The use of drugs in the study of excitation-contraction (E-C) coupling in skeletal muscle during the 25-30 years and the role of these studies in the development of the "trigger-
calcium" hypothesis was reviewed. In early studies,
caffeine was used as a tool to test the function of the intracellular contraction apparatus when the twitch or depolarization
contracture was eliminated by a procedure that was thought to block the coupling part of the E-C coupling process. Later it was shown that
caffeine produced
contractures by releasing Ca2+
ions from intracellular binding sites and then that
caffeine produced this effect by sensitizing the sarcoplasmic reticulum to Ca2+-induced Ca2+ release. More recently, organic
calcium channel blocking drugs (
verapamil,
D-600, and
nitrendipine) were used to confirm earlier results showing that depolarization
contractures but not twitches require the entrance into the cells via the slow Ca2+ channels of extracellular
calcium ions for E-C coupling. Most recently, we have investigated the effects of
TMB-8 (8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate) on E-C coupling in frog skeletal muscle. This compound was shown by other workers to act in several tissues by stabilizing Ca2+ bound at intracellular sites. It was found that at the appropriate concentration
TMB-8 blocked twitches but neither high K+ nor
caffeine induced
contractures. These results suggest that
TMB-8 blocks twitches by preventing the release of Ca2+
ions bound to the intracellular surface of the t-tubular membrane, which is often called the store of "trigger-
calcium"
ions.(ABSTRACT TRUNCATED AT 250 WORDS)