The effect of the calcium ion antagonist 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate on malignant hyperpyrexia-susceptible porcine skeletal muscle

Abstract

In malignant hyperpyrexia susceptible (MHS) porcine skeletal muscle, a low concentration (100 mumol/l) of the calcium ion antagonist 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) inhibited KCl-induced contractures, but potentiated contractures induced by halothane, caffeine and succinylcholine. Higher concentrations of TMB-8 (333 mumol/l to 1 mmol/l) contracted MHS muscle, but had little effect on muscle tension in control preparations. Treatments which inhibit excitation-contraction coupling abolished TMB-8-induced hyper-reactivity in MHS muscle. TMB-8 (50 mumol/l and 1 mmol/l) did not alter 45Ca2+ levels in actively loaded microsomal preparations from MHS swine. These results suggest that in malignant hyperpyrexia the primary abnormality occurs proximal to the release of calcium from the sarcoplasmic reticulum, probably at the level of excitation-contraction coupling.