Prior studies have shown cardioprotective effects of the phosphodiesterase-5 inhibitor, sildenafil, in the setting of myocardial ischemia and reperfusion (MI/R) in mice and rabbits. To verify these results in a rigorous (clinical trial-like) manner, we investigated the effect of sildenafil in the highly standardized mouse, rabbit, and pig models of MI/R carried out by the CAESAR Cardioprotection Consortium. The studies were randomized and blinded, using the independent core laboratories of the consortium to assess myocardial infarct size (TTC and histology) and measure cardiac troponin I plasma levels. The statistical analyses were performed in an unbiased fashion. MI/R was performed in mice (n= 26-36/group), rabbits (n= 32-33/group), and pigs (n= 8-10/group). Sildenafil was administered intravenously as a bolus (1.4 mg/kg) 5 minutes prior to reperfusion. The results showed no differences in hemodynamics during MI/R or myocardial area-at-risk (AAR) in any species. Sildenafil failed to reduce myocardial infarct size (INF) or reduce peak plasma levels of cardiac troponin I in any species.

Although sildenafil has been reported to be protective in other models, we conclude that it does not afford measurable protection in this standardized, rigorous, and clinically relevant MI/R protocol. These divergent results highlight the importance of using a CAESAR-type approach when studying potential infarct-sparing therapies in preclinical models.