S A Douglas1, M Gellai, M Ezekiel, E H Ohlstein. 1. Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Abstract
OBJECTIVE: To investigate the role of endothelin-1 in the pathogenesis of hypertension directly by using the selective endothelin subtype A-receptor antagonist BQ-123. METHODS: The antihypertensive and hemodynamic effects of sustained BQ-123 administration were examined in conscious, unrestrained spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto (WKY) rats and renin hypertensive rats. RESULTS: Sustained infusions of BQ-123 (0.16-164 nmol/kg per min, intravenously, for 6 h) produced dose-dependent reductions in mean arterial pressure in SHR, the maximal reduction being obtained with a dose of 16 nmol/kg per min. This reversible response was evident up to 14 h after the cessation of antagonist infusion. The antihypertensive response to a maximal dose of BQ-123 was associated with bradycardia, but only a minimal reduction in cardiac output (since the stroke volume was elevated) in the SHR. Therefore, the antihypertensive effect of BQ-123 resulted from a decrease in total peripheral resistance. In contrast, in WKY rats the infusion of the high dose (164 nmol/kg per min, intravenously for 6 h) produced a small but significant reduction in mean arterial pressure. BQ-123 did not alter the pressor response or tachycardia observed in pithed SHR following stimulation of the thoracolumbar sympathetic outflow. BQ-123 was also antihypertensive in renin hypertensive rats, lowering the blood pressure to an extent similar to that observed in SHR. CONCLUSION: The data presented indicate a role for endothelin in the pathophysiology of hypertension.
OBJECTIVE: To investigate the role of endothelin-1 in the pathogenesis of hypertension directly by using the selective endothelin subtype A-receptor antagonist BQ-123. METHODS: The antihypertensive and hemodynamic effects of sustained BQ-123 administration were examined in conscious, unrestrained spontaneously hypertensiverats (SHR), normotensive Wistar-Kyoto (WKY) rats and renin hypertensiverats. RESULTS: Sustained infusions of BQ-123 (0.16-164 nmol/kg per min, intravenously, for 6 h) produced dose-dependent reductions in mean arterial pressure in SHR, the maximal reduction being obtained with a dose of 16 nmol/kg per min. This reversible response was evident up to 14 h after the cessation of antagonist infusion. The antihypertensive response to a maximal dose of BQ-123 was associated with bradycardia, but only a minimal reduction in cardiac output (since the stroke volume was elevated) in the SHR. Therefore, the antihypertensive effect of BQ-123 resulted from a decrease in total peripheral resistance. In contrast, in WKY rats the infusion of the high dose (164 nmol/kg per min, intravenously for 6 h) produced a small but significant reduction in mean arterial pressure. BQ-123 did not alter the pressor response or tachycardia observed in pithed SHR following stimulation of the thoracolumbar sympathetic outflow. BQ-123 was also antihypertensive in renin hypertensiverats, lowering the blood pressure to an extent similar to that observed in SHR. CONCLUSION: The data presented indicate a role for endothelin in the pathophysiology of hypertension.