title: Effects of chlorpromazine on excitation-contraction coupling events in fast-twitch skeletal muscle fibres of the rat.
abstract: 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 microM 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 microM, 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]> or =2.5 microM, 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] > or =10 microM, with a 50% predicted shift of 0.11 pCa (-log [Ca(2+)]) units at 82.3 microM CPZ. 4. CPZ did not alter the rate of SR-Ca(2+) loading at 1 and 10 microM, but reversibly reduced it by approximately 40% at 100 microM 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 microM 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.
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, INF 326, 69120 Heidelberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Wagner
authors.forename: R H A
authors.initials: RH
authors.lastname: Fink
authors.forename: D G
authors.initials: DG
authors.lastname: Stephenson
mesh_terms: D000465:Algorithms; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002746:Chlorpromazine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects*; D009459:Neuroleptic Malignant Syndrome / Q000503:physiopathology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects; D012519:Sarcoplasmic Reticulum / Q000187:drug effects; D012964:Sodium / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D002121:Calcium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; D012964:Sodium; D011188:Potassium; D002746:Chlorpromazine