ACUTE EFFECTS OF AN ENDOTHELIN-1 RECEPTOR ANTAGONIST BOSENTAN AT DIFFERENT STAGES OF HEART-FAILURE IN CONSCIOUS DOGS

Objective: Inhibition by endothelin antagonist is a potential therapy in heart failure. However, the effect of endothelin inhibition during the development of heart failure has not been evaluated. The goal of o ur study was to examine the acute hemodynamic effects of the mixed end othelin receptor antagonist bosentan in the control state and at diffe rent stages of heart failure induced by right ventricular pacing (250 bpm) in conscious dogs. Methods: Nine dogs were chronically instrument ed for the measurements of left ventricular pressure and its first der ivative (dP/dt), cardiac output, left ventricular regional wall thickn ess and aortic pressure. Bosentan (3 mg/kg, i.v. bolus) and placebo we re given at control, at 1 week of pacing (stage of left ventricular dy sfunction with perserved cardiac output) and at 3 weeks of pacing (pha se of heart failure with low cardiac output). Results: With the develo pment of heart failure, baseline plasma endothelin level increased pro gressively. Placebo did not induce hemodynamic and plasma endothelin c hanges during the 30 min recording at any stage. At control, bosentan did not change hemodynamics. At 1 and 3 weeks of pacing, bosentan did not modify left ventricular myocardial function indices but reduced me an arterial pressure (by 7+/-2 and 8+/-1 mm Hg respectively, p<0.005). Bosentan increased stroke volume at 3 weeks of pacing only. Conclusio ns: Endothelin inhibition by endothelin antagonist bosentan, decreases aortic pressure in both early left ventricular dysfunction and in hea rt failure in contrast with the control state. In the phase of heart f ailure with low cardiac output, bosentan increases stroke volume. In t he early left ventricular dysfunction, bosentan, by reducing arterial pressure, may limit the deterioration of cardiac function through a re duction of the workload imposed on the heart. (C) 1998 Elsevier Scienc e B.V. All rights reserved.