ROLE OF ENDOTHELIN IN THE MAINTENANCE OF BLOOD-PRESSURE IN CONSCIOUS RATS WITH CHRONIC HEART-FAILURE - ACUTE EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST RO-47-0203 (BOSENTAN)

Background Endothelin (ET) is a potent vasoconstrictor, and its concen tration is increased in patients with heart failure. The purpose of th is study was to investigate the role of endothelin in heart failure by use of a rat model. Methods and Results Experiments were performed on rats at 1 through 16 weeks after sham operation or coronary artery li gation. Rats with left ventricular end-diastolic pressures >15 mm Hg w ere considered to have chronic heart failure (CHF), while the others w ere considered to have uncomplicated myocardial infarction (MI). There were increased ET-1 concentrations in CHF rats at weeks 1 to 16 (Sham , 20+/-0.5 pg/mL, n=45; CHF, 31+/-2 pg/mL, n=50; P<.001) and transient increases in ET-3 concentrations at week 1 in both the MI and CHF gro ups. There were no significant increases in big ET-1 concentrations, s uggesting an increased conversion of ET-1 from big ET-1 in the CHF gro up. At weeks 2 through 8, oral administration of the mixed (ET(A) and ET(B)) endothelin receptor antagonist bosentan significantly decreased mean arterial pressure in conscious CHF rats, an effect that increase d over time. Furthermore, bosentan had an additive effect to the angio tensin-converting enzyme inhibitor cilazapril. Conclusions Endothelin plays a role in the maintenance of blood pressure in CHF rats, as evid enced by the significant reduction in mean arterial pressure after ora l administration of bosentan. Therefore, endothelin antagonists may be useful therapeutic agents in the treatment of CHF.