Role of endogenous endothelin in the extension of myocardial infarct size studied with the endothelin receptor antagonist, TAK-044.

The effects of TAK-044 on the extension of ischemia/reperfusion-induced myocardial infarction were studied in rats. Acute myocardial infarction was induced by occlusion of the left coronary artery for 1 h followed by reperfusion for 24 h. Infarct size and the area at risk were determined histochemically. Infarct size as a percentage of the area at risk (IS) was significantly reduced in a dose-dependent manner by TAK-044 administered 30 min before reperfusion (0.3-3.0 mg/kg, i.v.). Size-limiting effects similar to those in rats were also obtained in rabbits and dogs. In addition, TAK-044 administered 3 h after reperfusion also reduced the IS significantly. Preconditioning (5 min of LAD occlusion preceding 1 h of coronary occlusion) inhibited the extension of the IS. These effects of preconditioning and TAK-044 were inhibited by glibenclamide (0.1 mg/kg, i.v.; an inhibitor of the ATP-sensitive K channel) but not by DPCPX (1 mg/kg, i.v.; an adenosine A1 receptor antagonist). These results indicate that endogenous endothelin plays an important role in the extension of myocardial infarction and that the cardioprotective effects of TAK-044 can be partially explained by a mechanism similar to that of preconditioning in rats.