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

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 μ M 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). At 1 μ M , 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 μ M , 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. 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 μ M , with a 50% predicted shift of 0.11 pCa (−log [Ca 2+ ]) units at 82.3 μ M CPZ. CPZ did not alter the rate of SR‐Ca 2+ loading at 1 and 10 μ M , but reversibly reduced it by ∼40% at 100 μ M 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 μ M CPZ. 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.British Journal of Pharmacology (2004) 141 , 624–633. doi: 10.1038/sj.bjp.0705655