Effects of endothelin ET(A) receptor antagonism with PD 156707 on hemodynamics and renal vascular resistance in rabbits

The objective of this study was to determine the in vivo effectiveness of the selective endothelin ET(A) receptor antagonist PD 156707 {sodium 2-benzo[1,3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5- trimethoxy-benzyl)-but-2-enoate}. Effectiveness was defined by the ability of the compound to block increases in renal vascular resistance and mean arterial blood pressure induced by an intravenous bolus of 0.3 nmol/kg of human endothelin-1 in pentobarbital anesthetized rabbits. Different groups of rabbits received hour long intravenous infusions of PD 156707 at doses of 0.003, 0.01, 0.03 or 0.3 mg/kg per h. During baseline conditions, mean arterial blood pressure, heart rate, renal blood flow, and renal vascular resistance were similar among the groups. The intravenous bolus of endothelin-l significantly decreased mean arterial blood pressure (82 +/- 3 mmHg to 65 +/- 3 mmHg, P < 0.05) and increased renal vascular resistance (2.8 +/- 0.3 mmHg/ml per min to 9.2 +/- 1.1 mmHg/ml per min, P < 0.05) in untreated control animals. At doses of 0.3 and 0.03 mg/kg per h, PD 156707 virtually abolished endothelin-l induced increases in renal vascular resistance, but did not affect the endothelin-l induced decrease in mean arterial blood pressure. At 0.01 and 0.003 mg/kg per h, PD 156707 also inhibited endothelin-l induced increases in renal vascular resistance but the effects were less striking, leading to the conclusion that the minimum effective intravenous dose of the compound in rabbits is in the range of 0.01-0.03 mg/kg per h. The results of this study demonstrate that PD 156707 is an extremely potent and highly selective endothelin ET(A) receptor antagonist. In addition, this study demonstrates the utility of renal vascular resistance as an in vivo bioassay for evaluating the selective vascular effects of endothelin receptor antagonists in this species.