Anti-ischemic actions of a new thromboxane receptor antagonist, SQ-29,548, in acute myocardial ischemia.
Thromboxane A2 (TxA2) has been implicated as a mediator of ischemic damage to the myocardium. A new, selective thromboxane receptor antagonist, SQ-29,548 (2 mg/kg bolus + 2 mg/kg per h infusion) was studied for its effects on the extension of ischemic damage following acute myocardial ischemia (MI) in the rat. Administration of SQ-29,548 to sham MI rats had no significant effect on mean arterial blood pressure or heart rate over the 6 h experimental protocol. Ischemic damage was assessed by measurement of the depletion of creatine kinase (CK) activity and amino-nitrogen concentration from the myocardium. Six hours following ligation of the left main coronary artery, there was a significant loss of both CK (P less than 0.001) and amino-nitrogen (P less than 0.001) from the left ventricular free wall (LVFW). Administration of SQ-29,548 significantly blunted this loss of CK activity (P less than 0.01) and amino-nitrogen concentration (P less than 0.001) from the ischemic myocardium. Furthermore, the survival rate at 6 h following acute coronary artery ligation was 100% (7/7) for rats given SQ-29,548 and 58% (11/19) for rats given only the vehicle (P less than 0.05). These data indicate that SQ-29,548 significantly prevents the extension of ischemic damage in the myocardium and improves survival following acute coronary artery ligation, suggesting an important role for TxA2 in the pathophysiology of acute myocardial ischemia.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003327:Coronary Disease / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D003331:Coronary Vessels / Q000502:physiology; D003402:Creatine Kinase / Q000378:metabolism; D005231:Fatty Acids, Unsaturated; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006834:Hydrazines / Q000627:therapeutic use*; D008297:Male; D009206:Myocardium / Q000201:enzymology; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000502:physiology*; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000502:physiology*; D017482:Receptors, Thromboxane
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011956:Receptors, Cell Surface; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C045749:SQ 29548; D003402:Creatine Kinase