Comparison of the acute effects of a selective endothelin ET and a mixedA ET / ET receptor antagonist in heart failureA

Objective: Both the selective endothelin (ET) ET receptor and mixed ET /ET receptor antagonists improve haemodynamics in A A B patients and experimental models with congestive heart failure (CHF) and reduce the mortality in CHF rats. However, it remains unclear which of these antagonists is superior in the treatment of CHF. In addition, there is little information as to whether these ET receptor antagonists contribute to the neuroendocrine regulation and body fluid balance. We therefore investigated the cardiorenal and neurohumoral benefits of selective ET receptor and mixed ET /ET receptor antagonists in CHF. Methods: We administered acutely A A B either the selective ET receptor antagonist FR139317 (FR, n56, 1 and 10 mg/kg) or the mixed ET /ET receptor antagonist TAK-044 A A B (TAK, n56, 1 and 3 mg/kg) to conscious dogs with CHF induced by rapid right ventricular pacing for ten days. Results: Both FR and TAK decreased the cardiac pressures and the plasma atrial natriuretic peptide level and increased the cardiac output and urinary sodium excretion. FR increased the urine flow rate in association with an increased glomerular filtration rate and renal plasma flow, while TAK reduced the plasma aldosterone level. Neither antagonist increased the plasma renin activity or norepinephrine levels. Conclusions: These findings suggest that a selective ET receptor antagonist has more beneficial acute effects on renal functions in CHF than a mixed A ET /ET antagonist. However, the long-term administration of a mixed ET /ET receptor antagonist would improve not only the A B A B haemodynamics but also prevent fluid retention by suppressing secretion of aldosterone during the treatment of chronic CHF.  1998 Elsevier Science B.V. All rights reserved.