Evidence that KF4939, a new anti-platelet agent, inhibits phospholipase activation in rabbit platelets: different aspects from cyclic AMP increasing agents and calmodulin antagonist.
KF4939 [2, 2'-dithiobis (N-2- hydroxypropylbenzamide )] inhibited malondialdehyde (MDA) production induced by thrombin and A23187. The per cent inhibitions obtained in the medium with and without external calcium were about the same. Thromboxane A2 (TXA2) production induced by thrombin and collagen was also inhibited by KF4939 . This agent, however, did not block the conversion of exogenous arachidonate to MDA and TXA2. In contrast to KF4939 , prostaglandin E1 and 3- isobuthyl -l-methyl xanthine caused an inhibition of thrombin but not of A23187 induced production of MDA. Although chlorpromazine caused an inhibition in both thrombin- and A23187-stimulated platelets, the per cent inhibitions obtained in the medium with external calcium were lower than that in the medium without calcium. In addition, no synergisms between KF4939 and PGE1 or theophylline were observed in platelet aggregation induced by ADP. These results indicate that KF4939 inhibits the stimulus-activated arachidonic acid mobilization from membrane phospholipids, possibly through other mechanisms than elevation of cyclic AMP and calmodulin antagonism.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D000242:Cyclic AMP / Q000097:blood*; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010743:Phospholipids / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D013917:Thrombin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000096:biosynthesis
D001095:Arachidonic Acids; D001549:Benzamides; D002147:Calmodulin; D010743:Phospholipids; D016718:Arachidonic Acid; D000001:Calcimycin; D008315:Malondialdehyde; D013928:Thromboxane A2; C037861:2,2'-dithiobis(N-2-hydroxypropylbenzamide); D000242:Cyclic AMP; D010740:Phospholipases; D013917:Thrombin; D002118:Calcium