In vivo evidence for KCa channel opening properties of acetazolamide in the human vasculature

1 The selective carbonic anhydrase inhibitor acetazolamide is known to increase blood flow in several organs. Acetazolamide directly dilates isolated resistance arteries associated with activation of calcium-activated potassium (K-Ca) channels. We examined both the presence and mechanism of the direct vascular action of acetazolamide in vivo in humans. 2 Forearm vasodilator responses of 30 healthy volunteers to infusion of placebo and increasing doses of acetazolamide (1-3-10 mg min(-1) dl(-1)) into the brachial artery were recorded by venous occlusion plethysmography, before and after local administration of L-NMMA (0.2 mg min(-1) dl(-1), an inhibitor of NO-synthase, n = 6), indomethacin (5.0 mug min(-1) dl(-1), an inhibitor of prostaglandin synthesis, n=6), glibenclamide (10 mug min(-1) dl(-1), an inhibitor of K-ATP channels, n=6), tetraethylammonium (0.1 mg min(-1) dl(-1), an inhibitor of K-Ca channels, n=6) or placebo (NaCl 0.9%, n = 6). Lower dosages of acetazolamide did not affect vascular tone (n = 6). 3 Acetazolamide infusions increased forearm blood flow from 2.41+/-0.17 to 2.99+/-0.18, 4.09+/-0.26 and 6.77+/-0.49 mi min(-1) dl(-1) in the infused forearm (P < 0.001), with no significant changes in the non-infused forearm, blood pressure or heart rate. Acetazolamide-induced vasodilation was not inhibited by L-NMMA, indomethacin, or glibenclamide but was significantly attenuated by TEA (vasodilation: 23 +/- 6, 82 +/- 19, 241 +/- 38% versus 27 +/- 8, 44 +/- 22, 42 +/- 35%). 4 We conclude that acetazolamide exerts a direct vasodilator effect in vivo in humans mediated by vascular K-Ca channel activation. This makes acetazolamide the first drug known that specifically modulates this channel.