Background Chronic treatment with high doses of angiotensin-converting enzyme (ACE) inhibitors prolongs survival after myocardial infarction. Since the plasma renin-angiotensin system (RAS) is not consistently activated in the chronic phase after myocardial infarction, the beneficial effects of ACE inhibition have been attributed, in part, to inhibition of an activated tissue RAS. However, a relation between tissue ACE inhibition and long-term efficacy (ie, concerning left ventricular (LV) hypertrophy and survival) has not been established. The present study was designed to evaluate the impact of low-dose ACE inhibition (predominant inhibition of plasma ACE) and high-dose ACE inhibition (associated with substantial tissue ACE inhibition) on reversal of LV hypertrophy and 1-year mortality after myocardial infarction in the rat.Methods and Results Infarcted rats were randomized to placebo, low-dose lisinopril, or high-dose lisinopril (each, n=80) and compared with sham-operated animals (n=40). In a separate group of animals, tissue ACE activity was determined after 6 weeks of therapy, demonstrating that both regimens were effective with regard to both plasma and pulmonary ACE inhibition; however, only high-dose lisinopril inhibited renal ACE. Neither dose affected LV ACE activity and ACE mRNA levels as determined by competitive polymerase chain reaction, whereas LV ANF mRNA levels were significantly reduced by high-dose lisinopril. High-dose lisinopril reduced arterial blood pressure and normalized right ventricular and LV weight and resulted in a substantial reduction of 1-year mortality, whereas the low dose did not (1 year mortality: placebo, 56.3%; low dose, 53.3%; high dose, 22.9%, P<.0001 versus low dose and versus placebo).Conclusions Hemodynamically effective ACE inhibition is required for reduction of LV hypertrophy and long-term mortality after myocardial infarction in the rat. Sustained inhibition of renal ACE during long-term therapy may contribute to the beneficial effect of high-dose lisinopril. Low-dose lisinopril, although exerting sustained inhibition of the plasma ACE, does not improve survival after myocardial infarction. (Circulation. 1994;90:2457-2467.)