Myocardial and endothelial protection by n,n, n -trimethylsphingosine in ischemia reperfusion injury. Murohara, Toyoaki, Michael Buerke, John Margiotta, Fuqiang Ruan, Yasuyuki Igarashi, Sen-Itiroh Hakomori, and Allan M. Lefer. Department of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107; and The Biomembrane Institute, 201 Elliott Avenue West, Seattle, WA 98119; and Department of Pathobiology, University of Washington, Seattle, WA 98195
APStracts 2:0072H, 1995.
N,N,N-trimethylsphingosine (TMS), a stable synthetic sphingosine derivative, was investigated in a feline model of myocardial ischemia (90 min) and reperfusion (270 min) injury. TMS (60 [mu]g/kg), administered intravenously 10 min prior to reperfusion, significantly attenuated myocardial necrosis (15+/-3 vs. 31+/-4 % necrosis of area at risk, p<0.01) and cardiac myeloperoxidase activities, a marker of neutrophil accumulation, compared to vehicle treated cats. Endothelium-dependent relaxation to acetylcholine in ischemic reperfused coronary artery rings treated with TMS was also significantly preserved compared to vehicle (73+/-4 % vs. 34+/-4 % vasorelaxation, p<0.01). PMN adherence to coronary endothelium 270 min after reperfusion was markedly attenuated in the TMS group compared to vehicle-treated cats (37+/-5 vs. 76+/-5 PMN /mm2, p<0.01). TMS also attenuated upregulation of P-selectin on coronary venular endothelium by immunohistochemistry. This was consistent with in vitro findings that TMS attenuates PMN adherence to thrombin -stimulated coronary endothelium and P-selectin upregulation on thrombin-stimulated cat platelets. A sphingolipid derivative, N,N,N -trimethylsphingosine at physiological concentrations exerts cardioprotective actions and preserves coronary endothelial function following myocardial ischemia and reperfusion in vivo. The effects appear to be mediated by the inhibition of PMN-endothelial interaction and subsequent accumulation into the ischemic myocardium. Thus, TMS may be a useful agent in attenuating myocardial reperfusion injury. 

Received 27 December 1994; accepted in final form 27 February
1995.
APS Manuscript Number H1139-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 21 March 1995.