HEMODYNAMIC-EFFECTS OF ACUTE AND CHRONIC TREATMENT WITH ALADOTRIL, A MIXED INHIBITOR OF NEUTRAL ENDOPEPTIDASE AND ANGIOTENSIN-I-CONVERTING ENZYME, IN CONSCIOUS RATS WITH MYOCARDIAL-INFARCTION

The aim of the present study was to determine, in rats with myocardial infarction, the systemic and cardiac hemodynamic effects of aladotril at and of its prodrug, aladotril, both of which display inhibitory act ivity toward both neutral endopeptidase (NEP, EC. 3.4.24.11) and angio tensin 1-converting enzyme (ACE). The effects of acute intravenous inj ection of aladotrilat (30 mg/kg bolus injection plus 30 mg/kg/hr infus ion) were measured for 1 hr in conscious infarcted rats and compared w ith the effects of SQ 28,603, a selective NEP inhibitor (30 mg/kg bolu s injection plus 30 mg/kg/hr infusion), and captopril, a selective ACE inhibitor (10 mg/kg bolus injection plus 10 mg/kg/hr infusion). Unlik e SQ 28,503, aladotrilat and captopril produced a slight fall in mean arterial blood pressure. The three treatments had no significant effec t on heart rate and rate of increase of left Ventricular pressure (LV + dP/dt) but caused significant decreases in left ventricular end-dias tolic pressure (LVEDP). The effect of aladotrilat on decreasing LVEDP was faster than those of captopril or SQ 28,603. In chronic experiment s, 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 decrea ses in mean arterial blood pressure and left ventricular systolic pres sure (similar to 15 mm Hg) and produced renal vasodilatation. Both tre atments had no significant effect on heart rate, cardiac index or rate of increase of left ventricular pressure, They decreased LVEDP to app roximately the same extent and reduced cardiac hypertrophy. These resu lts show that chronic coinhibition of NEP and ACE causes a favorable r esponse in heart failure by reducing cardiac preload and hypertrophy. The lack of hypotensive effect of aladotril differentiates the mixed i nhibitor from selective BCE inhibitors.