S1P1-Selective Agonist SEW2871 Exacerbates Reperfusion Arrhythmias.
Tsukada, Yayoi T MD, PhD *; Sanna, M Germana PhD +; Rosen, Hugh MD, PhD +; Gottlieb, Roberta A MD *
Journal of Cardiovascular Pharmacology.
50(6):660-669, December 2007.
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Sphingosine-1-phosphate (S1P) has been considered to play an important role in ischemia/reperfusion (I/R) injury. We used SEW2871 (SEW), a novel receptor-selective agonist for S1P1, to elucidate the role of S1P1 in myocardial I/R. Isolated perfused rat hearts exposed to S1P (1 and 10 mM) or SEW (1 and 0.1 mM) were subjected to 30 minutes of global no-flow ischemia and 2 hours of reperfusion. S1P at 1 and 10 mM significantly reduced infarct size and CK release compared with vehicle-control. The effect of 0.1 [mu]M SEW on infarct size was modest. After I/R, S1P at both doses and SEW at 0.1 [mu]M improved developed pressure (LVDP). SEW at 1 mM significantly prolonged the duration of ventricular tachycardia and ventricular fibrillation, leading to irreversible reperfusion tachyarrhythmias in 60% of the hearts. This is the first demonstration of the critical role of the S1P1 receptor in I/R injury.
(C) 2007 Lippincott Williams & Wilkins, Inc.