Effect of thromboxane synthetase inhibitors on platelet function: enhancement by inhibition of phosphodiesterase.
The effects of several selective thromboxane synthetase inhibitors, alone and in combination with inhibitors of cyclic AMP phosphodiesterase, on the aggregation of human platelets in response to collagen, ADP, 1-0-alkyl-2-acetyl-sn-glycerophosphocholine (1-alkyl-2-acetyl-GPC), 9,11-azo-PGH2 and sodium arachidonate were studied in vitro. The thromboxane synthetase inhibitors caused little or no inhibition of aggregation at the concentrations used, while the phosphodiesterase inhibitors caused partial to complete inhibition of aggregation induced by all of the aggregating agents, with anagrelide being the most potent inhibitor and sodium arachidonate the agent most susceptible to inhibition. Combination of inhibitors of thromboxane synthetase with inhibitors of cyclic AMP phosphodiesterase, at concentrations of each which caused little or no effect when used alone, produced marked inhibition of platelet aggregation induced by collagen or arachidonic acid but not by the other aggregating agents studied. This interaction between the two classes of inhibitors appears to be due to the accumulation of cyclic AMP as it can be reversed by 9-(tetrahydro-2-furyl) adenine, an inhibitor of adenylate cyclase. Furthermore, as no synergistic inhibition was found using aggregating agents that are poor inducers of thromboxane formation, or using collagen after the ingestion of aspirin, it is most likely that activation of adenylate cyclase occurs because of diversion of thromboxanes into prostaglandins particularly PGD2. The present results suggest that combined use of inhibitors of thromboxane synthetase and inhibitors of cyclic AMP phosphodiesterase may provide a new approach to antithrombotic therapy.
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D003864:Depression, Chemical; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D011799:Quinazolines / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011799:Quinazolines; C029166:dazoxiben; C017759:9-(tetrahydro-2-furyl)-adenine; D000244:Adenosine Diphosphate; D003094:Collagen; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase; D000225:Adenine; C021139:anagrelide