Trimetazidine improves post-ischemic recovery by preserving endothelial nitric oxide synthase expression in isolated working rat hearts.

OBJECTIVE: Previous investigations have consistently shown that the piperazine derivative trimetazidine (TMZ, 1-[2,3,4-trimethoxybenzil] piperazine, dihydrocloride) has cardioprotective effects in the experimental ischemia-reperfusion model. We tested the hypothesis that cardioprotective effect of TMZ is partly mediated by preservation of the endothelial barrier of the coronary microcirculation. METHODS: Isolated Wistar rat (250-300 g) hearts were subjected to a 15 min period of global ischemia and 180 min reperfusion in the presence or absence of 1 microM TMZ. Hemodynamic parameters, heart weight, creatinekinase (CK) release and microvascular permeability (FITC-albumin extravasation) were evaluated. In addition, eNOS gene expression was estimated by rt-PCR, and eNOS protein levels were assessed by Western analysis. In order to confirm the involvement of NO in mediating the cardioprotective effects of TMZ, 30 microM N(omega)-nitro-l-arginine methylester (L-NAME), a specific inhibitor of nitric oxide synthase, was used. RESULTS: After ischemia and reperfusion, TMZ produced a significant improvement of mechanical function associated with a reduction of CK release and FITC-albumin diffusion (P<0.001); the agent also resulted in improvement in coronary flow (at 45 min+27% vs control). The eNOS mRNA and protein levels were significantly higher in TMZ-treated hearts compared to controls. The addition of L-NAME significantly reduced the beneficial effects of TMZ on contractile function, CK release and FITC-albumin diffusion. CONCLUSIONS: in the isolated rat heart, TMZ exerts a relevant, NO-dependent, cardioprotection against ischemia-reperfusion injury and preserves the endothelial barrier of the coronary circulation. This could contribute to explain the cardioprotective action of TMZ following ischemia and reperfusion.