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Methanesulfonanilide Class III antiarrhythmic agents have been shown to block a specific outward delayed rectifier K+ current, Ikr in cardiac cells. K+ conductance also is recognized to be an important regular of contractile tone in vascular smooth muscle. The purpose of the present investigation was to assess the effects of the new and potent methanesulfoanilide Class III agents E-4031, UK-68,798, UK-66,914 and the Class III standard d-sotalol in vitro in phasically active and electrically quiescent vascular smooth muscle preparations. All four Class III agents augmented phasic contractile tension in spontaneously active rat portal veins at concentrations similar to those effecting significant Class III electrophysiologic activity in cardiac muscle, but failed to contract electrically quiescent rabbit aortic rings. At concentrations exceeding effective cardiac Class III electrophysiologic concentrations, E-4031 relaxed methoxamine- and histamine-contracted rabbit aortic rings, and d-sotalol relaxed methoxamine-contracted aortic rings. UK-68,798 and UK-66,914 failed to relax spasmogen-contracted aortic rings. The similarity in effective concentrations required for the four Class III agents to augment phasic contractile tension in the rat portal vein and increase myocardial refractoriness in cardiac muscle is consistent with the presence of similar K+ channel subtypes in the two tissues. Alternatively, the observed activities in the two tissues may be due to actions of these four Class III agents on another, non-Ikr ion channel present in rat portal vein, with an order of potency for blockade similar to block of Ikr in cardiac tissue. © 1992 wiley-Liss, Inc.