title: Clearance receptors and endopeptidase 24.11: equal role in natriuretic peptide metabolism in conscious sheep.
abstract: Although 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-ANP-(4-23), 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 guanosine 3',5'-cyclic monophosphate (cGMP). Synergistic increments in plasma ANP, BNP, and cGMP observed during combined administration are likely to be due to the reduced clearance of C-ANP-(4-23) 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.
authors.affiliation: Department of Medicine, Christchurch Hospital, New Zealand.
authors.forename: C J
authors.initials: CJ
authors.lastname: Charles
authors.forename: E A
authors.initials: EA
authors.lastname: Espiner
authors.forename: M G
authors.initials: MG
authors.lastname: Nicholls
authors.forename: A M
authors.initials: AM
authors.lastname: Richards
authors.forename: T G
authors.initials: TG
authors.lastname: Yandle
authors.forename: A
authors.initials: A
authors.lastname: Protter
authors.forename: T
authors.initials: T
authors.lastname: Kosoglou
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000494:pharmacology; D006152:Cyclic GMP / Q000097:blood; D004151:Dipeptides / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects; D004338:Drug Combinations; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D009318:Natriuresis / Q000187:drug effects; D045283:Natriuretic Agents / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000097:blood; D010446:Peptide Fragments / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor / Q000502:physiology*; D012756:Sheep
chemical_list: D004151:Dipeptides; D004338:Drug Combinations; D045283:Natriuretic Agents; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C065367:atrial natriuretic factor (4-23)NH2, de-Gln(18)-de-Ser(19)-de-Gly(20,22)-de-Leu(21)-; D020097:Natriuretic Peptide, Brain; C062344:SCH 32615; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C; D006152:Cyclic GMP