CHRONIC ORAL ENDOTHELIN TYPE-A RECEPTOR ANTAGONISM IN EXPERIMENTAL HEART-FAILURE

Endothelin-1 (ET-1) is a cardiovascular peptide that binds to two dist inct receptors, ETA and ETB, resulting in systemic and regional vasoco nstriction, alteration in sodium excretion, mitogenesis, and release o f other vasoactive peptides such as atrial natriuretic peptide (ANP). A role for ET-1 has been proposed in congestive heart failure (CHF) ba sed on the increase in circulating ET-1 in this cardiovascular disease state. The present study determined the cardiorenal and endocrine res ponses to chronic selective oral ETA antagonism in experimental CHF. T wo groups of conscious dogs underwent 21 days of pacing-induced CHF. T hese groups included a control untreated group (n=6) and a group that received ail orally active ETA receptor antagonist (A-127722, Abbott P harmaceuticals, 5mg/kg PO bid, n=6). Each group was studied at baselin e before the onset of CHF and after 14 and 21 days of CHF. Compared wi th the CHF control group, the ETA receptor antagonism group at 14 days of CHF showed lower mean arterial pressure and systemic vascular resi stance. Similarly, ETA receptor antagonism markedly attenuated the inc rease in circulating ANP despite similar atrial pressures. At 21 days of CHF, ETA receptor antagonism lowered pulmonary artery pressure, pul monary vascular resistance, and systemic vascular resistance in associ ation with a higher cardiac output. Plasma ANP remained suppressed. De spite the lower mean arterial pressure and circulating ANP in the ETA, receptor antagonist group, the absolute decrease in sodium excretion from baseline was less compared with the untreated CHF control group. The present investigation supports the conclusion that endogenous ET-1 participates in the systemic and pulmonary vasoconstriction, the elev ation of ANP, and the sodium retention that characterize this model of experimental CHF, suggesting a potential therapeutic role for ETA rec eptor antagonism in CHF.