Pinane thromboxane A2 (PTA2), a thromboxane A2 analog has been shown to antagonize the vasoconstriction and platelet aggregation induced by thromboxane A2, in addition to specifically inhibiting thromboxane synthetase. Because thromboxane A2 generation would be detrimental in acute myocardial ischemia (MI) by both decreasing coronary blood flow and increasing platelet aggregation, inhibition of thromboxane production and action may be beneficial in myocardial ischemia. In pentobarbital-anesthetized cats, the left anterior descending coronary artery was ligated, and PTA2 (0.5 mumol . kg-1 . h-1) or a Na2CO3 vehicle was infused 30 min post-MI for 270 min. Compared to vehicle-treated MI cats, PTA2 prevented the increase in plasma thromboxane levels seen at 2 through 5 h (P less than 0.005 at 2 through 5 h) and prevented the large increase in plasma CK activities at 4 and 5 h (P less than 0.025). In addition, PTA2 treatment abolished the differences in myocardial CK activities between ischemic and nonischemic regions and prevented the decrease in percent-bound cathepsin D in the ischemic region. Moreover, ECG analysis revealed a decreased incidence of premature beats in PTA2-treated MI cats as compared to MI-vehicle cats. In summary, these data indicate that PTA2 protects the ischemic myocardium and provide further evidence that inhibition of thromboxane formation, in addition to antagonism of its activity, is beneficial during the early stages of acute myocardial ischemia.
PINANE THROMBOXANE A2 ANALOGUES ARE NON-SELECTIVE PROSTANOID ANTAGONISTS IN RAT AND HUMAN STOMACH MUSCLE
