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

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 (250-300 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.

• Authors: Pericle Di Napoli, Sergio Chierchia, Alfonso Antonio Taccardi, Alfredo Grilli, Mario Felaco, Raffaele De Caterina, Antonio Barsotti
• Journal: Nitric oxide : biology and chemistry (Nitric Oxide) Vol. 16 Issue 2 Pg. 228-36 (Mar 2007) ISSN: 1089-8603 [Print] United States
• PMID: 17049285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• RNA, Messenger
• Nitric Oxide Synthase Type III
• Trimetazidine

Topics

• Animals
• Base Sequence
• Blotting, Western
• Capillary Permeability (drug effects)
• DNA Primers
• Heart (drug effects)
• Male
• Myocardium (enzymology)
• Nitric Oxide Synthase Type III (antagonists & inhibitors, genetics, metabolism)
• RNA, Messenger (genetics)
• Rats
• Rats, Wistar
• Reperfusion Injury
• Trimetazidine (pharmacology)