Beneficial actions of the thromboxane receptor antagonist, AH-23,848, in acute myocardial ischemia.
Thromboxane A2 (TxA2) production increases significantly during acute myocardial ischemia. Since TxA2 induces platelet aggregation, coronary vasoconstriction and has a direct cytolytic effect, thromboxane receptor antagonists would be expected to be beneficial in acute myocardial ischemia. A new thromboxane A2 receptor antagonist, AH-23,848, was studied in a cat model of acute myocardial ischemia. Myocardial ischemia was induced by ligation of the left anterior descending (LAD) coronary artery. Thirty minutes later, AH-23,848 or vehicle was given as a bolus (1 mg.kg-1) followed by a continuous infusion (1 mg.kg-1.h-1). AH-23,848 effectively reduced the S-T segment elevation while vehicle treated cats showed an increase. From direct myocardial biopsies, it was also seen that AH-23,848 prevented the loss of creatine kinase (CK) activity from the ischemic myocardium. Furthermore, the loss of amino-nitrogen compounds was also significantly reduced (p less than 0.05) by treatment with the receptor antagonist. This protective effect was not due to an indirect reduction of myocardial oxygen demand since blood pressure, heart rate or their product was unaltered by AH-23,848 administration. Moreover, the specificity of AH-23,848 to thromboxane receptors was confirmed in isolated cat coronary arteries and in cat platelets. These experiments demonstrate that blockade of the thromboxane receptor by AH-23,848 is an effective means of preventing acute myocardial ischemic damage in the cat, and thus thromboxane A2 plays a role in propagating the extension of ischemic damage during acute myocardial ischemia.
Brezinski
M E
ME
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA.
Osborne
J A
JA
Yanagisawa
A
A
Lefer
A M
AM
D000208:Acute Disease; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002415:Cats; D003327:Coronary Disease / Q000188:drug therapy*; D003331:Coronary Vessels / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D004562:Electrocardiography; D005609:Free Radicals; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects
D001713:Biphenyl Compounds; D005609:Free Radicals; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; C046926:AH 23848; D003402:Creatine Kinase