BENEFICIAL-EFFECTS OF N,N,N-TRIMETHYLSPHINGOSINE FOLLOWING ISCHEMIA AND REPERFUSION IN THE ISOLATED-PERFUSED RAT-HEART

Objective: Ischemia followed by reperfusion in the presence of polymor phonuclear leukocytes (PMNs) results in cardiac contractile dysfunctio n as well as myocardial injury. These deleterious effects are due in l arge part to endothelial dysfunction leading to an upregulation of cel l adhesion molecules and subsequent neutrophil-induced cardiac injury. At physiologically relevant concentrations, N,N,N-trimethylsphingosin e (TMS), a synthetic N-methylated sphingosine derivative, has been sho wn 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 ischemi a (I) (20 min) and reperfusion (R) (45 min) injury. Results: Administr ation of TMS (20 mu g/kg) to I/R hearts perfused with PMNs improved co ronary flow and preserved left ventricular developed pressure as an in dex 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) releas e from rat vascular endothelium. Conclusion: These results provide evi dence that TMS is a potent and effective cardioprotective agent that i nhibits leukocyte-endothelial cell interactions and preserves cardiac contractile function and coronary perfusion following myocardial ische mia and reperfusion. (C) 1998 Elsevier Science B.V. All rights reserve d.