03 and 0.3 nmol/kg), an agonist of the ETB receptor, are not blocked by treatment with ABT-627 (10 mu g/kg/min). However, complete blockade of the S6C response c ould be achieved using the ETB antagonist, A-192621 (0.33 mg/kg/min). Our r esults define the dose-response relation for the ETA-receptor antagonist AB T-627 in the vasculature of the domestic pig and suggest the presence of an ETB-receptor subtype that mediates vasoconstriction in this species.