We have shown that the vasopeptidase inhibitor (VPI) omapatrilat improves peri-myocardial infarction (MI) survival, but the mechanisms involved and whether these effects are sustained remains to be determined, and are the subject of this study. Rats (n=279) received omapatrilat 20 mg/kg/day starting 7 days pre-MI, and continued peri- and post-MI, or no treatment (control). One group of rats had continuous ambulatory ECG and blood pressure recordings started 6 hours pre-MI and continued 24 hours post-MI when survival was evaluated, rats sacrificed and MI size evaluated. A second group had left ventricular (LV) remodelling evaluated by echocardiography at 30 days and, at 38 days had cardiac hemodynamics and morphology done, and survival evaluated. Survival 24 hours post-MI (N=267) improved with omapatrilat (60% versus 46% for control, p=0.0378). Over the next 37 days, there was no further improvement with omapatrilat, but the early benefit was sustained. Omapatrilat reduced MI size 24 hours post-MI, 36±2mm² versus 42±2mm² for controls, p=0.034. Omapatrilat reduced ventricular arrhythmia score 1 to 12 hours post-MI. Ompatrilat decreased blood pressure, but not during the first 24 hours post-MI. Omapatrilat reduced LV diastolic and systolic dimensions, and reduced LV and right ventricular (RV) weights as compared with control large MI, indicating a decrease in reactive hypertrophy. The improvement in cardiac remodelling was accompanied by improved cardiac hemodynamics. Thus, this study indicates that pre-, peri- and post-MI treatment with the VPI omapatrilat is beneficial on survival, ventricular arrhythmias, LV remodelling, and cardiac function.