Hypertension and left ventricular hypertrophy (LVH) are known to increase susceptibility to ventricular arrhythmias during and before myocardial ischemia and to increase the risk of periinfarction mortality. Although regression of LVH has been advocated as a therapeutic goal, little evidence exists to suggest that it can reduce periinfarction mortality, and if it does, by which mechanisms it may do this. In this study, we evaluated the effects of control of systemic arterial blood pressure, of regression of myocardial hypertrophy, and of cardiac fibrosis on the susceptibility to ventricular arrhythmias and periinfarction mortality in the spontaneously hypertensive rat (SHR) model of hypertension and LVH. After 12 weeks of treatment, captopril and hydralazine reduced systolic blood pressure to 93 +/- 14 and 126 +/- 13 mm Hg, respectively, as compared with 193 +/- 12 mm Hg, p < 0.05, in the untreated control SHR group. The decrease with propranolol (to 185 +/- 12 mm Hg) was of borderline significance. There was a significant decrease in inducibility of ventricular arrhythmias by programmed electrical stimulation with captopril (5%; p < 0.05). One hour after infarction, there was a trend toward reduced mortality in the rats treated with hydralazine, 9.5% (p = 0.20 vs. control; p = 0.10 vs. propranolol), and captopril, 5% (p = 0.08 vs. control; p = 0.010 vs. propranolol). However, only captopril reduced 3-h postinfarction mortality (40%; p = 0.022) compared with 72% in the control group. The results showed a significant decrease of the left ventricular weight/body weight ratio in the rats treated with hydralazine (2.6 +/- 0.2 mg/g; p < 0.05) and captopril (2.2 +/- 0.2 mg/g; p < 0.05) compared with the control group (2.8 +/- 0.2 mg/g). An assessment of cardiac fibrosis indicated that captopril decreased the volume percentage of collagen the most (2.01 +/- 0.53; p < 0.05), followed by propranolol (2.29 +/- 0.64; p < 0.05) and hydralazine (2.92 +/- 0.58; p < 0.05) versus controls (3.23 +/- 0.61). This study suggests that regression of myocardial hypertrophy or long-term normalization of arterial systolic blood pressure or both are the major determinants of very early mortality (within 1 h after infarction) and that later mortality (3 h after infarction) may be the result of a more complex interplay of regression of myocardial hypertrophy and fibrosis and of control of blood pressure.