Role of adenosine and nitric oxide on the mechanisms of action of dipyridamole.
OBJECTIVE
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 mug/min increased FBF from 4.6+/-0.9 to 29.4+/-5.3 (539% increase) with dipyridamole/aspirin and from 3.9+/-0.8 to 12+/-2.5 mL/100 mL forearm/min (208% increase) with aspirin alone (P=0.007). 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 (r2=0.6); 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.


CONCLUSIONS
The effects of dipyridamole on resistance vessels are preferentially explained by potentiation of adenosine mechanisms rather than potentiation of nitric oxide or other cGMP-mediated actions.
Gamboa
Alfredo
A
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
Abraham
Robert
R
Diedrich
Andre
A
Shibao
Cyndya
C
Paranjape
Sachin Y
SY
Farley
Ginnie
G
Biaggioni
Italo
I
D000109:Acetylcholine / Q000008:administration & dosage; D000241:Adenosine / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D001241:Aspirin / Q000008:administration & dosage; D001783:Blood Flow Velocity / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D018592:Cross-Over Studies; D006152:Cyclic GMP / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D008954:Models, Biological; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D009599:Nitroprusside / Q000008:administration & dosage; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D004176:Dipyridamole; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP; D000241:Adenosine; D000109:Acetylcholine; D001241:Aspirin