(Hypertension. 1995;25:818-822.)
© 1995 American Heart Association, Inc.
Articles |
Antihypertensive Actions of the Novel Nonpeptide Endothelin Receptor Antagonist SB 209670
From the Departments of Cardiovascular (S.A.D., M.E., G.Z.F., E.H.O.) and Renal (M.G.) Pharmacology and Medicinal Chemistry (J.D.E.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.
Abstract Indirect evidence has implicated endothelin-1 in the pathogenesis of hypertension. In the present study we examined such a role directly with SB 209670, a novel nonpeptide endothelin receptor antagonist. The antihypertensive and hemodynamic effects of SB 209670 were examined in conscious, unrestrained spontaneously hypertensive (SHR), normotensive Wistar-Kyoto (WKY), and renin-hypertensive rats. Sustained intravenous infusion of SB 209670 (10 µg · kg-1 · min-1 for 6 hours) produced a significant, reversible reduction in mean arterial pressure in SHR but not in WKY rats. The antihypertensive response to 10 µg · kg-1 · min-1 SB 209670 (~25 mm Hg reduction in blood pressure) was associated with bradycardia (16% decrease in heart rate) but only a minimal reduction (3%) in cardiac output, because stroke volume was elevated (by 15%). Therefore, the antihypertensive effect of SB 209670 resulted from a decrease (13%) in total peripheral resistance. A sustained antihypertensive effect could also be observed after intraduodenal administration of SB 209670 (3 mg/kg) in conscious SHR (reduction of ~35 mm Hg 5 hours after administration). SB 209670 (3 mg/kg intravenous bolus) did not alter the pressor response or tachycardia observed in pithed SHR after stimulation of thoracolumbar sympathetic outflow. SB 209670 was also antihypertensive in renin-hypertensive rats, lowering blood pressure to an extent similar to that observed in SHR. Thus, the data presented provide evidence to support a role for endothelin-1 in the pathophysiology of two animal models of hypertension.
Key Words: endothelins • hypertension, experimental • rats, inbred SHR • rats, inbred WKY • antihypertensive agents
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