Effects of chlorpromazine on excitation-contraction coupling events in fast-twitch skeletal muscle fibres of the rat

摘要

1 Single mechanically skinned fibres from the rat extensor digitorum longus muscle, which allow access to intracellular compartments, were used to examine the effects of 0.5-100 μM chlorpromazine hydrochloride (CPZ) on the major steps of the excitation-contraction (E-C) coupling to elucidate the involvement of skeletal muscle in the neuroleptic malignant syndrome (NMS). 2 At 1 μM, CPZ caused a 20-30% increase in the force response induced by t-system depolarisation and a marked increase in the rate of caffeine-induced SR Ca~(2+) release. At [CPZ] ≥2.5 μM, there was an initial increase followed by a marked decrease of the t-system depolarisation-induced force responses, while the potentiating effect on the caffeine-induced SR Ca~(2+) release remained. These effects were reversible. 3 CPZ had no effect on the maximum Ca~(2+) -activated force, but caused reversible, concentration-dependent increases in the Ca~(2+) sensitivity of the contractile apparatus at [CPZ] ≥ 10 μM, with a 50% predicted shift of 0.11 pCa (-log [Ca~(2+)]) units at 82.3 μM CPZ. 4 CPZ did not alter the rate of SR-Ca~(2+) loading at 1 and 10 ≥M, but reversibly reduced it by ～40% at 100 μM by reducing the SR Ca~(2+) pump. Nevertheless, the SR Ca~(2+) content was greater when fibres became unresponsive to t-system-induced depolarisation in the presence than in the absence of 100 μM CPZ. 5 The results show that CPZ has concentration-dependent stimulatory and inhibitory effects on various steps of the E-C coupling, which can explain the involvement of skeletal muscle in NMS and reconcile previous divergent data on CPZ effects on muscle.