Beneficial effects of N,N,N-trimethylsphingosine following ischemia and reperfusion in the isolated perfused rat heart

초록

Objective: Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as myocardial injury. These deleterious effects are due in large part to endothelial dysfunction leading to an upregulation of cell adhesion molecules and subsequent neutrophil-induced cardiac injury. At physiologically relevant concentrations, N,N,N-trimethylsphingosine (TMS), a synthetic N-methylated sphingosine derivative, has been shown to attenuate leukocyte-endothelial cell interactions. We wanted to test the effects of TMS on neutrophil-mediated cardiac dysfunction in ischemia/reperfusion. Methods: This study examines the effects of TMS in a neutrophil-dependent isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min) injury. Results: Administration of TMS (20 mu g/kg) to I/R hearts perfused with PMNs improved coronary flow and preserved left ventricular developed pressure as an index of cardiac contractile function (95+/-5%) in comparison to those I/R hearts receiving only vehicle (60+/-7%) (P<0.001). Ln addition, TMS significantly reduced PMN accumulation in the ischemic myocardium, as evidenced by an attenuation in cardiac myeloperoxidase activity from 1.12+/-0.04 in untreated hearts to 0.01+/-0.02 in treated hearts (P<0.001). However, TMS did not directly stimulate nitric oxide (NO) release from rat vascular endothelium. Conclusion: These results provide evidence that TMS is a potent and effective cardioprotective agent that inhibits leukocyte-endothelial cell interactions and preserves cardiac contractile function and coronary perfusion following myocardial ischemia and reperfusion. (C) 1998 Elsevier Science B.V. All rights reserved.

키워드