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 < 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 < 0.01); group 2, 2.3 ± 0.4 vs. 5.6 ± 0.8 L/min (P < 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 < 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 < 0.01); group 2, 19.3 ± 1.9% vs. 18.0 ± 2.7% (P < 0.01)]. Basal and stimulated cGMP concentrations in both plasma and urine were significantly enhanced by candoxatril in the two groups (P < 0.001 and P < 0.01, respectively, for combined data). Urinary ANF immunoreactivity was significantly enhanced by candoxatril in both groups (P < 0.05 and P < 0.01 in groups 1 and 2, respectively), with a more pronounced effect evident at the higher dose (P < 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.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Clinical Biochemistry
- Biochemistry, medical