Efflux of 42K+ was measured in frog sartorius muscles equilibrated in depolarizing solutions with external K+ concentrations [( K+]0) between 75 and 300 mM and NaCl concentrations of 60, 120, or 240 mM. For several combinations of KCl and NaCl, steady-state internal potentials (Vi) were the same for different [K+]0. For the range of Vi examined, K+ efflux occurs principally through the K+ inward rectifier channels. When external K+ is removed Vi remains constant for 2 to 3 hr because of the high membrane conductance to Cl-, but K+ efflux drops by about one order of magnitude. External Ba2+ in the presence or absence of external K+ produces an inhibition of K+ efflux described by a relation of the form u = (u1/(1 + C [Ba2+]0] + u2, where u is the uninhibited fraction of K+ efflux; u1, u2 and C are constants; and u1 + u2 = 1. C depends both on [K+]0 and Vi. When [K+]0 greater than or equal to 75 mM, increasing [K+]0 at constant Vi reduces Ba2+ sensitivity. For constant Vi greater than or equal to -30 mV, Ba2+ sensitivity is less when [K+]0 = 0 than when [K+]0 greater than or equal to 75 mM. When [K+]0 = 0, Ba2+ sensitivity decreases as Vi is made more positive. The dependence of the Ba2+ sensitivity on Vi at constant [K+]0 is greater when [K+]0 = 0 than when [K+]0 greater than or equal to 75 mM. Both the activation of K+ efflux by external K+ and the Ba2+ inhibition of K+ efflux can be explained on the basis of two membrane control sites associated with each channel. When both sites are occupied by K+, the channels are in a high flux state. When one or both sites are empty, the channels are in a low, nonzero flux state. When Ba2+ occupies either site, K+ efflux is further reduced. The reduction of Ba2+-sensitivity by increasing [K+]0 at high [K+]0 is attributable to the displacement of Ba2+ from the control sites by K+. The increased Ba2+ sensitivity produced by going from [K+]0 = 0 to [K+] greater than or equal to 75 mM when Vi greater than or equal to -30 mV is attributable to states in which Ba2+ occupies one site and K+ the other when [K+]0 not equal to 0.(ABSTRACT TRUNCATED AT 400 WORDS)