SHORT-TERM HEMODYNAMIC-EFFECTS OF ENDOTHELIN RECEPTOR BLOCKADE IN DOGS WITH CHRONIC HEART-FAILURE

Background Plasma endothelin levels are increased in heart failure and may contribute to the increased peripheral vasoconstriction that char acterizes this disease state. In the present study, we examined the ef fects of intravenous bosentan, a nonpeptide, competitive endothelin-l receptor antagonist, on hemodynamics in dogs with chronic heart failur e. Methods and Results Chronic heart failure was produced in 11 dogs b y multiple sequential intracoronary microembolization. At the time of study, left ventricular (LV) ejection fraction was 25+/-2%. Hemodynami c and echocardiographic measurements were made at baseline and at 15, 30, and 60 minutes after a bolus injection of bosentan (10 mg/kg). Bos entan had no significant effect on heart rate or mean aortic blood pre ssure. At 60 minutes, bosentan reduced LV end-diastolic pressure (17+/ -2 versus 11+/-2 mm Hg; P<.05) and systemic vascular resistance (3891/-379 versus 3071+/-346 dyne . s . cm(-5); P<.05) compared with baseli ne and increased cardiac output (2.63+/-0.29 versus 3.33+/-0.46 L/min; P<.05), peak rate of change of LV pressure during isovolumic contract ion and relaxation (1751+/-92 versus 2197+/-170 mm Hg/s; P<.05), and L V fractional shortening determined by echocardiography (30+/-2% versus 36+/-2%; P<.05). Conclusions Short-term intravenous bosentan reduced systemic vascular resistance and improved overall LV performance in do gs with chronic heart failure. These results suggest that endothelin-l receptor antagonists may be useful therapeutic agents in the treatmen t of heart failure.