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

We compared the pharmacologic profiles of thiorphan, a neutral endopep tidase (NEP) inhibitor which is cleared rapidly from the circulation, and CGS 24128, an inhibitor with a much longer half-life (t1/2). Thior phan 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 w ere >500 nM for 4 h but plasma thiorphan was detectable for only 60 mi n. Thiorphan 3 mg/kg administered intraarterially (i.a.) increased pla sma atrial natriuretic peptide immunoreactivity (ANPir) levels by 58 /- 12% in rats administered exogenous ANP(99-126). This response laste d <60 min, whereas the same dose of CGS 24128 produced an average incr ease of 191 +/- 19% in ANPir concentrations that persisted for 4 h. AN P-induced (1 mu g/kg i.v.) natriuresis was significantly potentiated i n anesthetized rats pretreated (60 min) with a bolus of CGS 24128 10 m g/kg i.v. The change in urinary sodium excretion (UNaV) produced by AN P was 28.8 +/- 4.0 and 15.8 +/- 1.8 mu Eq/kg/min in CGS 24128- and veh icle-treated rats, respectively. ANP-induced natriuresis was also grea ter 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 w as administered as a bolus (10 mg/kg i.v.) 60 min before the ANP chall enge. 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 arteri al pressure (MAP) by 26 +/- 7 and 31 +/- 6 mm Hg, respectively, in DOC A-salt hypertensive rats. This antihypertensive effect was not observe d after i.v. bolus injection of thiorphan 30 mg/kg. These data indicat e that potent NEP inhibitors can potentiate the biologic actions of en dogenous and exogenous ANP, but the efficacy of some compounds is sign ificantly limited by their rate of clearance in vivo.