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.
Kojima
M
M
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Kusumoto
K
K
Fujiwara
S
S
Watanabe
T
T
Fujino
M
M
D000818:Animals; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D005905:Glyburide / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000502:physiology; D014970:Xanthines / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D018047:Receptors, Purinergic P1; D014970:Xanthines; C088196:TAK 044; C051360:1,3-dipropyl-8-cyclopentylxanthine; D005905:Glyburide