S1P1-selective agonist SEW2871 exacerbates reperfusion arrhythmias.
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 microM SEW on infarct size was modest. After I/R, S1P at both doses and SEW at 0.1 microM 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.
Tsukada
Yayoi T
YT
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
Sanna
M Germana
MG
Rosen
Hugh
H
Gottlieb
Roberta A
RA
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D015394:Molecular Structure; D009203:Myocardial Infarction / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D010477:Perfusion; D010647:Phenyl Ethers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
D000814:Aniline Compounds; D010069:Oxadiazoles; D010647:Phenyl Ethers; D049349:Receptors, Lysosphingolipid; C430918:SEA 0400; C503964:SEW2871; D019831:Sodium-Calcium Exchanger; D013876:Thiophenes