Calcium activation of electrically inexcitable muscle fibers in primary hypokalemic periodic paralysis

IN EITHER SPONTAXEOUS or induced attacks of primary hypokalemic periodic paralysis, abbreviated -KP (Pri) , the muscle fibers become electrically inexcitable, action-potential propagation fails, and the twitch tension decreases.’-5 These phenomena may be reexamined with reference to the currently accepted scheme of events of excitation-contraction coupling: 5-14 11 An end-plate potential of sufficient amplitude generates a propagated action potential. 21 After propagation of the action potential by the surface membrane, excitation spreads into the interior of the muscle fiber through the transverse tubular system (t-system) . 31 Event 2 causes displacement of calcium from the sarcoplasmic reticulum into the myofilament space by an undefined mechanism. 41 The increased calcium concentration in the myofilament space inhibits native tropomyosin (troponin + tropomyosin B, or “EGTAsensitizing factor”), resulting in activation of actomyosin adenosine triphosphatase (ATPase) and of the contractile mechanism. 51 Relaxation occurs with uptake of calcium from the myofilament space by the sarcoplasmic reticulum. Thus, the electrical inexcitability of muscle fibers in periodic paralysis could be due to one or more of the following derangements in the above sequence: [l] failure of synaptic transmission to generate an end-plate potential which can give rise to a propagated action potential, [ 21 failure of action-potential propagation by the surface membrane, [3] failure of transverse impulse conduction by the tsystem, [4] failure of transverse impulse conduction to effect displacement of calcium from the sarcoplasmic reticulum into the myofilament space, and [5] failure of calcium to activate the contractile mechanism. Inexcitability of paralyzed muscle fibers on direct electrical stimulation would be consistent with a postsynaptic membrane defect, but this, in itself, does not indicate normal synaptic transmission. Evidence for persistence of an electrical potential in the end-plate region was obtained by Grob and co-workers3 in a case of -KP(Pri). On indirect stimulation, this potential was propagated decrementally from the end-plate region at a time when a propagated action potential could not be recorded from the surface of the affected muscle. More direct evidence for adequate neuromuscular transmission in vitro was obtained recently by Elmqvist and co-workersl3 in -KP (Pri) : endplate potentials (of normal size or larger than that required to give rise to an action potential in normal fibers) were recorded intracellularly from indirectly stimulated muscle fibers which failed to propagate an action potential. While the studies by Grob and his associates and by Elmqvist and co-workers also provided evidence for inability of the surface membrane to propagate an action potential, there is no direct proof that subsequent steps in excitation-contraction coupling are unaffected. Previous observations by Merton16 and by Feldman and co-workers” in fact suggest that