Comparison of the Effects of Selective Endothelin ETimage and ETimage Receptor Antagonists in Congestive Heart Failure

Objectives. This study was designed 1) to determine the extent to which endogenous endothelin (ET) affects hemodynamic, hormonal and body fluid balance through ETimage and ETimage receptors in congestive heart failure (CHF); and 2) to assess the therapeutic benefits and adverse effects of ET receptor antagonists for ETimage and ETimage on cardiorenal and neurohormonal variables. Background. ET has two receptors, ETimage and ETimage, both of which are distributed in various tissues and cells. In vascular beds, ETimage receptors mediate vasoconstriction, whereas ETimage receptors mediate vasorelaxation. However, ETimage receptors also exist in smooth muscle and mediate vasoconstriction. Methods. We administered either the ETimage receptor antagonist FR139317 (FR [n = 8], 1 and 10 mg/kg body weight) or the ETimage receptor antagonist RES-701-1 (RES [n = 8], 0.2 and 1.5 mg/kg) to dogs with CHF induced by rapid ventricular pacing. The effects of both antagonists on cardiorenal and hormonal functions were studied. Results. FR decreased cardiac pressures and the plasm atrial natriuretic peptide (ANP) level and increased cardiac output (CO). Urinary flow rate and urinary sodium excretion increased in association with an increase in the glomerular filtration rate and renal plasm flow (RPF). In contrast, RES increased cardiac pressures and decreased CO. It also decreased the plasm aldosterone level and RPF. Neither antagonist affected plasm norepinephrine levels. Conclusions. Endogenous ETs increase cardiac pressures and the retention of body fluid through ETimage receptors in CHF. The vasodilative action through ETimage receptors is overall functionally more important than the constrictive action through ETimage receptors. ETs may regulate the secretion of ANP and aldosterone. Our findings suggest that selective ETimage receptor antagonists have potential therapeutic benefits affecting both hemodynamic variables and diuresis, whereas ETimage receptor antagonists have adverse hemodynamic effects, with the possibility of preventing fluid retention through suppression of aldosterone secretion in dogs with CHF.