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(Hypertension. 1998;31:766-770.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Chronic Oral Endothelin Type A Receptor Antagonism in Experimental Heart Failure

Daniel D. Borgeson; J. Aaron Grantham; Eric E. Williamson; Andreas Luchner; Margaret M. Redfield; Terry J. Opgenorth; ; John C. Burnett, Jr

From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases and Department of Physiology, Mayo Clinic and Foundation, Rochester, Minn.

Correspondence to Daniel D. Borgeson, MD, Cardiorenal Research Laboratory, Guggenheim 915, Mayo Clinic and Foundation, 200 First St SW, Rochester, MN 55905. E-mail borgeson.daniel{at}mayo.edu

Abstract—Endothelin-1 (ET-1) is a cardiovascular peptide that binds to two distinct receptors, ET_A and ET_B, resulting in systemic and regional vasoconstriction, alteration in sodium excretion, mitogenesis, and release of other vasoactive peptides such as atrial natriuretic peptide (ANP). A role for ET-1 has been proposed in congestive heart failure (CHF) based on the increase in circulating ET-1 in this cardiovascular disease state. The present study determined the cardiorenal and endocrine responses to chronic selective oral ET_A antagonism in experimental CHF. Two groups of conscious dogs underwent 21 days of pacing-induced CHF. These groups included a control untreated group (n=6) and a group that received an orally active ET_A receptor antagonist (A-127722, Abbott Pharmaceuticals, 5mg/kg PO bid, n=6). Each group was studied at baseline before the onset of CHF and after 14 and 21 days of CHF. Compared with the CHF control group, the ET_A receptor antagonism group at 14 days of CHF showed lower mean arterial pressure and systemic vascular resistance. Similarly, ET_A receptor antagonism markedly attenuated the increase in circulating ANP despite similar atrial pressures. At 21 days of CHF, ET_A receptor antagonism lowered pulmonary artery pressure, pulmonary vascular resistance, and systemic vascular resistance in association with a higher cardiac output. Plasma ANP remained suppressed. Despite the lower mean arterial pressure and circulating ANP in the ET_A 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 elevation of ANP, and the sodium retention that characterize this model of experimental CHF, suggesting a potential therapeutic role for ET_A receptor antagonism in CHF.

Key Words: natriuretic peptides • endothelium • vasoconstriction • neurohormones • kidney

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