title: Sphingosine modulates myocyte electrophysiology, induces negative inotropy, and decreases survival after myocardial ischemia.
abstract: Contractility studies in isolated feline myocytes have demonstrated that sphingosine, a metabolite stimulated by tumor necrosis factor (TNF) binding, decreases intracellular calcium release and depresses inotropic activity. This study investigated the electrophysiologic effects of sphingosine in isolated cat myocytes as well as the cardiodynamic consequence of TNF, sphingosine, and its metabolic precursors in vivo. In cat myocytes, sphingosine markedly decreased action potential duration, lowered action potential plateau, and inhibited L-type calcium current (I(Ca-L)). After administration of TNF, sphingomyelin, C2-ceramide, or sphingosine, only C2-ceramide and sphingosine depressed cardiac function in normal rats. Negative inotropic effects of C2-ceramide were attenuated by N-oleoylethanolamine (NOE), a ceramidase inhibitor that blocks sphingosine formation. Rats pretreated with NOE before undergoing 30 min of acute regional myocardial ischemia followed by 150 min of reperfusion exhibited improved survival. Most deaths could be attributed to acute pump failure accompanied by bradycardia. Myocardial infarct size and peak serum TNF were not different between NOE- and vehicle-treated groups (3,908 +/- 1097 pg/ml and 3,027 +/- 846 pg/ml, respectively). These results indicate that sphingosine exerts direct inhibitory effects on the action potential and I(Ca-L) in isolated feline myocytes, consistent with previously reported sphingosine activity on I(Ca-L) in isolated rat myocytes. The in vivo study suggests that reducing sphingosine production with N-oleoylethanolamine attenuates cardiodepression and can improve overall survival after ischemic injury. Clearly, agents that modulate sphingosine production limit cardiodepression and may provide a therapeutic benefit in clinical conditions of myocardial inflammatory injury.
authors.affiliation: Wyeth-Ayerst Research, Radnor, Pennsylvania, USA. gregory.friedrichs@spcorp.com
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Friedrichs
authors.forename: Robert E
authors.initials: RE
authors.lastname: Swillo
authors.forename: Brian
authors.initials: B
authors.lastname: Jow
authors.forename: Terry
authors.initials: T
authors.lastname: Bridal
authors.forename: Randy
authors.initials: R
authors.lastname: Numann
authors.forename: Linda M
authors.initials: LM
authors.lastname: Warner
authors.forename: Loran M
authors.initials: LM
authors.lastname: Killar
authors.forename: Kurex
authors.initials: K
authors.lastname: Sidek
mesh_terms: D000200:Action Potentials; D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D002118:Calcium / Q000502:physiology; D002415:Cats; D055572:Ceramidases; D003864:Depression, Chemical; D063388:Endocannabinoids; D004797:Enzyme-Linked Immunosorbent Assay; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009829:Oleic Acids; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D063388:Endocannabinoids; D004983:Ethanolamines; D009829:Oleic Acids; D014409:Tumor Necrosis Factor-alpha; C033595:N-oleoylethanolamine; D000581:Amidohydrolases; D055572:Ceramidases; D013110:Sphingosine; D002118:Calcium