Antagonism of platelet aggregation by 13-azaprostanoic acid in acute myocardial ischemia and sudden death.
The effects of 13-azaprostanoic acid (13-APA) were studied during acute myocardial ischemia in cats and in rabbit sudden death induced by sodium arachidonate (Na-Ar). To more clearly define the mechanism of action of 13-APA, we also examined its effects on isolated cat and rabbit coronary arteries, in vitro aggregation of cat and rabbit platelet-rich plasma (PRP) and circulating rabbit platelet count measured in vivo. 13-APA provided minimal protection during myocardial ischemia in cats, partially reversing ischemia-induced ST segment elevations by 3-5 hours after coronary artery occlusion. However, 13-APA was ineffective in inhibiting the rise in plasma creatine kinase (CK) activity or the loss of CK from ischemic myocardial tissue. 13-APA (1.0 - 100 microM) did not inhibit contraction of cat coronary arteries produced by a stable thromboxane A2 analog. However, 13-APA (100 microM) inhibited aggregation of cat PRP induced by AA (1.0 microM). 13-APA also provided significant protection against sudden death induced by Na-Ar in rabbits. While this agent was ineffective in reducing vasoconstriction of rabbit coronary arteries or inhibiting platelet aggregation in response to 500 microM AA, aggregation of rabbit PRP by 250 microM AA was completely inhibited. AA injection produced a significant decrease in circulating platelet count in vehicle-treated rabbits. However, 13-APA reduced the decrease in circulating platelet count in rabbits which survived AA injection during the 13-APA infusion. These results indicate that antagonism of thromboxane A2 receptors in platelets may be an important feature in protecting against sudden death. The difference in sensitivities of vascular and platelet thromboxane receptors as well as the accessability of 13-APA to these receptors may explain the lack of protection of 13-APA in myocardial ischemia.
D000818:Animals; D002415:Cats; D003327:Coronary Disease / Q000097:blood* / Q000201:enzymology / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D003645:Death, Sudden; D004562:Electrocardiography; D005227:Fatty Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010976:Platelet Count; D011466:Prostanoic Acids / Q000494:pharmacology*; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects
D005227:Fatty Acids; D011466:Prostanoic Acids; C022574:13-azaprostanoic acid; D003402:Creatine Kinase