Anti-ischemic actions of a new thromboxane receptor antagonist during acute myocardial ischemia in cats.
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 antagonism would be expected to be beneficial in acute myocardial ischemia. Thirty minutes after ligation of the left anterior descending coronary artery (LAD) in anesthetized cats, the TxA2 receptor antagonist BM-13,177 or its vehicle was given as a bolus injection at 20 mg/kg, followed by continuous infusion of 20 mg/kg/hr for 4.5 hours. ST segment elevation declined significantly (p less than 0.02) after BM-13,177 treatment, suggesting a reduction in cellular ischemia. The loss in myocardial creatine kinase (CK) activity and in free amino-nitrogen concentration in the ischemic area was also significantly reduced (p less than 0.01). No significant changes in blood pressure or heart rate were seen with BM-13,177 during myocardial ischemia or in nonischemic control cats. Blood levels of BM-13,177 were sufficient to inhibit ex vivo platelet aggregation induced by the prostaglandin endoperoxide analog, U-46,619. Data from isolated cat coronary arteries suggest that BM-13, 177 antagonizes the thromboxane/endoperoxide receptor in coronary vascular smooth muscle. These experiments indicate that TxA2 plays a significant role in propagating the extension of ischemic damage, and that thromboxane receptor antagonism is an effective means of reducing the damage provoked by TxA2 in acute myocardial ischemia.
D000818:Animals; D001794:Blood Pressure; D002415:Cats; D003327:Coronary Disease / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D003402:Creatine Kinase / Q000378:metabolism; D006339:Heart Rate; D009206:Myocardium / Q000201:enzymology; D010179:Pancreas / Q000378:metabolism; D010974:Platelet Aggregation; D011506:Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects*; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013449:Sulfonamides / Q000627:therapeutic use*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000502:physiology
D011506:Proteins; D011956:Receptors, Cell Surface; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013928:Thromboxane A2; C040624:sulotroban; D003402:Creatine Kinase