Chronic oral dipyridamole as a 'novel' antianginal drug: the collateral hypothesis

Dipyridamole is an adenosine transport blocker that produces elevation of tissue adenosine levels. The oral formulation has long been used as a 'coronary vasodilator', but inappropriate vasodilation can lead to a pro-ischemic effect. However, available evidence linking adenosine to angiogenesis raises the possibility of a therapeutically relevant anti-ischemic effect of the drug. Molecular biology data show that in a hypoxic milieu, increased interstitial adenosine increases proliferation of endothelial cells in culture by stimulating A1 and A2 adenosine receptors and induces vascular endothelial growth factor which leads to angiogenesis. Morphologic data indicate that chronic, intermittent dipyridamole administration increased endomyocardial capillary length density by 33% in hypertensive and 11% in normotensive rabbits. Experimental data suggest that chronic treatment with dipyridamole increases collateral flow and decreases exercise-induced left ventricular dysfunction in the territory dependent upon a critical coronary stenosis. Clinical data indicate that the meta-analysis of all published double-blind, placebo-controlled, randomized trials assessing the effect of dipyridamole as an antianginal agent showed a highly significant drug benefit (odds ratio = 0.299, confidence intervals = 0.202-0.443). Treatment duration (log time in days) was significantly correlated to the observed benefit (log odds) (r = -75, P = 0.0031), consistently with a structural change in the collateral coronary circulation requiring time to emerge. The available data support the 'adenosine collateral hypothesis' (i.e., a beneficial angiogenetic effect of chronic endogenous adenosine accumulation). The angiogenetic effect would be different from the coronary vasodilator effect in several respects: coronary anatomical target (mainly capillaries instead of arterioles); cellular target (mainly endothelium rather than smooth muscle cell); receptor target (A1 and A2 rather than A2 adenosine receptors); time required for effect (weeks or months rather than minutes or hours); clinical use (possibly therapeutic for angiogenesis; mainly diagnostic for vasodilator stress testing). Prospective, properly designed trials are needed to assess convincingly the efficacy of a drug used for 40 years and yet possibly prematurely discarded as an effective antianginal treatment.