Clearance receptors and endopeptidase 24.11: equal role in
natriuretic peptide metabolism in conscious sheep.
Charles, Christopher J., Eric A. Espiner, M. Gary Nicholls, A. Mark
Richards, Timothy G. Yandle, Andy Protter, Teddy Kosoglou.
Department of Medicine, Christchurch Hospital, Christchurch, NEW
ZEALAND, Scios Nova, Palo Alto, CA, USA, and Schering-Plough Research
Institute, Kenilworth, NJ, USA
APStracts 3:0065R, 1996.
While many studies have examined the effects of administering
natriuretic peptide receptor-C (NPR-C) ligands and endopeptidase
24.11 (EP 24.11) inhibitors on clearance and bioactivity of atrial
natriuretic peptide (ANP) none have systematically compared their
effects on the endogenous levels of both ANP and brain natriuretic
peptide (BNP) under physiological conditions. Accordingly, we
examined the hemodynamic, hormonal and renal actions of an EP 24.11
inhibitor, SCH 32615 and an NPR-C ligand, C-ANP4-23 both alone and in
combination, in eight normal conscious sheep. NPR-C blockade and EP
24.11 inhibition induce similar rises in plasma ANP, BNP and cyclic
GMP. Synergistic increments in plasma ANP, BNP and cyclic GMP
observed during combined administration are likely to be due to the
reduced clearance of C-ANP4-23 in the setting of EP 24.11 inhibition
leading to increased inhibition of the receptor pathway. Combined
administration was also associated with enhanced hemodynamic actions
and diuretic and natriuretic effects. Our findings show that both
enzymatic and receptor clearance pathways contribute equally to
natriuretic peptide clearance and induce potentially important
hemodynamic and renal effects in normal conscious sheep.
Received 22 September 1995; accepted in final form 15 February
1996.
APS Manuscript Number R594-5.
Article publication pending Am. J. Physiol. (Regulatory Integrative
Comp. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 13 March 96