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 eVects in the experimental ischemia–reperfusion model. We tested the hypothesis that cardioprotective eVect 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 15min period of global ischemia and 180min reperfusion in the presence or absence of 1 M 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 conWrm the involvement of NO in mediating the cardioprotective eVects of TMZ, 30 M N-nitro-L-arginine methylester (L-NAME), a speciWc inhibitor of nitric oxide synthase, was used. Results: After ischemia and reperfusion, TMZ produced a signiWcant improvement of mechanical function associated with a reduction of CK release and FITC–albumin diVusion (P <0.001); the agent also resulted in improvement in coronary Xow (at 45 min +27% vs control). The eNOS mRNA and protein levels were signiWcantly higher in TMZ-treated hearts compared to controls. The addition of L-NAME signiWcantly reduced the beneWcial eVects of TMZ on contractile function, CK release and FITC–albumin diVusion. 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