Reduction of myocardial leukocyte accumulation and myocardial infarct size following administration of BAY u3405, a thromboxane A2 receptor antagonist, in myocardial ischaemia-reperfusion injury.
We investigated the effect of BAY u3405, a thromboxane A2 receptor antagonist in pentobarbital anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham operated rats were used as controls (Sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase activity were studied. Ischaemia-reperfusion injury significantly reduced the survival rate (45%), caused a marked myocardial necrosis, increased serum creatine phosphokinase activity (Sham MI/R = 26 +/- 10.2 U/ml; MI/R = 213 +/- 19 U/ml) and produced a rise in myocardial myeloperoxidase activity in the area-at-risk and in the necrotic area (6.1 +/- 0.4 U x 10(-3)/g tissue and 6.7 +/- 0.9 U x 10(-3)/g of tissue, respectively). The administration of BAY u3405 (30 and 60 mg/kg/i.v., 30 min before occlusion) significantly increased survival rate, lowered the area of myocardial necrosis, blunted the increase in serum creatine phosphokinase activity and reduced the increase in myeloperoxidase activity in both the area-at-risk and the necrotic area. Furthermore, the protective effect of BAY u3405 was dose-dependent. These data are consistent with an involvement of TXA2 in myocardial ischaemia-reperfusion injury and suggest that BAY u3405 may represent a novel therapeutic approach to the treatment of acute ischaemia-reperfusion injury.
Squadrito
F
F
Institute of Pharmacology, School of Medicine, University of Messina, Italy.
Ioculano
M
M
Altavilla
D
D
Zingarelli
B
B
Canale
P
P
Campo
G M
GM
Saitta
A
A
Oriti
S
S
Faggiotto
A
A
Caputi
A P
AP
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D003402:Creatine Kinase / Q000037:antagonists & inhibitors / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects; D007962:Leukocytes; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology*; D017202:Myocardial Ischemia / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology; D009206:Myocardium / Q000166:cytology* / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D002227:Carbazoles; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013928:Thromboxane A2; D009195:Peroxidase; D003402:Creatine Kinase; C063119:ramatroban