Interaction of calcium and local anesthetics with skeletal muscle microsomes

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Abstract
The influence of Ca++, several drugs, and pH on the binding of Ca++ by skeletal muscle microsomes was studied in vitro. A mass‐law graphic analysis revealed the presence of three distinct species of Ca++‐binding sites in the microsomes, and the binding at only one of these sites was antagonized by local anesthetics and quinidine. These drugs also decreased the maximum Ca++‐binding capacity of the microsomes. Caffeine and ouabain exerted no effect on the binding at any of the sites. Procaine was also bound by microsomes, and this binding was antagonized by Ca++, which also decreased the maximum procaine‐binding capacity of microsomes. The sites that bind procaine and Ca++ are not identical because the maximum‐binding capacities of the interacting sites are distinctly different. The influence of pH on the ability of drugs to antagonize Ca++ binding indicates that the displacing activity increases as the percentage of the drug in the nonionized form increases. All of the data obtained in the above studies are consistent with the interpretation that quinidine and local anesthetics of the procaine type noncompetitively antagonize the binding of Ca++ by microsomes. The pharmacological significance of a noncompetitive interaction may be related to the property of local anesthetics and quinidine to increase contractile tension in skeletal muscle rather than to their ability to stabilize the cell membrane.