Thromboxane receptor antagonist BMS-180291, but not aspirin, reduces the severity of pacing-induced ischemia in dogs.
We determined the effect of thromboxane A2 (TXA2) prostaglandin endoperoxide (TP) receptor antagonism, using BMS-180291 or aspirin, on the severity of pacing-induced ischemia in anesthetized dogs. Thromboxane receptor antagonists may not only have antithrombotic activity, but may also have direct cardioprotective effects, unlike aspirin. Left anterior descending coronary artery (LAD) stenosis was adjusted so that a significant (10-12 mV) ST segment elevation was observed only when superimposed on atrial pacing. Each heart was subjected to 5-min episodes of pacing-induced ischemia 10, 40, and 70 min after initiation of BMS-180291 (1 mg/kg + 1 mg/kg/h) or vehicle. In the vehicle group, ST segment elevation was reproducible at all pacing-induced ischemia episodes, whereas BMS-180291 significantly reduced it by 30% at the later ischemia episodes. This reduction in ST segment increase was not accompanied by alterations in regional myocardial blood flow (RMBF) nor in hemodynamic status. Aspirin in the same model [10 mg/kg intravenously (i.v.) given 10 min before pacing-induced ischemia] did not significantly reduce ST segment elevation, indicating a lack of protective effect in this model. Thromboxane receptor blockade appears to protect myocardium subjected to pacing-induced ischemia, an effect not produced by aspirin.
Grover
G J
GJ
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Schumacher
W A
WA
Ogletree
M L
ML
D000787:Angina Pectoris / Q000188:drug therapy; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002304:Cardiac Pacing, Artificial; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy*; D010080:Oxazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D011422:Propionates / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D011869:Radioligand Assay; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D010080:Oxazoles; D011422:Propionates; D017482:Receptors, Thromboxane; C078904:ifetroban; D001241:Aspirin