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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


, : 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. Journal of Pharmacology and Experimental Therapeutics 275(3): 1324-1331

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 1-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 ( apprx 15 mm Hg) and produced renal vasodilatation. Both treatments had no significant effect on heart rate, cardiac index or rate of increase of left ventricular pressure. They decreased LVEDP to approximately the same extent and reduced cardiac hypertrophy. These results show that chronic coinhibition of NEP and ACE causes a favorable response in heart failure by reducing cardiac preload and hypertrophy. The lack of hypotensive effect of aladotril differentiates the mixed inhibitor from selective ACE inhibitors.

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PMID: 8531099


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