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Molecular Pharmacology

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Research ArticleArticle

Regulation of Cyclic AMP Metabolism in Human Platelets

Sequential Activation of Adenylate Cyclase and Cyclic AMP Phosphodiesterase by Prostaglandins

ROBERT ALVAREZ, ADAIR TAYLOR, JASMINE J. FAZZARI and JOHN R. JACOBS
Molecular Pharmacology September 1981, 20 (2) 302-309;
ROBERT ALVAREZ
Institute of Biological Sciences, Syntex Research, Palo Alto, California 94304
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ADAIR TAYLOR
Institute of Biological Sciences, Syntex Research, Palo Alto, California 94304
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JASMINE J. FAZZARI
Institute of Biological Sciences, Syntex Research, Palo Alto, California 94304
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JOHN R. JACOBS
Institute of Biological Sciences, Syntex Research, Palo Alto, California 94304
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Abstract

Prostacyclin (PGI2) produces a transient elevation in cyclic AMP in washed human platelets. Intracellular cyclic AMP increases rapidly to a maximal level after 1-2 min of incubation and then gradually declines. This temporal pattern appears to involve a sequential activation of adenylate cyclase and cyclic AMP phosphodiesterase. The following three observations support this interpretation: (a) inhibition of endogenous phosphodiesterase activity with 1-methyl-3-isobutylxanthine eliminates the transient elevation pattern and permits accumulation of the cyclic nucleotide, (b) PGI2 indirectly stimulates the activity of a cyclic AMP phosphodiesterase when preincubated with intact platelets, and (c) the gradual decrease in endogenous cyclic AMP coincides with an increase in phosphodiesterase activity. The potency and efficacy of prostaglandins (PGs) as stimulators of phosphodiesterase activity correlate with their capacity to increase intracellular cyclic AMP (PGI2 > PGD2 ≥ PGE1). PGD2 increases cyclic AMP to a higher maximal level than does PGE1 in intact cells, but stimulates adenylate cyclase to a lower maximal velocity in broken-cell preparations. This discrepancy was observed under a variety of assay conditions. When washed platelets were preincubated in a hypotonic buffer containing EDTA prior to the assay, the discrepancy was eliminated. Thus, under appropriate incubation conditions, the potency and efficacy of several naturally occurring PGs as stimulators of adenylate cyclase correspond to their ability to increase the intracellular concentration of cyclic AMP (PGI2 > PGD2 ≥ PGE1 » PGE2 ≥ PGA1 > PGF2α). Similarly, their potency as inhibitors of ADP-induced platelet aggregation corresponds to their capacity to elevate cyclic AMP to a critical, submaximal level. These results lend further support to the concept that cyclic AMP mediates the effect of PGs on platelet function and that activation of adenylate cyclase is the primary biochemical event responsible for the accumulation of cyclic AMP.

ACKNOWLEDGMENTS We gratefully acknowledge the many useful discussions with Dr. John J. Bruno and his support of this project. This study was facilitated by the technical assistance of Ms. Gail Winter. Platelet electron micrographs were provided by Mrs. Friederike M. Freymark.

  • Copyright © 1981 by The American Society for Pharmacology and Experimental Therapeutics

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Molecular Pharmacology
Vol. 20, Issue 2
1 Sep 1981
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Research ArticleArticle

Regulation of Cyclic AMP Metabolism in Human Platelets

ROBERT ALVAREZ, ADAIR TAYLOR, JASMINE J. FAZZARI and JOHN R. JACOBS
Molecular Pharmacology September 1, 1981, 20 (2) 302-309;

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Research ArticleArticle

Regulation of Cyclic AMP Metabolism in Human Platelets

ROBERT ALVAREZ, ADAIR TAYLOR, JASMINE J. FAZZARI and JOHN R. JACOBS
Molecular Pharmacology September 1, 1981, 20 (2) 302-309;
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