The aim of the present study was to determine, in rats with
myocardial infarction, the systemic and cardiac hemodynamic effects of
aladotrilat and of its
prodrug,
aladotril, both of which display inhibitory activity toward both
neutral endopeptidase (NEP, EC. 3.4.24.11) and
angiotensin I-converting enzyme (ACE). The effects of acute
intravenous injection of
aladotrilat (30 mg/kg bolus injection plus 30 mg/kg/hr infusion) were measured for 1 hr in conscious infarcted rats and compared with the effects of
SQ 28,603, a selective NEP inhibitor (30 mg/kg bolus injection plus 30 mg/kg/hr infusion), and
captopril, a selective
ACE inhibitor (10 mg/kg bolus injection plus 10 mg/kg/hr infusion). Unlike
SQ 28,603,
aladotrilat and
captopril produced a slight fall in mean arterial blood pressure. The three treatments had no significant effect on heart rate and rate of increase of left ventricular pressure (LV + dP/dt) but caused significant decreases in left ventricular end-diastolic pressure (LVEDP). The effect of
aladotrilat on decreasing LVEDP was faster than those of
captopril or
SQ 28,603. In chronic experiments, groups of rats received orally, twice daily,
captopril (10 mg/kg),
aladotril (100 mg/kg) or vehicle. Treatments were started 18 to 20 hr after coronary artery
ligation and continued for 4 weeks. Hemodynamic parameters and
cardiac hypertrophy were measured at the end of
therapy. Unlike
aladotril,
captopril treatment resulted in significant decreases in mean arterial blood pressure and left ventricular systolic pressure (approximately 15 mm Hg) and produced renal vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)