Cl efflux induces depolarization and contraction of smooth muscle cells. This study was undertaken to explore the role of Cl flux in histamine-induced contraction in the rabbit basilar artery. Male New Zealand White rabbits (n = 16) weighing 1.8-2.5 kg were euthanized by an overdose of pentobarbital sodium. The basilar arteries were removed for isometric tension recording. Histamine produced a concentration-dependent contraction that was attenuated by the H₁ receptor antagonist chlorpheniramine (10⁸ M) but not by the H₂ receptor antagonist cimetidine (3 × 10⁶ M) in normal Cl Krebs-Henseleit bicarbonate solution (123 mM Cl). The histamine-induced contraction was reduced by the following manipulations: 1) inhibition of Na⁺-K⁺-2Cl cotransporter with bumetanide (3 × 10⁵ and 10⁴ M), 2) bicarbonate-free HEPES solution to disable Cl/HCO exchanger, and 3) blockade of Cl channels with the use of niflumic acid, 5-nitro-2-(3-phenylpropylamino) benzoic acid, and indoleacetic acid 94 R-(+)-methylindazone. In addition, substitution of extracellular Cl (10 mM) with methanesulfonate acid (113 mM) transiently enhanced histamine-induced contraction. Manipulation of Cl flux affects histamine-induced contraction in the rabbit basilar artery.