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

• Published in: Stroke (1970) Vol. 36; no. 10; pp. 2170 - 2175
• Main Authors: Gamboa, Alfredo, Abraham, Robert, Diedrich, Andre, Shibao, Cyndya, Paranjape, Sachin Y., Farley, Ginnie, Biaggioni, Italo
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.10.2005
• Subjects: Acetylcholine - administration & dosage; Adenosine - chemistry; Adenosine - metabolism; Adenosine - physiology; Adult; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Aspirin - administration & dosage; Biological and medical sciences; Blood Flow Velocity - drug effects; Cardiovascular System - drug effects; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Cross-Over Studies; Cyclic GMP - metabolism; Dipyridamole - pharmacology; Dose-Response Relationship, Drug; Double-Blind Method; Fundamental and applied biological sciences. Psychology; General and cellular metabolism. Vitamins; Humans; Medical sciences; Models, Biological; Neurology; Nitric Oxide - chemistry; Nitric Oxide - metabolism; Nitric Oxide - physiology; Nitroprusside - administration & dosage; Pharmacology. Drug treatments; Phosphoric Diester Hydrolases - metabolism; Time Factors; Vascular diseases and vascular malformations of the nervous system; Vasodilator Agents - pharmacology; Vertebrates: nervous system and sense organs; Antianginal agent; Prostaglandin-endoperoxide synthase; Purine nucleoside; Coronary vasodilator agent; Cardiovascular disease; Acetylsalicylic acid; Vascular disease; aspirin; Salicylates; Mechanism of action; Cerebrovascular disease; Regional blood flow; Stroke; Adenosine; Nervous system diseases; Enzyme; Dipyridamole; Enzyme inhibitor; Antiplatelet agent; Cerebral disorder; Endothelium; Non steroidal antiinflammatory agent; Analgesic; Nitric oxide; Central nervous system disease; Antipyretic; Oxidoreductases
• ISSN: 0039-2499; 1524-4628; 1524-4628
• DOI: 10.1161/01.STR.0000179044.37760.9d

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 μg/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 ( r 2 =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. Conclusion— 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.