Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Aniline Compounds / pharmacology
-
Animals
-
Arrhythmias, Cardiac / physiopathology
-
Arrhythmias, Cardiac / prevention & control*
-
Dose-Response Relationship, Drug
-
Heart / drug effects
-
Heart / physiopathology
-
In Vitro Techniques
-
Male
-
Models, Biological
-
Molecular Structure
-
Myocardial Infarction / physiopathology
-
Myocardial Infarction / prevention & control
-
Myocardial Reperfusion Injury / physiopathology
-
Myocardial Reperfusion Injury / prevention & control*
-
Oxadiazoles / chemistry
-
Oxadiazoles / pharmacology*
-
Perfusion
-
Phenyl Ethers / pharmacology
-
Rats
-
Rats, Sprague-Dawley
-
Receptors, Lysosphingolipid / agonists*
-
Sodium-Calcium Exchanger / antagonists & inhibitors
-
Thiophenes / chemistry
-
Thiophenes / pharmacology*
-
Time Factors
-
Ventricular Function, Left / drug effects
Substances
-
Aniline Compounds
-
Oxadiazoles
-
Phenyl Ethers
-
Receptors, Lysosphingolipid
-
SEA 0400
-
SEW2871
-
Sodium-Calcium Exchanger
-
Thiophenes