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Pharmacologic profile of CGS 24128, a potent, long-acting inhibitor of neutral endopeptidase 24.11.
- Source :
-
Journal of cardiovascular pharmacology [J Cardiovasc Pharmacol] 1994 Mar; Vol. 23 (3), pp. 358-64. - Publication Year :
- 1994
-
Abstract
- 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 microgram/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 muEq/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 muEq/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.(ABSTRACT TRUNCATED AT 250 WORDS)
- Subjects :
- Amino Acid Sequence
Animals
Atrial Natriuretic Factor blood
Atrial Natriuretic Factor pharmacology
Blood Pressure drug effects
Desoxycorticosterone
Diuresis drug effects
Heart Rate drug effects
Hypertension chemically induced
Hypertension physiopathology
Kidney drug effects
Male
Molecular Sequence Data
Natriuresis drug effects
Organophosphonates pharmacokinetics
Peptide Fragments pharmacology
Rats
Rats, Sprague-Dawley
Thiorphan pharmacokinetics
Thiorphan pharmacology
beta-Alanine pharmacokinetics
beta-Alanine pharmacology
Neprilysin antagonists & inhibitors
Organophosphonates pharmacology
beta-Alanine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0160-2446
- Volume :
- 23
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of cardiovascular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 7515977