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Correlation between the inhibition of platelet aggregation by prostaglandins and intracellular cyclic AMP
CORRELATION BETWEEN THE INHIBITION OF PLATELET AGGREGATION BY P R O S T A G L A N D I N S AND INTRACELLULAR CYCLIC AMP* ROBERT ALVAREZ, LESLIEA. TAYLOR and JOHN J. BRUNO Institute of Biological Sciences Syntex Research, Palo Alto, Cal([brnia 94304, U.S.A.
ABSTRACT
The maximum accumulation of cyclic AMP in washed human platelets in the presence of prostacyclin (PGI2) is substantially greater than that obtained with saturating concentrations of either prostaglandin D2 or E1 (PGD2 or PGE0. A good correlation exists between the capacity of several naturally-occurring prostaglandins to inhibit ADPinduced platelet aggregation and their ability to increase the intracellular accumulation of cyclic AMP to a submaximal level (i.e., less than 30~ of the maximum stimulation elicited by PGI2). The rank order of potency in both assays agrees (PGI2 > PGD2 > PGEt > PGE2 > PGAt > PGF2a~. However, the concentration required for half-maximal inhibition of platelet aggregation by PGI2 (2.7 nr~) is ten times lower than that required for half-maximal elevation in intracellular cyclic AMP (27 nM). For this reason, it is desirable to indicate both potency and efficacy (fold-stimulation or percent of maximal stimulation elicited by PGI2t in describing the effect of prostaglandins on cyclic AMP accumulation. The results of this study lend further support to the proposal that cyclic AMP mediates the effect of prostaglandins on platelet function. *Full manuscript not available for this presentation.
595
ABSTRACT
The maximum accumulation of cyclic AMP in washed human platelets in the presence of prostacyclin (PGI2) is substantially greater than that obtained with saturating concentrations of either prostaglandin D2 or E1 (PGD2 or PGE0. A good correlation exists between the capacity of several naturally-occurring prostaglandins to inhibit ADPinduced platelet aggregation and their ability to increase the intracellular accumulation of cyclic AMP to a submaximal level (i.e., less than 30~ of the maximum stimulation elicited by PGI2). The rank order of potency in both assays agrees (PGI2 > PGD2 > PGEt > PGE2 > PGAt > PGF2a~. However, the concentration required for half-maximal inhibition of platelet aggregation by PGI2 (2.7 nr~) is ten times lower than that required for half-maximal elevation in intracellular cyclic AMP (27 nM). For this reason, it is desirable to indicate both potency and efficacy (fold-stimulation or percent of maximal stimulation elicited by PGI2t in describing the effect of prostaglandins on cyclic AMP accumulation. The results of this study lend further support to the proposal that cyclic AMP mediates the effect of prostaglandins on platelet function. *Full manuscript not available for this presentation.
595