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J Pharmacol Exp Ther. 1993 Sep;266(3):1156-63.

U73122 affects the equilibria between the phosphoinositides as well as phospholipase C activity in unstimulated and thrombin-stimulated human and rabbit platelets.

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Department of Pathology, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.


The effect of the putative phospholipase C inhibitor U73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)trien-17-yl]amino]hexyl]-1H- pyrrole-2,5-dione) on platelet phosphoinositide metabolism was examined. In unstimulated rabbit platelets prelabeled with [32P]phosphate and [3H]glycerol, U73122 caused decreases of up to 50% in the amount and labeling of phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 4-phosphate (PIP), but not phosphatidylinositol, within 1 min of addition and inhibited incorporation of [32P]phosphate and [3H]glycerol into PIP2 and PIP during incubations of up to 1 hr. These results point to inhibition by U73122 of the phosphatidylinositol and PIP kinases, although stimulation of the PIP and PIP2 phosphomonoesterases could be involved. In platelets stimulated with thrombin, U73122 blocked the thrombin-induced increases in PIP and phosphatidic acid; most increases in the inositol phosphates were blocked, but significant formation of inositol phosphate was found at 120 sec. The effects on inositol phosphates and phosphatidic acid were consistent with U73122 inhibiting phospholipase C; however, parallel dose-response curves with U73122 for the decreases in PIP2 and inhibition of thrombin-stimulated formation of inositol phosphates indicate that the inhibition of phospholipase C by U73122 may be due to decreased substrate availability rather than direct inhibition. Thrombin-stimulated decreases in PIP2 and PIP, found in the presence of U73122, could be explained by the action of phospholipase C in the absence of resynthesis. Although the changes were not as large, U73122 had a similar effect on PIP2 and PIP in unstimulated and stimulated human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

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