ah-23848 and Coronary-Disease

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.

Topics: Acute Disease; Animals; Biphenyl Compounds; Cats; Coronary Disease; Coronary Vessels; Creatine Kinase; Electrocardiography; Free Radicals; Hemodynamics; In Vitro Techniques; Male; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Vasoconstriction

The effects of the thromboxane antagonist AH23848 (1 mg kg-1 i.v.) were examined in anaesthetized greyhounds prepared for occlusion of the left anterior descending coronary artery with subsequent reperfusion after 40 min of myocardial ischaemia. Pretreatment with AH23848 30 min before coronary artery occlusion reduced the number of ischaemia-induced extrasystoles to 339 +/- 111 compared with 736 +/- 153 in the control group. The incidence of ventricular fibrillation following reperfusion was also markedly reduced; 25% compared with 88% in the controls. Late intervention with AH23848, 25 min after the onset of myocardial ischaemia did not significantly alter the incidence of reperfusion-induced ventricular fibrillation; 70% of the control group died and 60% of those that received AH23848. The ischaemia-induced release of thromboxane A2 and prostacyclin was not altered by pretreatment with AH23848. The results suggest that blockade of thromboxane receptors before myocardial ischaemia is an effective antiarrhythmic strategy in this model.

Topics: Anesthesia; Animals; Arrhythmias, Cardiac; Biphenyl Compounds; Coronary Disease; Dogs; Female; Hemodynamics; Male; Oxygen; Perfusion; Prostaglandins; Thromboxanes