Glyburide Inhibits Dipyridamole‐induced Forearm Vasodilation but not Adenosine‐induced Forearm Vasodilation

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Abstract
Background: The mechanism of the vasodilator response to adenosine has not been elucidated in humans. Stimulation of adenosine receptors on endothelial and vascular smooth muscle cells with subsequent endothelial release of nitric oxide and opening of adenosine triphosphate (ATP)–sensitive potassium (KATP) channels has been suggested.Aim: The aim of this study was to investigate the involvement of KATP channels in the vasodilator response to adenosine and the nucleoside transport inhibitor dipyridamole.Methods and results: In healthy male volunteers, adenosine (0.6, 1.9, 5.6, 19, 57, and 190 nmol · min−1 · dL−1) was infused into the brachial artery, and forearm blood flow (FBF) was measured by use of strain‐gauge plethysmography. Adenosine increased the FBF ratio (FBF in experimental arm/FBF in control arm) from 1.3 ± 0.2 to 1.2 ± 0.2, 1.5 ± 0.2, 2.8 ± 0.4, 7.3 ± 2.3, 11.1 ± 4.1, and 12.9 ± 3.7 for the six increasing adenosine doses, respectively. Simultaneous infusion of glyburide (INN, glibenclamide), a blocker of KATP channels, did not affect this response (from 1.7 ± 0.4 to 1.5 ± 0.2, 2.2 ± 0.3, 4.0 ± 1.0, 9.3 ± 4.0, 13.5 ± 6.4, and 15.9 ± 5.3 for the 6 increasing doses of adenosine, respectively; P = .439, n = 6). The increase in FBF ratio during infusion of the nucleoside transport inhibitor dipyridamole (20, 60, and 200 nmol · min−1 · dL−1) was significantly reduced by glyburide, as follows: from 1.2 ± 0.1 to 1.7 ± 0.2, 2.4 ± 0.5, and 2.9 ± 0.4, respectively, during saline solution and from 1.6 ± 0.2 to 1.8 ± 0.2, 2.1 ± 0.3, and 2.2 ± 0.4, respectively, during glyburide (P = .010 for effect of glyburide on response from baseline, ANOVA for repeated measures; n = 8). The vasodilator response to dipyridamole was significantly inhibited by the adenosine receptor antagonist theophylline.Conclusion: Opening of vascular KATP channels is involved in the forearm vasodilator response to dipyridamole but not to adenosine. Differences in stimulated cell type (endothelium for adenosine versus smooth muscle cells for dipyridamole) may underlie this divergent pharmacologic profile.Clinical Pharmacology & Therapeutics (2004) 75, 147–156; doi: 10.1016/j.clpt.2003.09.016