Purines and Regulation of Platelet Activation

Abstract

Purines play key roles in platelet physiological regulatory processes (1–3). Human platelets in comparison with human erythrocytes and leukocytes, contain greater concentrations of adenine nucleotides (4,5), which are distributed between the metabolic and storage pools (5–10). During the induction of platelet aggregation by an agent such as thrombin or collagen, the storage pool nucleotides (principally ADP) as well as other vasoactive agents of the storage granules (e.g. serotonin, Ca2+) are released into the plasma (11,12). Platelet aggregation is strongly inhibited by other adenine nucleotides, adenosine 5′-tetraphosphate (AP4) (13,14), ATP (13–15), AMP (13,14,16,17), and adenosine (18–20). Adenosine is continuously produced in the body by many tissues including the vascular endothelium (21), brain, heart (22) and platelets (23). However, only low amounts of adenosine (100 to 300 nM) (23,24) are seen in human plasma due to its rapid cellular uptake and metabolism primarily by adenosine deaminase and adenosine kinase (25,26). Recent studies have shown that even these low plasma adenosine levels contribute greatly in the physiological regulatory process of platelet function (23,27,28). In addition, plasma adenosine plays an important role in the antiplatelet activity of cAMP phosphodiesterase inhibitors (29), forskolin (30), and nitric oxide [Maddali and Agarwal, unpublished results]. Theophylline and caffeine, which act as adenosine receptor antagonists, produce stimulation of platelet aggregation in human PRP with adenosine (27,28).