title: EC 24.11 inhibition in man alters clearance of atrial natriuretic peptide.
abstract: Metabolic clearance and the biological effects of exogenous human atrial natriuretic factor (ANF) were assessed in two groups each of eight normal volunteers receiving 2-h iv infusions of ANF (2.5 pmol/kg.min) on the fifth day of dosing with the orally active inhibitor of endopeptidase 24.11, candoxatril (25 mg every 12 h in group 1 and 100 mg every 12 h in group 2), and placebo in balanced randomized, double blind, placebo-controlled, cross-over experiments. Although 4 days of pretreatment with the endopeptidase inhibitor did not affect basal plasma ANF, candoxatril enhanced mean ANF-induced increases in plasma ANF by 27 pmol/L (P = NS) and 42 pmol/L (P less than 0.002) in groups 1 and 2, respectively. Calculated MCRs for ANF were significantly reduced by both doses of candoxatril [group 1, 2.5 +/- 0.4 vs. 4.3 +/- 0.6 L/min (P less than 0.01); group 2, 2.3 +/- 0.4 vs. 5.6 +/- 0.8 L/min (P less than 0.001)]. ANF significantly enhanced urinary sodium excretion above preinfusion values in both study phases in both groups. Candoxatril significantly further augmented natriuresis in group 2 (P less than 0.01), but not group 1. Inulin clearance was minimally enhanced, and para-aminohippuran clearance was slightly decreased by candoxatril in both groups. Neither effect alone was statistically significant, but derived renal filtration fractions were significantly enhanced in both groups [group 1, 15.5 +/- 0.5% vs. 13.9 +/- 0.6% (P less than 0.01); group 2, 19.3 +/- 1.9% vs. 18.0 +/- 2.7% (P less than 0.01)]. Basal and stimulated cGMP concentrations in both plasma and urine were significantly enhanced by candoxatril in the two groups (P less than 0.001 and P less than 0.01, respectively, for combined data). Urinary ANF immunoreactivity was significantly enhanced by candoxatril in both groups (P less than 0.05 and P less than 0.01 in groups 1 and 2, respectively), with a more pronounced effect evident at the higher dose (P less than 0.01). These results show that chronic pretreatment with an endopeptidase inhibitor in normal man causes a dose-related reduction in the metabolic clearance of exogenous ANF, amplifies cGMP, and increases renal filtration and the natriuretic responses to infused ANF.
authors.affiliation: Department of Endocrinology, Princess Margaret Hospital, Christchurch, New Zealand.
authors.forename: A M
authors.initials: AM
authors.lastname: Richards
authors.forename: G
authors.initials: G
authors.lastname: Wittert
authors.forename: E A
authors.initials: EA
authors.lastname: Espiner
authors.forename: T G
authors.initials: TG
authors.lastname: Yandle
authors.forename: C
authors.initials: C
authors.lastname: Frampton
authors.forename: H
authors.initials: H
authors.lastname: Ikram
mesh_terms: D000328:Adult; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009994:Osmolar Concentration
chemical_list: D009320:Atrial Natriuretic Factor; D015260:Neprilysin