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The precise mechanisms behind the direct inhibitory action of sevoflurane on vascular smooth muscle have not been fully elucidated.Endothelium-denuded smooth muscle strips were prepared from rat small mesenteric arteries. Isometric force and intracellular Ca2+ concentration ([Ca2+]i) were measured simultaneously in the fura-2–loaded strips. In another series of experiments, only isometric force was measured in the β-escin-membrane–permeabilized strips.Sevoflurane (3–5%) inhibited the increases in both the [Ca2+]i and the force induced by either norepinephrine (0.5–10 μm) or 40 mm K+. Sevoflurane still inhibited the increase in [Ca2+]i induced by norepinephrine after depletion of intracellular Ca2+ stores with ionomycin, although it little influenced the increase in [Ca2+]i induced by norepinephrine after treatment with verapamil. In the fura-2–loaded membrane-intact muscle, sevoflurane caused a rightward shift of Ca2+-force relation during force development to stepwise increment of extracellular Ca2+ concentration during 40-mm K+ depolarization in either the presence or the absence of norepinephrine. In contrast, sevoflurane did not influence Ca2+-activated contraction in the β-escin–permeabilized muscle, in which α-adrenergic receptor coupling was not retained.The inhibitory effects of sevoflurane on both norepinephrine- and potassium chloride (KCl)–induced contractions are caused by reduction of [Ca2+]i in vascular smooth muscle and inhibition of the myofilament Ca2+ sensitivity. The [Ca2+]i-reducing effect of sevoflurane observed in both the norepinephrine- and the K+-stimulated muscle is mainly caused by inhibition of voltage-gated Ca2+ influx. The inhibitory effect of sevoflurane on Ca2+ activation of contractile proteins seems to be mediated by the cell membrane or by some diffusible substances that are lost in the β-escin–permeabilized cells.