PHARMACOLOGICAL PROFILE OF CGS-24128, A POTENT, LONG-ACTING INHIBITOR OF NEUTRAL ENDOPEPTIDASE-24.11

We compared the pharmacologic profiles of thiorphan, a neutral endopeptidase (NEP) inhibitor which is cleared rapidly from the circulation, and CGS 24128, an inhibitor with a much longer half-life (t1/2). Thiorphan and CGS 24128 inhibited NEP in vitro with IC50 values of 5.0 +/- 0.2 and 4.3 +/- 0.2 nM, respectively. After administration at 10 mg/kg intravenously (i.v.), the concentrations of CGS 24128 in the plasma were >500 nM for 4 h but plasma thiorphan was detectable for only 60 min. Thiorphan 3 mg/kg administered intraarterially (i.a.) increased plasma atrial natriuretic peptide immunoreactivity (ANPir) levels by 58 +/- 12% in rats administered exogenous ANP(99-126). This response lasted <60 min, whereas the same dose of CGS 24128 produced an average increase of 191 +/- 19% in ANPir concentrations that persisted for 4 h. ANP-induced (1 mu g/kg i.v.) natriuresis was significantly potentiated in anesthetized rats pretreated (60 min) with a bolus of CGS 24128 10 mg/kg i.v. The change in urinary sodium excretion (UNaV) produced by ANP was 28.8 +/- 4.0 and 15.8 +/- 1.8 mu Eq/kg/min in CGS 24128- and vehicle-treated rats, respectively. ANP-induced natriuresis was also greater during continuous infusion of thiorphan (5 mg/kg bolus + 0.1 mg/kg/min i.v.; Delta UNaV = 29.2 +/- 5.8 and 13.8 +/- 3.2 mu Eq/kg/min in drug- and vehicle-treated rats, respectively) but not when thiorphan was administered as a bolus (10 mg/kg i.v.) 60 min before the ANP challenge. Similarly, continuous infusion of thiorphan (0.5 mg/kg/min i.v.) or CGS 24128, given as a bolus (10 mg/kg i.v.), decreased mean arterial pressure (MAP) by 26 +/- 7 and 31 +/- 6 mm Hg, respectively, in DOCA-salt hypertensive rats. This antihypertensive effect was not observed after i.v. bolus injection of thiorphan 30 mg/kg. These data indicate that potent NEP inhibitors can potentiate the biologic actions of endogenous and exogenous ANP, but the efficacy of some compounds is significantly limited by their rate of clearance in vivo.