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(Hypertension. 2002;39:93.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Combined Endopeptidase Inhibition and Adrenomedullin in Sheep With Experimental Heart Failure

Miriam T. Rademaker; Chris J. Charles; Garth J.S. Cooper; David H. Coy; Eric A. Espiner; Lynley K. Lewis; M. Gary Nicholls; A. Mark Richards

From the Christchurch Cardioendocrine Research Group, Department of Medicine, The Christchurch School of Medicine (M.T.R., C.J.C., E.A.E., L.K.L., M.G.N., A.M.R.), Christchurch, New Zealand; the Developmental Biology and Cancer Research Group, School of Biological Sciences, University of Auckland (G.J.S.C.), Auckland, New Zealand; and the Department of Medicine, Tulane University (D.H.C.), New Orleans, La.

Correspondence to Dr M.T. Rademaker, Department of Medicine, The Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand. E-mail miriam.rademaker{at}chmeds.ac.nz

Adrenomedullin and the natriuretic peptides exert vasodilator, natriuretic, and aldosterone-inhibitory actions, making augmentation of both systems potential therapeutic strategies in heart failure. Adrenomedullin and an endopeptidase inhibitor (SCH32615) were administered separately and in combination in 8 sheep with heart failure. Compared with the control condition, SCH32615 (5 mg bolus+1 mg/kg per hour infusion for 3 hours) reduced arterial pressure, left atrial pressure, and peripheral resistance and increased cardiac output, urinary volume, sodium, creatinine, and cAMP excretion. Plasma atrial and brain natriuretic peptide and cGMP concentrations were increased, whereas aldosterone tended to fall. Adrenomedullin (50 ng/kg per minute infusion for 3 hours) induced directionally similar but significantly greater changes in all hemodynamic variables compared with SCH32615. Urinary cAMP, sodium, and creatinine excretion rose, whereas urinary volume was maintained. Circulating adrenomedullin, cAMP, renin, and angiotensin II levels were increased, aldosterone was reduced, and natriuretic peptide levels were unchanged. Coadministration of adrenomedullin and SCH32615 produced hemodynamic effects greater than those achieved during adrenomedullin administration alone. Despite the larger falls in blood pressure, renal function (urinary volume, sodium excretion, and creatinine clearance) was improved to a level similar to that during SCH32615 administration. Elevations in plasma adrenomedullin and cAMP were greater than those during adrenomedullin administration alone, whereas increments in natriuretic peptides were similar to those during SCH32615 alone. Plasma renin and angiotensin II were increased and aldosterone levels were reduced. In conclusion, cotreatment with adrenomedullin and an endopeptidase inhibitor has beneficial hemodynamic and renal effects in heart failure beyond those of either agent separately.

Key Words: adrenomedullin • natriuretic peptides • enzyme • heart failure • natriuresis

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