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Sequential activation of adenylate cyclase and cyclic AMP phosphodiesterase in human platelets by prostaglandins
SEQUENTIAL ACTIVATION OF ADENYLATE CYCLASE AND CYCLIC AMP PHOSPHODIESTERASE IN H U M A N P L A T E L E T S BY P R O S T A G L A N D I N S * ROBERT ALVAREZ, JOHN J. BRUNO and JASMINEFAZZARI Institute of Biolo,qical Sciences, Syntex Re.search, Palo Alto, California 94304, U.S.A. ABSTRACT
Prostacyclin (PGI2) induces a rapid increase in cyclic AMP in washed platelets which is followed by a gradual decline. This transient pattern appears to involve a sequential activation of adenylate cyclase and cyclic AMP phosphodiesterase. Three observations support this interpretation: (1) inhibition of endogenous phosphodiesterase activity with l-methyl-3-isobutylxanthine (MIX) eliminates the transient pattern and permits accumulation of the cyclic nucleotide, (2) prostaglandins activate a soluble cyclic AMP phosphodiesterase when preincubated with intact platelets, and (3) the time course of phosphodiesterase activation coincides with the decrease in cyclic AMP. Although PGI2 and PGE1 stimulate adenylate cyclase to the same maximum velocity, PGI2 increases intracellular cyclic AMP to a higher maximum level than PGEI. MIX reduces the difference in efficacy between PGEt and PGI2. If phosphodiesterase activation by prostaglandins is responsible for the gradual decrease in cyclic AMP, then these results suggest that the interval between activation of adenylate cyclase and the subsequent increase in phosphodiesterase activity determines, in part, the efficacy of prostaglandins with respect to cyclic AMP accumulation and their potency as inhibitors of platelet aggregation. *Full manuscript not available for this presentation.
597
Prostacyclin (PGI2) induces a rapid increase in cyclic AMP in washed platelets which is followed by a gradual decline. This transient pattern appears to involve a sequential activation of adenylate cyclase and cyclic AMP phosphodiesterase. Three observations support this interpretation: (1) inhibition of endogenous phosphodiesterase activity with l-methyl-3-isobutylxanthine (MIX) eliminates the transient pattern and permits accumulation of the cyclic nucleotide, (2) prostaglandins activate a soluble cyclic AMP phosphodiesterase when preincubated with intact platelets, and (3) the time course of phosphodiesterase activation coincides with the decrease in cyclic AMP. Although PGI2 and PGE1 stimulate adenylate cyclase to the same maximum velocity, PGI2 increases intracellular cyclic AMP to a higher maximum level than PGEI. MIX reduces the difference in efficacy between PGEt and PGI2. If phosphodiesterase activation by prostaglandins is responsible for the gradual decrease in cyclic AMP, then these results suggest that the interval between activation of adenylate cyclase and the subsequent increase in phosphodiesterase activity determines, in part, the efficacy of prostaglandins with respect to cyclic AMP accumulation and their potency as inhibitors of platelet aggregation. *Full manuscript not available for this presentation.
597