The effect of the thromboxane A2/prostaglandin endoperoxide receptor antagonist SQ 30,741 on myocardial infarct size and blood flow during myocardial ischemia and reperfusion.
The effect of the thromboxane A2 (TXA2) receptor antagonist SQ 30,741 on infarct size and myocardial blood flow during coronary occlusion and reperfusion was determined. In anesthetized dogs, the left circumflex coronary artery (LCX) was occluded and after 10 min a continuous infusion of SQ 30,741 (1 mg/kg + 1 mg/kg/h, i.v.) or saline was begun. After 90 min of LCX occlusion, the LCX was reperfused for 5 h and infarct size was then determined. Myocardial blood flows before, during, and after occlusion were determined using radioactive microspheres. SQ 30,741 resulted in a significant decrease in infarct size (34% +/- 6% of left ventricular area at risk) compared to controls (60% +/- 9%). Cardioprotection was also found with SQ 30,741 when infarct size was normalized for both area at risk and predrug collateral flow. The protective effect of SQ 30,741 occurred without an increase in collateral flow. At 1 h postreperfusion, subendocardial flow was significantly higher in SQ 30,741-treated animals (109 +/- 15 ml/min/100 g) compared to controls (71 +/- 16 ml/min/100 g). SQ 30,741, in the dose resulting in infarct size reduction, produced a 95% inhibition of platelet TXA2 receptors throughout the experiment as measured by dose-dependent inhibition of the ex vivo platelet shape change response to U-46,619, a TXA2 mimetic. Thus, a dose of SQ 30,741 that results in TXA2 blockade also results in myocardial salvage without changes in collateral flow.
Grover
G J
GJ
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
Schumacher
W A
WA
Simon
M
M
Parham
C
C
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000648:ultrastructure; D003326:Coronary Circulation / Q000187:drug effects*; D003327:Coronary Disease / Q000188:drug therapy* / Q000503:physiopathology; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015425:Myocardial Reperfusion; D010101:Oxygen Consumption / Q000187:drug effects; D011449:Prostaglandin Endoperoxides / Q000378:metabolism*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use
D011449:Prostaglandin Endoperoxides; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; C054215:SQ 30741; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid