The novel thromboxane A2 receptor antagonist KW-3635 reduces infarct size in a canine model of coronary occlusion and reperfusion.
The effect of KW-3635, a novel thromboxane A2 receptor antagonist, on infarct size was examined in anesthetized dogs subjected to 1.5 hr of occlusion of the left anterior descending coronary artery followed by 4.5 hr of reperfusion. KW-3635 (1 mg/kg, i.v.) was administered 1 hr before reperfusion and continuously infused (1 mg/kg/hr, i.v.) throughout the experiment. KW-3635 significantly (p < 0.001) reduced the infarct size (30.5% in the KW-3635-treated group as compared with 58.7% in the vehicle-treated group). KW-3635 almost completely inhibited platelet aggregation (ex vivo) induced by epinephrine (10 microM) + U-46619 (1 microM). KW-3635 attenuated the loss of creatine phosphokinase activity from the ischemic myocardium. Histopathological examination revealed that KW-3635 prevented neutrophil accumulation into the ischemic myocardium, ameliorated eosinophilic changes and inhibited contraction band formation in the ischemic myocardium. These results indicate that KW-3635 has a cardioprotective activity and suggest that the inhibition of activation or accumulation of neutrophils is involved in the cardioprotection following thromboxane A2 receptor blockade.
Higo
K
K
Department of Cardiovascular Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Sano
J
J
Karasawa
A
A
Kubo
K
K
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001584:Benzoxepins / Q000494:pharmacology*; D003402:Creatine Kinase / Q000187:drug effects; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*
D001562:Benzimidazoles; D001584:Benzoxepins; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D003402:Creatine Kinase; C065729:KW 3635