Short-term Hemodynamic Effects of Endothelin Receptor Blockade in Dogs With Chronic Heart Failure

Abstract

Background Plasma endothelin levels are increased in heart failure and may contribute to the increased peripheral vasoconstriction that characterizes this disease state. In the present study, we examined the effects of intravenous bosentan, a nonpeptide, competitive endothelin-1 receptor antagonist, on hemodynamics in dogs with chronic heart failure. Methods and Results Chronic heart failure was produced in 11 dogs by multiple sequential intracoronary microembolization. At the time of study, left ventricular (LV) ejection fraction was 25±2%. Hemodynamic and echocardiographic measurements were made at baseline and at 15, 30, and 60 minutes after a bolus injection of bosentan (10 mg/kg). Bosentan had no significant effect on heart rate or mean aortic blood pressure. 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 baseline 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 contraction and relaxation (1751±92 versus 2197±170 mm Hg/s; P <.05), and LV 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 dogs with chronic heart failure. These results suggest that endothelin-1 receptor antagonists may be useful therapeutic agents in the treatment of heart failure.