Role of Adenosine and Nitric Oxide on the Mechanisms of Action of Dipyridamole

Abstract

Background and Purpose-The combination of dipyridamole and aspirin has been shown to be more effective than aspirin alone in the secondary prevention of stroke. Dipyridamole may act by inhibiting adenosine uptake, thus potentiating its actions. Dipyridamole also inhibits cGMP-specific phosphodiesterases (PDE) and, through this mechanism, could potentiate cGMP-mediated actions of nitric oxide. Methods-To define the mechanism of action of dipyridamole, we studied the local vascular effects of adenosine, acetylcholine (NO-mediated dilation), and nitroprusside (cGMP-mediated dilation) in a double-blind study after treatment with dipyridamole/aspirin (200 mg dipyridamole/25 mg aspirin twice a day) or aspirin control for 7 days in 6 normal volunteers. Vasodilators were administered into the brachial artery in the nondominant arm in random order and forearm blood flow (FBF) was measured by venous occlusion plethysmography. Results-Adenosine at a dosage of 125 g/min increased FBF from 4.6Ϯ0.9 to 29.4Ϯ5.3 (539% increase) with dipyridamole/aspirin and from 3.9Ϯ0.8 to 12Ϯ2.5 mL/100 mL forearm/min (208% increase) with aspirin alone (Pϭ0.007). In contrast, dipyridamole/aspirin did not alter the response to acetylcholine or to nitroprusside. The magnitude of adenosine-induced vasodilation correlated with plasma dipyridamole concentrations (r 2 ϭ0.6); no correlation was observed with acetylcholine-or nitroprusside-induced vasodilation. Similar potentiation of adenosine, but not acetylcholine or nitroprusside, was observed in 7 additional subjects when adenosine, acetylcholine, and nitroprusside were given in random order before and 2 hours after a single dose of dipyridamole/aspirin. Conclusion-The

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

“…We and others have shown previously that dipyridamole very effectively inhibits the uptake of adenosine into red cells in whole blood 11,25,26 and thereby leaves the adenosine available to interact with platelets. 27,28 Once again, very similar results were obtained irrespective of the type of P2Y 12 antagonist used.…”

“…We have already discussed the ability of dipyridamole to inhibit adenosine uptake into red cells, but in addition to its inhibitory effects on adenosine uptake, dipyridamole is also an inhibitor of cAMP phosphodiesterase. 27,28 cAMP phosphodiesterase inhibitors inhibit platelet function by preventing the breakdown of cAMP, thus helping to maintain elevated intracellular levels of the nucleotide. Thus, in the presence of adenosine, this additional property could bring about even further inhibition of platelet aggregation.…”

“…It is known, for example, that dipyridamole is an inhibitor of adenosine uptake into red cells acting via the equilibrative nucleoside transporter. [25][26][27][28] Also, the P2Y 12 antagonist ticagrelor has been reported to inhibit adenosine uptake into red cells, as well as acting on platelets via P2Y 12 antagonism, and might therefore allow adenosine to add to the effects of P2Y 12 blockade. 29 Against this background, we report here the results of a number of experiments that we have performed in both platelet-rich plasma (PRP; in which red cells are absent) and whole blood.…”

Translational Therapeutics of Dipyridamole

“…Indeed, DP has been shown to potentiate NO/cGMP vasodilatory and platelet antiaggregatory effects, 40 enhance ischemia-induced angiogenesis, 41 increase myocardial perfusion in heart failure and stable coronary artery disease, 21,42 and ameliorate the severity of ischemic strokes via NO-and adenosine-mediated effects. 43 …”

Dipyridamole inhibits intracellular calcium transients in isolated rat arteriole smooth muscle cells

“…In the present study, we further demonstrated that, in the presence of adenosine, an ATP-induced [Ca 2+ ]i response was observed in arteriole smooth muscle cells -although this reaction was partially inhibited. Because adenosine A1 receptors mediate the inhibition of L-type Ca 2+ channels (Di Perri et al, 1989;Rocher et al, 1999), the effects of dipyridamole on resistance vessels may be partly explained by the potentiation of adenosine mechanisms rather than the potentiation of NO or other cGMP-mediated actions (Gamboa et al, 2005).…”