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Abstract: 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 (250–300g) hearts were subjected to a 15min period of global ischemia and 180min reperfusion in the presence or absence of 1μM 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, 30μM Nω-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 45min+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. [Copyright &y& Elsevier]