Abstract

Contractures of the toe muscles of frogs produced by 123 mM K+ were reduced or blocked by verapamil (or D-600) when applied in concentrations of 10(-7) M or more. In concentrations between 10(-7) and 3 X 10(-5) M or less, little or no reduction was produced in the first test with high K+ after drug application. When tests were repeated at 10- to 15-min intervals, block was produced. This block decreased and eventually disappeared if the muscles were kept in the drug solution without testing for 25 min or more. In contrast, at 10(-4) M verapamil, the first contracture in response to high K+ was reduced or blocked. If exposure to 10(-4) M verapamil was limited to 0.5 hr, then recovery occurred in drug-free solution, but if the muscles were exposed to this concentration of verapamil for 2.5 hr or longer, the K+ contracture remained blocked, even in drug-free solution. These results provided an explanation for the frequency- and use-dependency effects of verapamil and D-600. Briefly, this explanation is that the drug receptor is inside the calcium channel which is closed to the extracellular fluid in the resting or in the inactivated state but open to the intracellular fluid at all times. The drug receptors will be effectively occupied and a block produced when lower drug concentrations are used if the calcium channels are opened, but verapamil will leave its receptor and diffuse into the intracellular fluid when the extracellular channel openings are closed. Further details of this mechanism are given in the paper.