benazeprilat and libenzapril

The present study was designed to examine the effects of two new angiotensin-converting enzyme (ACE) inhibitors, CGS 14831 and CGS 16617 (3 mg/kg i. v. 1 min prior to occlusion and 4 and 24 h after occlusion), on myocardial ischemic (MI) damage and left-ventricular hypertrophy in rats. Administration of CGS 14831 or CGS 16617 inhibited angio-tensin-I-induced pressor responses by 40-100% for 4 h after each dose. Myocardial creatine phosphokinase (CK) levels were 10.6 +/- 0.6 U/mg protein in sham-MI animals, and following coronary artery occlusion for 48 h were decreased to 4.1 +/- 0.2 U/mg protein in MI + vehicle animals (p less than 0.01). CGS 14831 and CGS 16617 attenuated the decrease in CK content and resulted in 47 and 40% sparing, respectively, of the left-ventricular free wall. Neither agent attenuated the left-ventricular hypertrophy which developed following coronary artery occlusion. These data indicate that the nonsulfhydryl ACE inhibitors CGS 14831 and CGS 16617 have a significant cardioprotective effect in rats surviving 48 h, and suggest a potential therapeutic usefulness of these agents for the treatment of ischemia-induced heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Blood Pressure; Cardiomegaly; Coronary Disease; Creatine Kinase; Male; Myocardium; Rats; Rats, Inbred Strains

We describe a simple, rapid, specific radioenzymatic assay for "CGS 16617," a new, potent inhibitor of angiotensin-converting enzyme (ACE; EC 3.4.15.1) in human plasma. This assay is based on the principle that the inhibitor (i.e., the drug) binds to the ACE in plasma and hence the amount of free ACE in plasma is inversely related to the amount of active inhibitor present. Free enzyme is reacted with a radiolabeled substrate, and the radioactive product is selectively extracted into the scintillation cocktail for quantification. Fivefold-diluted plasma samples are incubated with [3H]hippuryl-glycyl-glycine enzyme substrate at 37 degrees C for 30 min and the liberated [3H]hippuric acid is selectively extracted into scintillation cocktail. The radioactivity is counted in a liquid scintillation counter. Both within-run and between-run, the variability (CV) of the assay is less than 10%. As little as 200 ng of the drug per liter can be quantified in 50-microL plasma samples. The method can also be used to assay two other ACE inhibitors, pentopril and CGS 14831, demonstrating that the method can be readily adapted to any ACE inhibitor having a single active component in plasma. The ester prodrug pentopril can also be assayed after ester hydrolysis. This method is suitable for analysis of large numbers of samples in clinical laboratories for routine monitoring of the concentrations of active ACE inhibitors in blood.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Gas Chromatography-Mass Spectrometry; Humans; Indoles; Mathematics; Methods