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Ketamine was previously suggested to relax vascular smooth muscle by reducing the intracellular Ca2+ concentration ([Ca2+]i). However, no direct evidence is available to indicate that ketamine reduces the [Ca2+]i in vascular smooth muscle of systemic resistance arteries.Endothelium-intact or -denuded smooth muscle strips were prepared from rat small mesenteric arteries. Isometric force and [Ca2+]i were measured simultaneously in the fura-2–loaded, endothelium-denuded strips. In some experiments, only isometric force was measured in either the endothelium-intact or β-escin–treated, endothelium-denuded strips.In the endothelium-intact strips, lower concentrations (≤ 30 μm) of ketamine slightly enhanced norepine-phrine-induced contraction, whereas higher concentrations (≥ 100 μm) of ketamine inhibited both norepinephrine- and KCl-induced contractions. In the fura-2–loaded strips, ketamine (≥ 100 μm) inhibited the increases in both [Ca2+]i and force induced by either norepinephrine or KCl. Ketamine also inhibited the norepinephrine-induced increase in [Ca2+]i after treatment with ryanodine. In the absence of extracellular Ca2+, ketamine notably inhibited the norepinephrine-induced increase in [Ca2+]i, whereas it only minimally inhibited caffeine-induced increase in [Ca2+]i. Ketamine had little influence on the [Ca2+]i–force relation during force development to stepwise increment of extracellular Ca2+ concentration during either KCl depolarization or norepinephrine stimulation. Ketamine did not affect Ca2+-activated contractions in the β-escin membrane–permeabilized strips.The action of ketamine on contractile response to norepinephrine consists of endothelium-dependent vasoconstricting and endothelium-independent vasodilating components. The direct vasorelaxation is largely a result of reduction of [Ca2+]i in vascular smooth muscle cells. The [Ca2+]i-reducing effects are caused by inhibitions of both voltage-gated Ca2+ influx and norepinephrine-induced Ca2+ release from the intracellular stores.