ANTIHYPERTENSIVE EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST BQ-123 IN CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS

Until recently, a role for endothelin-1 (ET-1) in the development and/or maintenance of hypertension has been based solely on indirect findings, e.g., elevated circulating levels of peptide. However, with the development of specific ET-1 receptor antagonists it is now possible to examine this relationship directly. The present study describes the hemodynamic effects of systemic infusions of BQ-123, a selective endothelin (ETA)-receptor antagonist, in conscious, freely moving spontaneously hypertensive (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Sustained infusions of BQ-123 (0.16-164 nmol/kg/min i.v. for 6 h) produced dose-dependent reductions in mean arterial pressure (approximately 30 mm Hg) in SHRs that were long-lasting (> 18 h) and reversible. Whereas cardiac output remained unaltered during BQ-123 infusion, the observed reduction in blood pressure was accompanied by a significant decrease (16%) in total peripheral resistance, indicating that the fall in blood pressure (an effect that was independent of the vehicle used and was not observed in WKY rats) was related primarily to peripheral vasodilation. Thus, the present study provides direct evidence showing that ET-1-receptor antagonists are effective antihypertensive (rather than hypotensive) agents and that endogenous ET-1 is involved in the pathophysiology of hypertension.