DUAL CARDIOVASCULAR EFFECTS OF ENDOTHELIN-1 DISSOCIATED BY BQ-153, A NOVEL ET(A) 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 less than or equal to 0.01). The vasodepressor response was accompanied by reductions in left ventricular (LV) + dp/dt(max) (1,834 +/- 104 to 1,493 +/- 87 mm Hg/s, p less than or equal to 0.001), LV - dp/dt (2,600 +/- 149 to 1,865 +/- 136 mm Hg/s; p less than or equal to 0.001) and cardiac output (CO 2.6 +/- 0.1 to 2.0 +/- 0.1 L/min, p less than or equal to 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 less than or equal to 0.001) and pulmonary arterial pressure (PAP 11 +/- 1 to 15 +/- 1 mm Hg; p less than or equal to 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 less than or equal to 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 less than or equal to 0.004) that lasted similar to 30 min. Infusion (0.5 mg/kg followed by 0.1 mg/kg/hr i.v.) of BQ-153 (cyclo-D-sulfalanine-L-pro-D-val-L-leu-D-trp-), a novel ET(A) receptor antagonist, blocked the presser effect of ET-1, but profound reductions in MAP (78 +/- 3 to 33 +/- 5 mm Hg; p less than or equal to 0.001), heart rate (HR 107 +/- 7 to 71 +/- 16 beats/min; p less than or equal to 0.02), and myocardial contractility (p less than or equal to 0.001) were observed. The reductions in RBF (93 +/- 12 to 33 +/- 9 ml/min, p less than or equal to 0.003) and CO (2.1 +/- 0.2 to 1.2 +/- 0.2 L/min, p less than or equal to 0.001) were maintained. Sarafotoxin S6c, an agonist at the ET(B) receptor, injected at the same nanomolar dose, mimicked the cardiovascular effects of ET-1 in the presence of BQ-153. There was a significant decrease from baseline in MAP (91 +/- 3 to 38 +/- 8 mm Hg, p less than or equal to 0.002), myocardial contractility (p less than or equal to 0.003), RBF (p less than or equal to 0.02), and CO (p less than or equal to 0.01). These data suggested the presence of an ET(B) receptor subtype which when stimulated had an inhibitory effect on myocardial performance and RBF. Our findings indicate the existence of two receptors involved in the cardiovascular responses to ET-1 in pigs: An ET(A) receptor is responsible for the prolonged vasoconstrictor response observed after administration of ET-1, and a non-ET(A) receptor, possibly ET(B), progressively became tachyphylactic with repeated exposure to ET-1. This receptor subtype, uncovered by BQ-153, appeared to mediate an inhibitory effect on cardiac contractility and RBF.