EFFECT OF PROLONGED INHIBITION OF NEUTRAL ENDOPEPTIDASE ON CARDIAC-HYPERTROPHY IN RATS WITH MYOCARDIAL-INFARCTION

Myocardial infarction was induced in rats by ligation of the left coro nary artery. Treatment with TM1, a prodrug of SQ 28,603, an inhibitor of neutral endopeptidase (NEP, EC 3.4.24.11), was started 18-20 hours after ligation and was continued for 4 weeks (100 mg/kg, orally, twice daily). Morphological and biochemical parameters were assessed at the end of therapy. The treatment resulted in a significant reduction of heart hypertrophy, which was restricted to the parts of myocardium hem odynamically upstream of the infarcted left ventricle. The weights of the right ventricle and atria were reduced by 15-20%, whereas the trea tment had no effect on the left ventricle and septum weights. Treatmen t led to an almost complete inhibition of plasma NEP activity and to a slight decrease (-14%, p < 0.05) in plasma ACE activity. Plasma ANF l evel increased 3.8-fold after ligation, and treatment resulted in a sl ight (+29%) and nonsignificant additional increase in the ANF level. T he amount of hydroxyproline in the right ventricle was enhanced by +20 7% in control ligated rats and by +140% (NS) in treated rats. These da ta indicate that prolonged NEP inhibition exerts a favorable effect in heart failure by reducing the development of right ventricular and at rial hypertrophy. These effects may result from an improvement in hemo dynamic conditions, leading to a reduction in cardiac preload.