Significant roles of endothelin-A- and -B-receptors in renal function in congestive heart failure

Endothelin-1 (ET-1) not only causes potent vasoconstriction but also leads to fluid retention, both actions mediated by ETA- and/or ETB-receptors. Sel ective ETA- and combined ETA/ETB-receptor antagonists improve hemodynamics in heart failure; however, it is also important to evaluate the effects of these antagonists on urine output in heart failure. We administered an acut e dose of either the selective ETA-receptor antagonist FR139317 (FR, n = 5, 1 and 3 mg/kg) or the mixed ETA/ETB-receptor antagonist TAK-044 (TAK, n = 5, 1 and 3 mg/kg) to dogs with heart failure induced by rapid ventricular p acing. Renal hemodynamic and tubular functions were subsequently investigat ed. FR increased urinary excretion in association with increased renal plas ma flow (RPF) and glomerular filtration rate (GFR) with no significant chan ges in the fractional reabsorption of water distally (FRWD). In contrast, d espite increased GFR, TAK did not alter urine volume or RPF with significan tly increased FRWD. The increase of GFR and RPF induced by FR was significa ntly larger than that of TAK. These findings indicate that ETB-receptor act ivation may result in diuresis by renal vasodilatation and reduction of wat er reabsorption in the distal tubules and collecting ducts. Acute ETA-recep tor antagonism may therefore be more beneficial to diuresis than dual ETA/E TB-receptor inhibition in heart failure.