Adenosine receptor‐induced cyclic AMP generation and inhibition of 5‐ hydroxytryptamine release in human platelets.

Abstract

5 In the presence of a cyclic AMP phosphodiesterase inhibitor, the effects of CGS 21680 on cyclic AMP accumulation and 5-HT release were enhanced to levels similar to those elicited by 10 gM NECA. In the absence of phosphodiesterase inhibition, CGS 21680 did not antagonise the effects of NECA. Furthermore, endogenous adenosine did not contribute to the effects of CGS 21680 when phosphodiesterase was inhibited. 6 We conclude that an A2a adenosine receptor appears to be involved in the NECAelicited increases in cyclic AMP levels and inhibition of 5-HT release in human platelets. However, the difference in efficacy between NECA and the A2a-selective agonist CGS 21680, observed in the absence but not the presence of a phosphodiesterase inhibitor, suggests that other mechanisms must underlie this differential effect.

Characterization of the human brain putative A2B adenosine receptor expressed in Chinese hamster ovary (CHO.A2B4) cells

“…PD 115,199 also showed high affinity for antagonism of 5'-N-ethylcarboxamidoadenosine (NECA)-evoked responses in human platelets with an apparent pA2 value of approximately 7.5. This pharmacology therefore is positive evidence for the presence of an A2A adenosine receptor subtype on human platelets (Cooper et al, 1995b).…”

“…A number of agents have been developed which exhibit some degree of selectivity for the A2A compared to the A2B adenosine receptor, including the agonists CGS 21680 (Lupica et al, 1990) and APEC (Fredholm et al, 1994), and the antagonist PD 115,199 (Bruns et al, 1987b). For example, in human platelets, NECA and CGS 21680 show a similar high potency (pD2>6) for stimulation of cyclic AMP generation and inhibition of 5-hydroxytryptamine (5-HT) release (Cooper et al, 1995b). PD 115,199 also showed high affinity for antagonism of 5'-N-ethylcarboxamidoadenosine (NECA)-evoked responses in human platelets with an apparent pA2 value of approximately 7.5.…”

Pharmacological and biochemical characterization of purified A2a adenosine receptors in human platelet membranes by [3H]‐CGS 21680 binding

“…To overcome the many difficulties associated with this interaction between the A2a adenosine receptors and adenotin sites, two approaches have been used to separate them: gel filtration (Lohse et al, 1988;Fein et al, 1994) and CHAPS solubilization followed by PEG precipitation and differential centrifugation (Zolnierowicz et al, 1990). With this background, it is clear that a key advance in understanding the function of the A2a receptors can be made with a specific substrate, such as platelets (Dionisotti et al, 1992;Cooper et al, 1995;Ongini et al, 1995), where it is possible to examine both affinity and potency of adenosine ligands. In platelets, A2a agonists inhibit aggregation (Dionisotti et al, 1992) and stimulate the formation of the second messenger, cyclic AMP (Jacobson et al, 1993).…”

Adenosine Derived From ADP Can Contribute to Inhibition of Platelet Aggregation in the Presence of a P2Y 12 Antagonist

“…It is secreted from platelets themselves when they undergo a release reaction and potentiates the aggregatory effects of other platelet agonists, such as thrombin and collagen. [1][2][3] The proaggregatory effects of ADP on platelets are via interaction with P2Y 1 and P2Y 12 receptors, [1][2][3][4] and one of the main effects of ADP at the P2Y 12 receptor is the inhibition of adenylate cyclase, leading to a reduction in cAMP levels and subsequent promotion of the aggregation response. Antagonists that act at P2Y 12 receptors markedly inhibit platelet aggregation, specifically by blocking the effects of ADP at this receptor, 5 thereby preventing inhibition of adenylate cyclase.…”

“…6 -8 Although ADP is conventionally regarded as a platelet agonist, the molecule can be broken down first to AMP and then to adenosine in blood and plasma. 9 -11 Adenosine, of course, is an inhibitor of platelet aggregation acting via A 2A and A 2B receptors on platelets to activate adenylate cyclase and increase cAMP, [12][13][14] and both ADP removal and adenosine production might be expected to modulate platelet function. [15][16][17][18][19][20] Such modulation may be particularly evident in the presence of a P2Y 12 antagonist that blocks the ability of the ADP to inhibit adenylate cyclase.…”