The effects of low and high doses of verapamil on expression of Na-K pump and Na channels in cultured rat skeletal muscle were studied and compared. Myotubes were treated for 3 days with either 20 or 100 microM verapamil, and measurements were made of transmembrane resting potential, spontaneous action potential frequency, and specific binding of [3H]ouabain and [3H]saxitoxin. Low verapamil upregulated both Na-K pumps and Na channels, whereas high verapamil down regulated the former and upregulated the latter. Changes in channel levels preceded those in pump levels. Spontaneous contractile activity could be observed during treatment with low but not high verapamil. Simultaneous treatment with verapamil and elevated external K+ reversed the effect on high verapamil-induced changes in pump levels, and potentiated the effects of both concentrations of verapamil on Na channel levels. Scatchard analysis showed that verapamil caused changes in Bmax without altering Kd. The verapamil-induced changes in both Na-K pumps and Na channels were blocked by inhibition of protein and RNA synthesis. We conclude that the differences in effects on Na-K pumps obtained with the two doses are due to the different effects on spontaneous activity and associated changes in intracellular Na concentration.