Volatile anesthetics vasodilate in part by direct action on vascular smooth muscle. Isoflurane-induced relaxation of portal vein smooth muscle involves alteration of membrane ionic currents that control cell excitability and contraction. Whole cell voltage clamp technique was used to examine outward Ca(2+)-activated K+ current (IK,Ca) in guinea pig portal vein cells. Isoflurane caused a concentration-dependent reduction in IK,Ca at steady-state conditions but had no significant effect on resting potential. Isoflurane transiently potentiated IK,Ca by a mechanism that may partly involve Ca2+ release from intracellular storage sites. The depression of IK,Ca by isoflurane may occur by direct action on the channel protein or on the lipid environment of the channel to alter conductance or kinetic properties. Since isoflurane reduces IK,Ca coincident with suppression of Ca2+ channel current, it was concluded that the depression of IK,Ca by isoflurane is of secondary importance to reduction in inward Ca2+ channel current. Potentiation of IK,Ca may preclude significant membrane activation during the onset of isoflurane's action.