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 concentration is increased in patients with heart failure. The purpose of this 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 ligation. Rats with left ventricular end-diastolic pressures >15 mm Hg were considered to have chronic heart failure (CHF), while the others were 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 groups. There were no significant increases in big ET-1 concentrations, suggesting an increased conversion of ET-1 from big ET-1 in the CHF group. 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 increased over time. Furthermore, bosentan had an additive effect to the angiotensin-converting enzyme inhibitor cilazapril. Conclusions Endothelin plays a role in the maintenance of blood pressure in CHF rats, as evidenced by the significant reduction in mean arterial pressure after oral administration of bosentan. Therefore, endothelin antagonists may be useful therapeutic agents in the treatment of CHF.