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The Role of Cyclic Nucleotides in Platelets

  • D. C. B. Mills
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 58 / 2)

Overview

Cyclic AMP in blood platelets is regulated by several endogenous factors and can also be influenced by drugs. Elevation of platelet cAMP, either by inhibition of phosphodiesterase or by stimulation of adenylate cyclase, leads to the suppression of their responsiveness to stimulation, and their participation in haemostatic and thrombotic processes is reduced.

Platelet adenylate cyclase is regulated by specific receptors for prostaglandins I2 and D2, for adenosine (“P”- and “R”-type receptors) and for ADP and catecholamines, (α and β. PGI2, PGE1, PGD2 adenosine and β-adrenergic agonists stimulate adenylate cyclase activity; ADP and α-adrenergic agonists inhibit the enzyme. Both receptor-mediated stimulation and inhibition are influenced by intracellular guanine nucleotides. The enzyme is also stimulated by histamine, cholera toxin and fluoride ion. Adenosine, acting on an intracellular “P” receptor, proaggregatory prostaglandins and endoperoxides inhibit the enzyme.

Platelets have three cyclic nucleotide phosphodiesterases, one relatively specific for cAMP (FI), one for cGMP (FIII) and a nonspecific, low affinity enzyme (FII). They differ in their physical characteristics, and in their susceptibility to inhibition by a variety of drugs.

Two cAMP-dependent protein kinases (type I and type II) have been detected, and an increase in platelet cAMP is associated with the phosphorylation of two membrane proteins, and with an increased ability of membrane vesicles to accumulate calcium. Many of the effects of cAMP may be mediated by the consequent reduction in intracellular free calcium ions.

Platelets have a powerful guanylate cyclase which, in contrast to the adenylate cyclase, is not membrane bound. The cGMP level in platelets is rapidly elevated during aggregation, and also when guanylate cyclase is stimulated by a variety of drugs, including inhibitors of aggregation (azide, nitroprusside), aggregating agents (fatty acids, calcium ionophore) and some compounds having no detectable effect on aggregation (ascorbic acid).

Elevation of cGMP level is a consequence rather than a cause of aggregation, and the function of this nucleotide remains a mystery.

Abnormalities of cAMP metabolism have been recognised in some conditions, Bartter’s syndrome, essential thrombocythemia and acute thrombosis, in which platelet haemostatic function is abnormal, as well as others in which no functional abnormally has been detected. It is possible that the adenylate cyclase system of platelets may have a useful role as an indicator of events occurring in the brain or in other inaccessible organs.

Keywords

Platelet Aggregation Cyclic Nucleotide Human Platelet Guanylate Cyclase Blood Platelet 
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© Springer-Verlag Berlin Heidelberg 1982

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  • D. C. B. Mills

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