Effect of adenosine A2 receptor stimulation on platelet activation-aggregation: differences between canine and human models.
BACKGROUND
Adenosine A(2) agonists improve arterial patency in experimental models of recurrent thrombosis, an effect purportedly triggered by stimulation of platelet A(2) receptors and subsequent down-regulation of platelet function. However: (i) there is no direct evidence to substantiate this premise; and (ii) given the recognized differences among species in platelet signaling, it is possible that the mechanisms of A(2) receptor stimulation may be model-dependent. Accordingly, we applied an integrated in vivo and in vitro approach, using both canine and human models, to test the hypothesis that the anti-thrombotic effects of A(2) agonist treatment are due in part to inhibition of platelet activation.


METHODS
In Protocol 1, recurrent coronary thrombosis was triggered in anesthetized dogs by application of a stenosis at a site of arterial injury. Coronary patency and flow cytometric indices of platelet activation (P-selectin expression; formation of heterotypic aggregates) were compared in dogs pre-treated with the A(2) agonist CGS 21680 versus controls. In Protocols 2 and 3, blood samples were obtained from dogs and human volunteers. In vitro aggregation and platelet activation (assessed by impedance aggregometry and flow cytometry, respectively) were quantified in paired aliquots pre-incubated with CGS versus vehicle.


RESULTS
In the canine models, CGS improved in vivo coronary patency and attenuated in vitro aggregation but, contrary to our hypothesis, did not evoke a down-regulation in platelet activation. In contrast, in human blood samples, CGS attenuated both in vitro aggregation and flow cytometric markers of platelet activation-aggregation.


CONCLUSIONS
The mechanisms contributing to the anti-thrombotic effect of A(2) agonist treatment are species-dependent: adenosine A(2) receptor stimulation inhibits platelet activation in human, but not canine, models.
Linden
Matthew D
MD
Center for Platelet Function Studies, University of Massachusetts Medical School, Worcester MA 01655, United States.
Barnard
Marc R
MR
Frelinger
A L
AL
Michelson
Alan D
AD
Przyklenk
Karin
K
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D004285:Dogs; D006801:Humans; D009000:Monocytes / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology; D015539:Platelet Activation; D010974:Platelet Aggregation; D043683:Receptors, Adenosine A2 / Q000502:physiology*; D013045:Species Specificity; D014654:Vascular Patency
D010627:Phenethylamines; D043683:Receptors, Adenosine A2; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine