Abstract
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 microg min(-1) dl(-1), an inhibitor of prostaglandin synthesis, n=6), glibenclamide (10 microg 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 2.410.17 to 2.990.18, 4.090.26 and 6.770.49 ml 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: 236, 8219, 24138% versus 278, 4422, 4235%). 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.
