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Am J Physiol Heart Circ Physiol 273: H2372-H2379, 1997;
0363-6135/97 $5.00
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Vol. 273, Issue 5, H2372-H2379, November 1997

Clearance receptors and endopeptidase: equal role in natriuretic peptide metabolism in heart failure

Miriam Tessa Rademaker1, Christopher John Charles1, Teddy Kosoglou2, Andrew A. Protter3, Eric Arnold Espiner1, Michael Gary Nicholls1, and Arthur Mark Richards1

1 Department of Medicine, The Christchurch School of Medicine, Christchurch, New Zealand; 2 Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539; and 3 Scios, Mountain View, California 94043

The effects of separate and combined endopeptidase inhibition (by SCH-32615) and natriuretic peptide receptor C blockade [by C-ANP-(4---23)] on the clearance and bioactivity of atrial (ANP) and brain (BNP) natriuretic peptides was investigated in eight sheep with heart failure. SCH-32615 and C-ANP-(4---23) administered separately induced significant and proportionate dose-dependent rises in plasma ANP, BNP, and guanosine 3',5'-cyclic monophosphate (cGMP) levels. Associated with these changes were reductions in arterial pressure, left atrial pressure, and peripheral resistance and increases in cardiac output, urine volume, sodium excretion, and creatinine clearance. SCH-32615 induced greater diuresis and natriuresis than C-ANP-(4---23). Combined administration of SCH-32615 and C-ANP-(4---23) induced greater than additive rises in plasma ANP, BNP, and cGMP concentrations, with enhanced hemodynamic effects, diuresis, and natriuresis and reduced plasma aldosterone levels. In conclusion, we find that the enzymatic and receptor clearance pathways contribute equally to the metabolism of endogenous ANP and BNP in sheep with heart failure. Combined inhibition of both degradative pathways was associated with enhanced hormonal, hemodynamic, and renal effects and may have greater potential therapeutic value than either agent separately.

guanosine 3',5'-cyclic monophosphate; ventricular pacing; hemodynamics; natriuresis


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