EFFECT OF DILTIAZEM AND DANTROLENE ON THE CONTRACTILITY OF ISOLATED MALIGNANT HYPERPYREXIA-SUSCEPTIBLE PORCINE SKELETAL MUSCLE

The clinical features of malignant hyperpyrexia (MH) and the observed hypercontractility of isolated MH-susceptible (MHS) skeletal muscle fibres to certain chemical stimuli indicate a dysfunction in the processes which regulate myoplasmic Ca2+ concentration [1]. While the precise site of the lesion which predisposes to the abnormally high Ca2+ concentration is unknown, events of excitation—contraction coupling and Ca2+ transport by the sarcoplasmic reticulum (SR) have been implicated [2,3]. In skeletal muscle, voltage-dependent Ca2+ currents flow almost exclusively across the trans-verse tubular (T-tubular) membrane and are blocked by calcium channel antagonists [4]. Calcium channel antagonist receptors are localized preferentially at the T-tubular mem-brane, consistent with their association with calcium channels [5]. While the role of Ca2+ inflow through these Ca2+ channels during excitation-contraction coupling is not fully understood, it may play a functional role in the regulation of intracellular Ca2+ [6]. Dantrolene, the drug of choice in the treatment of MH, inhibits and antagonizes the abnormal contractile response of isolated MHS muscle [7]. The skeletal neuro-muscular blocker acts primarily to decrease myo-plasmic Ca2+ concentration by suppressing excitation-contraction coupling at the level of the triadic junction [8,9]. Calcium channel antagon-ists may therefore be able specifically to modify events of excitation—contraction coupling at the&apos