title: Myocardial and endothelial protection by TMS in ischemia-reperfusion injury.
abstract: 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 micrograms/kg), administered intravenously 10 min before 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 with vehicle-treated cats. Endothelium-dependent relaxation to acetylcholine in ischemic-reperfused coronary artery rings treated with TMS was also significantly preserved compared with vehicle (73 +/- 4 vs. 34 +/- 4% vasorelaxation, P < 0.01). Polymorphonuclear neutrophil (PMN) adherence to coronary endothelium 270 min after reperfusion was markedly attenuated in the TMS group compared with 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, TMS 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.
authors.affiliation: Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: T
authors.initials: T
authors.lastname: Murohara
authors.forename: M
authors.initials: M
authors.lastname: Buerke
authors.forename: J
authors.initials: J
authors.lastname: Margiotta
authors.forename: F
authors.initials: F
authors.lastname: Ruan
authors.forename: Y
authors.initials: Y
authors.lastname: Igarashi
authors.forename: S
authors.initials: S
authors.lastname: Hakomori
authors.forename: A M
authors.initials: AM
authors.lastname: Lefer
mesh_terms: D000818:Animals; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects*; D004594:Electrophysiology; D004730:Endothelium, Vascular / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000473:pathology* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology
chemical_list: D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D013481:Superoxides; C071600:N,N,N-trimethylsphingosine; D013917:Thrombin; D013110:Sphingosine