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The effects of the increase of arterial potassium upon the excitability of normal and dystrophic myotonic muscles in man
Journal of' the Neurological Sciences, 1982, 55 : 249-257
249
Elsevier Biomedical Press
THE EFFECTS OF THE INCREASE OF ARTERIAL POTASSIUM UPON T H E E X C I T A B I L I T Y OF N O R M A L A N D D Y S T R O P H I C M Y O T O N I C M U S C L E S IN M A N
LUCA DURELLI*, ROBERTO MUTANI, FRANCO FASSIO and MICHELE DELSEDIME* Clinica Neurologica, Universitdl di Sassari, 1-07100 Sassari (Italy)
(Received 29 October, 1981) (Revised, received 18 January, 1982) (Accepted 21 January, 1982)
SUMMARY Progressively increasing concentrations of potassium chloride were administered intra-arterially to patients affected with dystrophia myotonica (Steinert's disease) and to healthy volunteers before and after parenteral taurine treatment. Changes in the excitability of thenar eminence muscles were related to plasma potassium concentrations. A rise in the plasma potassium brought about a parallel increase of muscular excitability in normal individuals whilst in dystrophic myotonic patients it was associated with a two-phase phenomenon : the severity of myotonia first decreased and then, at higher plasma potassium levels, greatly worsened with the occurrence of spontaneous myotonic discharges. The administration of taurine, a membrane-stabilizing drug, considerably lowered the excitability of both normal and dystrophic myotonic muscles. The effects of potassium and taurine on muscular membrane conductance may explain the observed changes in muscular excitability.
INTRODUCTION The membrane of the myotonic or dystrophic myotonic muscle is extremely sensitive to changes in extracellular potassium concentration ([K + ]o) (Bryant 1973; Barchi 1975; Durelli and Mutani 1979; Iyer et al. 1981; Durelli et al. 1982). Increasing [K+]o brings about depolarization and simultaneously affects potassium This work was supported by grants from Muscular Dystrophy Association of America, Inc., New York, NY, U.S.A., and Istituto Farmochimico Falorni, S.p.A., Florence, Italy. * Present address: Clinica Neurologica,Universithdi Torino, Via Cherasco 15, 1-10126Turin, Italy. Please send all correspondence and reprint requests to: Dr. Luca Durelli, M.D., Clinica Neurologica, Universitlt di Torino, Via Cherasco, 15, 1-10126 Turin, Italy. 0022-510X/82/0000-0000/$02.75 © Elsevier Biomedical Press
250 conductance (Hodgkin and Horovicz 1959; Falk and Landa 1960; Nakajima et ~ll. 1962; Adrian et al. t968; Horovicz et al. 1968; Adrian et al. 1970; Hille and Campbell 1976; Lorkovi6 1976). If potassium conductance decreases by about 30",~, the excitable membrane will be on the verge of spontaneous firing (Falk and Landa 1960); and if chloride conductance is somehow impaired (Bryant 1973 ; Roses et al. 1979), the decreased potassium conductance will produce a greater effect on muscular excitability. Since experimental models of myotonic dystrophy are not currently available, in vivo studies deserve close attention and we have recently developed a method of testing the effect of intra-arteriaUy given potassium chloride on normal and dystrophic myotonic muscle in man (Durelli et al. 1982). The method also permits an indirect evaluation of transmembrane ionic fluxes, which appeared to be defective across the dystrophic myotonic muscular membrane. The administration of taurine, a drug known to increase both potassium and chloride conductances (Gruener et al. 1976; Izumi et al. 1978), has been shown to decrease the hyperexcitability and to restore the membrane permeability of dystrophic myotonic muscle (Durelli et al. 1982). We have therefore studied in detail the effects of increased potassium concentrations in the immediate environment of the muscular membrane in vivo in normal subjects and dystrophic myotonic patients. METHODS The diagnosis of dystrophia myotonica (Steinert's disease) was established according to well accepted clinical criteria (Munsat 1967; Harper 1979). Nine adult patients of both sexes were studied, and 9 medical students in whom a routine electromyographic (EMG) evaluation ruled out muscle or nerve disorders acted as controls. Each participant received a detailed explanation of the procedures to be used and spontaneously accepted the attendant discomfort. Potassium chloride (KCI) was given intra-arterially at increasing concentrations before and after parenteral taurine treatment following a method previously described (Duretli et al. 1982). The electrical activity of thenar eminence muscles was recorded by means of routine EMG needle electrodes. The severity of myotonia was evaluated by: (a) the appearance of potassium elicited myotonic discharges (Durelli and Mutani 1979; Durelli et al. 1982); (b) the EMG relaxation time after maximal voluntary effort (Leyburn and Walton 1959; Lewis 1966); (c) the occurrence of 'percussion' myotonia evoked by a simple mechanical device capable of generating a quite constant force; (d) the occurrence of myotonic discharges elicited by the electrical stimulation of the median nerve at the wrist with trains of two or more maximal stimuli, of 0.2 ms duration and 300 Hz frequency (Desmedt 1964). In normal volunteers we considered signs of increased muscular excitability: (a) the increase of the number of phases of the evoked motor response in the absence of an increased response duration or of any apparent displacements of the needle electrode; (b) the appearance of potassium elicited muscular electrical activity.
251 The evaluation of the muscular excitability was performed before and after taurine treatment and during each potassium infusion at intervals greater than 5 min (Leyburn and Walton 1959). Room temperature was kept constant at about 21 °C. RESULTS
Control group
The intra-arterial administration of progressively increasing concentrations of KC1 produced in all subjects electromyographic signs of muscular hyperexcitability. Before taurine treatment, the supramaximal stimulation of the median nerve at the wrist with single shocks evoked two-phase or three-phase muscular responses similar to that displayed in Fig. 1A. At the plasma potassium concentration of 8.8 + 1.3 mEq/1 polyphasic muscular responses following single-shock indirect stimulation
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Fig. 1. Motor responses to single-shock electrical stimulation of the median nerve at the wrist recorded in the same normal subject from opponens pollicis muscle. Supramaximal stimuli of 0.2 ms duration were used. A: baseline recording before administration of potassium chloride or taurine. B: before taurine treatment and during intra-arterial perfusion with potassium chloride (plasma potassium concentration 8.3 mEq/l). C: after taurine treatment and during intra-arterial perfusion with potassium chloride (plasma potassium concentration 9.1 mEq/1).
252 KCI
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Fig. 2. Electrical activity occurring in opponens pollicis muscle at rest during intra-arterial infusion with potassium chloride (plasma potassium concentration 11.6 mEq/l). The onset of the potassium chloride infusion (solid line) was 20 s before the shown recording. Note that muscular electrical activity disappeared a few seconds after stopping the infusion.
appeared (Fig. 1B), and at the potassium level of 11.1 + 1.5 mEq/1 spontaneous muscular discharges occurred due to motor unit activity discharging in multiplespike trains with repetitive features (Fig. 2). Spontaneous discharges appeared 10-40 s after starting and disappeared 3-7 s after stopping the infusion pump. Parenteral treatment with taurine greatly decreased KCl-induced muscular hyperexcitability. No more spontaneous electrical activity could be recorded in any of the treated subjects at potassium concentrations which had been effective before treatment. Higher concentrations could not be tested because of pain. After taurine treatment, electrically-induced polyphasic muscular responses were not observed in any of the subjects at the plasma potassium concentrations that had been effective before treatment (Fig. 1C), although they were recorded in 6 out of the 9 individuals at the potassium level of 10.3 + 1.1 mEq/1, which is significantly higher than the effective pre-taurine level (P < 0.05; Student's t-test).
Dystrophia myotonica group Before taurine treatment the stimulation of the median nerve at the wrist with trains of 2-3 maximal stimuli evoked myotonic discharges of variable length in all patients. Percussion myotonia was present in all subjects, and the mean duration of the relaxation time after maximal voluntary effort was 1.33 _+0,71 s. The intra-arterial infusion of progressively increasing concentrations of KC1 caused a striking two-phase phenomenon. At plasma potassium concentrations between
253
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Electrically- induced myotonia
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Potassium elicited myotonia
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PLASMA POTASSIUM CONCENTRATION (mEq/I)
Fig. 3. Effects of the increase in plasma potassium concentration upon the severity of myotonia in dystrophic myotonic patients before (A) and after (B) parenteral taurine treatment. The blocks above the abscissae represent either the number of patients displaying myotonic after-discharges elicited by electrical stimulation of the motor nerve or by the increased plasma potassium; or the EMG duration (in s) of the relaxation time after maximal voluntary effort. Increasing plasma potassium concentrations produced a striking two-phase phenomenon : the initial improvement of myotonic symptoms was followed by the worsening of myotonia at higher potassium concentrations.
254 4.3 and 6.4 mEq/1 a decrease of the severity of myotonia occurred (Fig. 3A). Percussion myotonia disappeared in one patient and electrically-induced aftcrdischarges disappeared in 6 patients. In 3 subjects electrically-induced after-potentials could still be obtained although trains of 4-6 maximal stimuli had to be used. The relaxation time after voluntary effort decreased to 0.25-0.42 s duration. At higher plasma potassium concentrations myotonia worsened with the occurrence of spontaneous myotonic discharges, in one patient at the concentration of 5.7 mEq/l and in all the others at above 7.2 mEq/l (Fig. 3A). Myotonic discharges occurred 8 30 s after starting and disappeared 2-7 s after stopping the infusion pump. The mean value of the plasma potassium concentration capable of inducing spontaneous activity in dystrophic myotonic muscles was 6.5 + 0.7 mEq/1, which is significantly lower (P < 0.001 ; Student's t-test) than that effective in normal muscles. Parenteral treatment with taurine was followed by a clinical and electromyographic improvement of myotonia. Relief of lid or hand-grip myotonia occurred in 7 patients, electrically-induced myotonic after-discharges disappeared in 4 subjects and percussion myotonia in 1 ; the relaxation time after maximal voluntary effort was 0.69 + 0.27 s. As observed before taurine administration, a further amelioration of myotonic symptoms occurred during infusions of KC1 at low concentrations (Fig. 3B): electrically-induced myotonic after-discharges disappeared in 8 out of 9 patients (elicitable in the remaining subject only with multiple-stimulus-trains), percussion myotonia disappeared in 2 individuals, and the relaxation time after voluntary effort further decreased. The mean plasma potassium concentration eliciting spontaneous myotonic activity after taurine treatment was 7.5 + 0.9 mEq/l, which is significantly higher than that effective before taurine (P < 0.01 ; Student's t-test). DISCUSSION The depolarization produced by increased potassium concentration at the external surface of the muscular fiber is a well-known phenomenon (Shanes 1958a; Hodgkin and Horovicz 1959; Falk and Landa 1960). The depolarization is associated with an increase of potassium conductance yielding an outward potassium flux (delayed rectification) (Hodgkin and Horovicz 1959; Adrian and Freygang 1962a; Adrian et al. 1970; Hille and Campbell 1976) which, for prolonged and sustained depolarizing currents, is then inactivated through the anomalous rectification mechanisms (Fatk and Landa 1960; Adrian and Freygang 1962b; Nakajima et at. 1962; Adrian et al. 1968; Horovicz et al. 1968; Lorkovi6 1976). The sites that control the delayed rectification mechanism are probably located on the surface membrane (Adrian and Freygang 1962a; Adrian et al. 1968)while those for the anomalous rectification appear to be both on surface and tubular membranes (Eisenberg and Gage 1969). The hypothesis has been put forward (Durelli and Mutani 1979) that a small increment of [K ÷ ]o would affect the more accessible sites at the fiber surface activating the delayed rectification and raising potassium conductance, while a more sustained and/or prolonged increase of [K ÷]o would activate both superficial and
255 deep sites for the anomalous rectification leading to a functional block of potassium conductance channels. In normal muscles the depolarization together with the initial increase of potassium conductance for small increments of [K + ]o would account for the polyphasic responses to single nerve shocks that we have recorded. Since the whole duration of the response was not incremented, the polyphasic waves cannot be interpreted in terms of a decreased conduction velocity, as observed for a more pronounced increase of [K+]o (Buchthal and Engbaek 1957). Polyphasic responses could indicate that the hyperexcitable muscle cells have developed after-spike oscillations of membrane potential wide enough to reach the threshold for a second action potential. Oscillations of membrane potential are, in fact, favored by cathodal depolarization associated with increased potassium conductance, that presumably would sustain an exaggerated positive after-potential, which, in turn, rapidly inactivates outward potassium currents (Shanes 1958b). Membrane potential therefore falls, coupled to an increase of sodium conductance, and a new spike is triggered. At higher [K + ]o the accumulation of potassium into the transverse tubular lumen enhances the rate of depolarization (Adrian and Bryant 1974; Adrian and Marshall 1976) and the inhibition of potassium permeability channels through the anomalous rectification mechanism favors the triggering of the spike. Then a prolonged and accumulating after-potential (Freygang et al. 1964; Adrian and Bryant 1974; Furman and Barchi 1978) generates an unstable state from which the further turn-off of potassium conductance (sustained by the persistently high [K + ]o) easily elicits repetitive firing activity. A complex two-phase effect of the intra-arterial administration of KC1 upon the excitability of dystrophic myotonic muscles was observed. At low KC1 infusion concentration a depression of muscular hyperexcitability was noted, while the further increase of the amount of infused KC1 sustained spontaneous myotonic electrical activity. It is known that increasing [K ÷ ]o worsens myotonia (Bryant 1973; Barchi 1975; Griggs et al. 1978) and, therefore, an improvement of myotonic symptoms associated with a moderate increase of [K + ]o seems a paradoxical and hardly conceivable result. Actually, the phenomenon has recently been reported in experimental myotonia in vitro (Birnberger and Klepzig 1979; Iyer et al. 1981). This result has been tentatively explained as the effect of the sudden depolarization produced by the increase of [K + ]o which may make the muscle incapable of repetitive discharges (Iyer et al. 1981). This explanation does not account for the worsening of myotonia that we observed for higher [K + ]o, Repetitive discharges of the unstable dystrophic myotonic fibers seem to be triggered either by the rhythmic turning-off of potassium conductance channels or by an increase of sodium permeability (Hofmann and De Nardo 1968; Bryant 1973; Lipiky 1979; Roses et al. 1979). In both cases the increase of potassium conductance associated with a small increment of [K +]o, could well counteract the enhancement of depolarizing forces that sustains repetitive discharges. A further increase of [K ÷]o would, finally, lead to a functional block of potassium conductance channels with an impairment of repolarizing forces, and the triggering of myotonic repetitive after-potentials will be more likely (Bryant 1973; Barchi 1975).
256 A f t e r t a u r i n e t r e a t m e n t , p o l y p h a s i c r e s p o n s e s to indirect electrical s t i m u l a t i o n were m o r e difficult to elicit in n o r m a l muscles, albeit they were still present in 6 o u t o f 9 t r e a t e d subjects. T h e i n c r e a s e d p o t a s s i u m c o n d u c t a n c e which p r o b a b l y underlies p o l y p h a s i c r e s p o n s e s can even be e n h a n c e d by t a u r i n e a c t i o n on p o t a s s i u m c h a n n e l s b u t the h y p e r p o l a r i z a t i o n a n d the increase o f c h l o r i d e c o n d u c t a n c e prom o t e d b y the a m i n o acid ( G r u e n e r et al. 1976; Izumi et al. 1978) w o u l d call for a m o r e p r o n o u n c e d i n c r e m e n t o f [K*],,. On the o t h e r h a n d , p o t a s s i u m - i n d u c e d repetitive d i s c h a r g e s were n o t l o n g e r r e c o r d e d after t a u r i n e at the p l a s m a p o t a s s i u m c o n c e n t r a t i o n s effective before t r e a t m e n t . In this case the t a u r i n e - i n d u c e d increase o f p o t a s s i u m c o n d u c t a n c e w o u l d selectively c o u n t e r a c t the p o s t u l a t e d m e c h a n i s m for triggering repetitive firing. T h e d e p r e s s a n t a c t i o n o f this a m i n o acid has recently been shown to be a s s o c i a t e d with the increase o f the defective m e m b r a n e perm e a b i l i t y to p o t a s s i u m a n d c h l o r i d e ions o f d y s t r o p h i c m y o t o n i c muscles (Durelli et al. 1982). B o t h E M G a n d clinical signs o f m y o t o n i a were d e c r e a s e d after t a u r i n e a n d d i m i n i s h e d f u r t h e r with a small i n c r e m e n t o f [K+],,. T h e latter, in fact, w o u l d sustain an increase o f p o t a s s i u m c o n d u c t a n c e p o t e n t i a t i n g t a u r i n e effects. Finally, in the presence o f this a m i n o acid the triggering o f m y o t o n i c repetitive firing r e q u i r e d a m o r e p r o n o u n c e d increase o f [K ÷ ]o since t a u r i n e a c t i o n on m e m b r a n e c o n d u c t a n c e s shunts a n d d e l a y s the d e p o l a r i z i n g effects o f e x t r a c e l l u l a r p o t a s s i u m . REFERENCES Adrian, R. H. and S. H. Bryant (1974) On the repetitive discharge in myotonic muscle fibers, J. Phy,shd. (Lond.), 240: 505-515. Adrian, R.H. and W.H. Freygang (1962a) The potassium and chloride conductance of frog muscle membrane, J. Physiol. (Lond.), 163: 61--103. Adrian, R.H. and W.H. Freygang (1962b) Potassium conductance of frog muscle membrane under controlled voltage, J. Physiol. ( Lond. ), 163:104-114. Adrian, R.H. and M.W. Marshall (1976) Action potentials reconstructed in normal and myotonic muscle fiber, J. Physiol. (Lond.), 258:125 143. Adrian, R.H., W.K. Chandler and A.L. Hodgkin (1968) Voltage clamp experiments in striated muscle fibers, J. gen. Physiol., 51(2): 1885-1925. Adrian, R. H., W.K. Chandler and A.L. Hodgkin (1970) Slow changes in potassium permeability in skeletal muscle, J. Physiol. (Lond.), 208: 645-668. Barchi, R.L. (1975) Myotonia - - An evaluation of the chloride hypothesis, Arch. Neurol. (Chic.), 32: 175-180. Birnberger, K. L. and M. Klepzig (1979) Influence of extracellular potassium and intracellular pH on myotonia, J. Neurol., 222: 23-35. Bryant, S.H. (1973) The electrophysiology of myotonia with a review of congenital myotonia of goats. In : J. E. Desmedt (Ed.), New Developments in Eleetromyography and Clinical Neurophysiology, Vol. 1, Karger, Basel, pp. 420-450. Buchthal, F. and L. Engbaek (1957) Propagation velocity of intracellularly recorded action potentials in striated frog muscle fibers, Aeta physiol, scand., (Suppl. 145): 42. Desmedt, J.E. (1964) Observations sur la r~action myotonique en stimulo-d~tection, Rev. neurol. (Paris), 110: 324-336. Durelli, L. and R. Mutani (1979) Myotonia, potassium and taurine ..... A preliminary report, J. neurol. Sci., 42: 103-109. Durelli, L., R. Mutani, F. Fassio, A. Satta and E. Bartoli (1982) Taurine and the hyperexcitable human muscle ..... Effects of taurine upon the potassium-induced hyperexcitability of dystrophic myotonic and normal muscles, Ann. Neurol.,:l 1:258 266. Eisenberg, R.S. and P.W. Gage (1969) Ionic conductance of the surface and transverse tubular membranes of frog sartorius fibers, J. gen. Physiol., 53 : 279-297.
257 Falk, G. and J. F, Landa (1960) Effects of potassium on frog skeletal muscle in a chloride-deficient medium, Amer. J. Physiol., 198: 1225-1231. Freygang, W.H., P.A. Goldstein and D.C. Hellam (1964) The after-potential that follows trains of impulses in frog muscles, J. gen. Physiol., 47: 929-952. Furman, R. E. and R.L. Barchi (1978) The pathophysiology of myotonia produced by aromatic carboxylic acids, Ann. Neurol., 4: 357-365. Griggs, R. C., R.T. Moxley, J. E. Riggs and W.K. Engel (1978) Effects of acetazolamide on myotonia, Ann. Neurol., 3:531 537. Gruener, R., H. Bryant, D. Markowitz, R. Huxtable and R. Bressler (1976) Ionic actions of taurine on nerve and muscle membranes - - Electrophysiologic studies. In: R. Huxtable and A. Barbeau (Eds.), Taurine, Raven Press, New York, pp. 225 242. Harper, P.S. (1979) The electrophysiological basis of myotonia. In: P.S. Harper (Ed.), Myotonic Dystrophy, Saunders, Philadelphia, pp. 274-290. Hille, B. and D.T. Campbell (1976) An improved vaseline gap voltage clamp for skeletal muscle fibers, J. gen. Physiol., 67: 265-293, Hodgkin, A. L. and P. Horovicz (1959) The influence of potassium and chloride ions on the membrane potential of single muscle fibers, J. Physiol. (Lond.), 148: 127-160. Hofmann, W.W. and G. L. De Nardo (1968) Sodium flux in myotonic muscular dystrophy, Amer. J. Physiol., 214: 33(~336. Horovicz, P., P.W. Gage and R.S. Eisenberg (1968) The role of the electrochemical gradient in determining potassium fluxes in frog striated muscle, J. gen. Physiol., 51(2): 1935-2035. Iyer, V.G., N.A. Ranish and G.M. Fenichel (1981) Ionic conductance and experimentally induced myotonia, J. neurol. Sci., 49: 159-164. Izumi, K., T. T. Ngo and A. Barbeau (1978) Metabolic modulation in central nervous system by taurine. In: A. Barbeau and R.J. Huxtable (Eds.), Taurine and Neurological Disorders, Raven Press, New York, pp. 137 149. Lewis, I. (1966) Trial of diazepam in myotonia A double blind single cross-over study, Neurology (Minneap.), 16: 831-836. Leyburn, P. and J. N. Walton (1959) The treatment of myotonia - - A controlled clinical trial, Brain, 82: 81-89. Lipicky, R.J. (1979) Myotonic syndromes other than myotonic dystrophy. In: P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 40 (Diseases of Muscle, Part l),North-Holland Publ. Comp.,Amsterdam, pp. 533 571. Lorkovi6, H. (1976) Effect of sodium ions on the voltage-current relationships in rat muscles, Arch. intern. Physiol. Biochim., 84: 838-849. Munsat, T. L. (1967) Therapy of myotonia, Neurology (Minneap.), 17: 359-367. Nakajima, S., S. Iwasaki and K. Obata (1962) Delayed rectification in frog's skeletal muscle membrane, J. gen. Physiol., 46: 97-115. Roses, A.D., P.S. Harper and E.H. Bossen (1979) Myotonic muscular dystrophy. In: P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 40 (Diseases o[' Muscle, Part 1), North-Holland Publ. Comp., Amsterdam, pp. 485 532. Shanes, A. M. (1958a) Electrochemical aspects of physiological and pharmacological action in excitable cells, Part 1 (The resting cell and its alteration by extrinsic factors), Pharmaeol. Rev., 10: 59-164. Shanes, A. M. (1958b) Electrochemical aspects of physiological and pharmacological action in excitable cells, Part 2 (The action potential and excitation), Pharmacol. Rev., 10:165 273.
249
Elsevier Biomedical Press
THE EFFECTS OF THE INCREASE OF ARTERIAL POTASSIUM UPON T H E E X C I T A B I L I T Y OF N O R M A L A N D D Y S T R O P H I C M Y O T O N I C M U S C L E S IN M A N
LUCA DURELLI*, ROBERTO MUTANI, FRANCO FASSIO and MICHELE DELSEDIME* Clinica Neurologica, Universitdl di Sassari, 1-07100 Sassari (Italy)
(Received 29 October, 1981) (Revised, received 18 January, 1982) (Accepted 21 January, 1982)
SUMMARY Progressively increasing concentrations of potassium chloride were administered intra-arterially to patients affected with dystrophia myotonica (Steinert's disease) and to healthy volunteers before and after parenteral taurine treatment. Changes in the excitability of thenar eminence muscles were related to plasma potassium concentrations. A rise in the plasma potassium brought about a parallel increase of muscular excitability in normal individuals whilst in dystrophic myotonic patients it was associated with a two-phase phenomenon : the severity of myotonia first decreased and then, at higher plasma potassium levels, greatly worsened with the occurrence of spontaneous myotonic discharges. The administration of taurine, a membrane-stabilizing drug, considerably lowered the excitability of both normal and dystrophic myotonic muscles. The effects of potassium and taurine on muscular membrane conductance may explain the observed changes in muscular excitability.
INTRODUCTION The membrane of the myotonic or dystrophic myotonic muscle is extremely sensitive to changes in extracellular potassium concentration ([K + ]o) (Bryant 1973; Barchi 1975; Durelli and Mutani 1979; Iyer et al. 1981; Durelli et al. 1982). Increasing [K+]o brings about depolarization and simultaneously affects potassium This work was supported by grants from Muscular Dystrophy Association of America, Inc., New York, NY, U.S.A., and Istituto Farmochimico Falorni, S.p.A., Florence, Italy. * Present address: Clinica Neurologica,Universithdi Torino, Via Cherasco 15, 1-10126Turin, Italy. Please send all correspondence and reprint requests to: Dr. Luca Durelli, M.D., Clinica Neurologica, Universitlt di Torino, Via Cherasco, 15, 1-10126 Turin, Italy. 0022-510X/82/0000-0000/$02.75 © Elsevier Biomedical Press
250 conductance (Hodgkin and Horovicz 1959; Falk and Landa 1960; Nakajima et ~ll. 1962; Adrian et al. t968; Horovicz et al. 1968; Adrian et al. 1970; Hille and Campbell 1976; Lorkovi6 1976). If potassium conductance decreases by about 30",~, the excitable membrane will be on the verge of spontaneous firing (Falk and Landa 1960); and if chloride conductance is somehow impaired (Bryant 1973 ; Roses et al. 1979), the decreased potassium conductance will produce a greater effect on muscular excitability. Since experimental models of myotonic dystrophy are not currently available, in vivo studies deserve close attention and we have recently developed a method of testing the effect of intra-arteriaUy given potassium chloride on normal and dystrophic myotonic muscle in man (Durelli et al. 1982). The method also permits an indirect evaluation of transmembrane ionic fluxes, which appeared to be defective across the dystrophic myotonic muscular membrane. The administration of taurine, a drug known to increase both potassium and chloride conductances (Gruener et al. 1976; Izumi et al. 1978), has been shown to decrease the hyperexcitability and to restore the membrane permeability of dystrophic myotonic muscle (Durelli et al. 1982). We have therefore studied in detail the effects of increased potassium concentrations in the immediate environment of the muscular membrane in vivo in normal subjects and dystrophic myotonic patients. METHODS The diagnosis of dystrophia myotonica (Steinert's disease) was established according to well accepted clinical criteria (Munsat 1967; Harper 1979). Nine adult patients of both sexes were studied, and 9 medical students in whom a routine electromyographic (EMG) evaluation ruled out muscle or nerve disorders acted as controls. Each participant received a detailed explanation of the procedures to be used and spontaneously accepted the attendant discomfort. Potassium chloride (KCI) was given intra-arterially at increasing concentrations before and after parenteral taurine treatment following a method previously described (Duretli et al. 1982). The electrical activity of thenar eminence muscles was recorded by means of routine EMG needle electrodes. The severity of myotonia was evaluated by: (a) the appearance of potassium elicited myotonic discharges (Durelli and Mutani 1979; Durelli et al. 1982); (b) the EMG relaxation time after maximal voluntary effort (Leyburn and Walton 1959; Lewis 1966); (c) the occurrence of 'percussion' myotonia evoked by a simple mechanical device capable of generating a quite constant force; (d) the occurrence of myotonic discharges elicited by the electrical stimulation of the median nerve at the wrist with trains of two or more maximal stimuli, of 0.2 ms duration and 300 Hz frequency (Desmedt 1964). In normal volunteers we considered signs of increased muscular excitability: (a) the increase of the number of phases of the evoked motor response in the absence of an increased response duration or of any apparent displacements of the needle electrode; (b) the appearance of potassium elicited muscular electrical activity.
251 The evaluation of the muscular excitability was performed before and after taurine treatment and during each potassium infusion at intervals greater than 5 min (Leyburn and Walton 1959). Room temperature was kept constant at about 21 °C. RESULTS
Control group
The intra-arterial administration of progressively increasing concentrations of KC1 produced in all subjects electromyographic signs of muscular hyperexcitability. Before taurine treatment, the supramaximal stimulation of the median nerve at the wrist with single shocks evoked two-phase or three-phase muscular responses similar to that displayed in Fig. 1A. At the plasma potassium concentration of 8.8 + 1.3 mEq/1 polyphasic muscular responses following single-shock indirect stimulation
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Fig. 1. Motor responses to single-shock electrical stimulation of the median nerve at the wrist recorded in the same normal subject from opponens pollicis muscle. Supramaximal stimuli of 0.2 ms duration were used. A: baseline recording before administration of potassium chloride or taurine. B: before taurine treatment and during intra-arterial perfusion with potassium chloride (plasma potassium concentration 8.3 mEq/l). C: after taurine treatment and during intra-arterial perfusion with potassium chloride (plasma potassium concentration 9.1 mEq/1).
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Fig. 2. Electrical activity occurring in opponens pollicis muscle at rest during intra-arterial infusion with potassium chloride (plasma potassium concentration 11.6 mEq/l). The onset of the potassium chloride infusion (solid line) was 20 s before the shown recording. Note that muscular electrical activity disappeared a few seconds after stopping the infusion.
appeared (Fig. 1B), and at the potassium level of 11.1 + 1.5 mEq/1 spontaneous muscular discharges occurred due to motor unit activity discharging in multiplespike trains with repetitive features (Fig. 2). Spontaneous discharges appeared 10-40 s after starting and disappeared 3-7 s after stopping the infusion pump. Parenteral treatment with taurine greatly decreased KCl-induced muscular hyperexcitability. No more spontaneous electrical activity could be recorded in any of the treated subjects at potassium concentrations which had been effective before treatment. Higher concentrations could not be tested because of pain. After taurine treatment, electrically-induced polyphasic muscular responses were not observed in any of the subjects at the plasma potassium concentrations that had been effective before treatment (Fig. 1C), although they were recorded in 6 out of the 9 individuals at the potassium level of 10.3 + 1.1 mEq/1, which is significantly higher than the effective pre-taurine level (P < 0.05; Student's t-test).
Dystrophia myotonica group Before taurine treatment the stimulation of the median nerve at the wrist with trains of 2-3 maximal stimuli evoked myotonic discharges of variable length in all patients. Percussion myotonia was present in all subjects, and the mean duration of the relaxation time after maximal voluntary effort was 1.33 _+0,71 s. The intra-arterial infusion of progressively increasing concentrations of KC1 caused a striking two-phase phenomenon. At plasma potassium concentrations between
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Fig. 3. Effects of the increase in plasma potassium concentration upon the severity of myotonia in dystrophic myotonic patients before (A) and after (B) parenteral taurine treatment. The blocks above the abscissae represent either the number of patients displaying myotonic after-discharges elicited by electrical stimulation of the motor nerve or by the increased plasma potassium; or the EMG duration (in s) of the relaxation time after maximal voluntary effort. Increasing plasma potassium concentrations produced a striking two-phase phenomenon : the initial improvement of myotonic symptoms was followed by the worsening of myotonia at higher potassium concentrations.
254 4.3 and 6.4 mEq/1 a decrease of the severity of myotonia occurred (Fig. 3A). Percussion myotonia disappeared in one patient and electrically-induced aftcrdischarges disappeared in 6 patients. In 3 subjects electrically-induced after-potentials could still be obtained although trains of 4-6 maximal stimuli had to be used. The relaxation time after voluntary effort decreased to 0.25-0.42 s duration. At higher plasma potassium concentrations myotonia worsened with the occurrence of spontaneous myotonic discharges, in one patient at the concentration of 5.7 mEq/l and in all the others at above 7.2 mEq/l (Fig. 3A). Myotonic discharges occurred 8 30 s after starting and disappeared 2-7 s after stopping the infusion pump. The mean value of the plasma potassium concentration capable of inducing spontaneous activity in dystrophic myotonic muscles was 6.5 + 0.7 mEq/1, which is significantly lower (P < 0.001 ; Student's t-test) than that effective in normal muscles. Parenteral treatment with taurine was followed by a clinical and electromyographic improvement of myotonia. Relief of lid or hand-grip myotonia occurred in 7 patients, electrically-induced myotonic after-discharges disappeared in 4 subjects and percussion myotonia in 1 ; the relaxation time after maximal voluntary effort was 0.69 + 0.27 s. As observed before taurine administration, a further amelioration of myotonic symptoms occurred during infusions of KC1 at low concentrations (Fig. 3B): electrically-induced myotonic after-discharges disappeared in 8 out of 9 patients (elicitable in the remaining subject only with multiple-stimulus-trains), percussion myotonia disappeared in 2 individuals, and the relaxation time after voluntary effort further decreased. The mean plasma potassium concentration eliciting spontaneous myotonic activity after taurine treatment was 7.5 + 0.9 mEq/l, which is significantly higher than that effective before taurine (P < 0.01 ; Student's t-test). DISCUSSION The depolarization produced by increased potassium concentration at the external surface of the muscular fiber is a well-known phenomenon (Shanes 1958a; Hodgkin and Horovicz 1959; Falk and Landa 1960). The depolarization is associated with an increase of potassium conductance yielding an outward potassium flux (delayed rectification) (Hodgkin and Horovicz 1959; Adrian and Freygang 1962a; Adrian et al. 1970; Hille and Campbell 1976) which, for prolonged and sustained depolarizing currents, is then inactivated through the anomalous rectification mechanisms (Fatk and Landa 1960; Adrian and Freygang 1962b; Nakajima et at. 1962; Adrian et al. 1968; Horovicz et al. 1968; Lorkovi6 1976). The sites that control the delayed rectification mechanism are probably located on the surface membrane (Adrian and Freygang 1962a; Adrian et al. 1968)while those for the anomalous rectification appear to be both on surface and tubular membranes (Eisenberg and Gage 1969). The hypothesis has been put forward (Durelli and Mutani 1979) that a small increment of [K ÷ ]o would affect the more accessible sites at the fiber surface activating the delayed rectification and raising potassium conductance, while a more sustained and/or prolonged increase of [K ÷]o would activate both superficial and
255 deep sites for the anomalous rectification leading to a functional block of potassium conductance channels. In normal muscles the depolarization together with the initial increase of potassium conductance for small increments of [K + ]o would account for the polyphasic responses to single nerve shocks that we have recorded. Since the whole duration of the response was not incremented, the polyphasic waves cannot be interpreted in terms of a decreased conduction velocity, as observed for a more pronounced increase of [K+]o (Buchthal and Engbaek 1957). Polyphasic responses could indicate that the hyperexcitable muscle cells have developed after-spike oscillations of membrane potential wide enough to reach the threshold for a second action potential. Oscillations of membrane potential are, in fact, favored by cathodal depolarization associated with increased potassium conductance, that presumably would sustain an exaggerated positive after-potential, which, in turn, rapidly inactivates outward potassium currents (Shanes 1958b). Membrane potential therefore falls, coupled to an increase of sodium conductance, and a new spike is triggered. At higher [K + ]o the accumulation of potassium into the transverse tubular lumen enhances the rate of depolarization (Adrian and Bryant 1974; Adrian and Marshall 1976) and the inhibition of potassium permeability channels through the anomalous rectification mechanism favors the triggering of the spike. Then a prolonged and accumulating after-potential (Freygang et al. 1964; Adrian and Bryant 1974; Furman and Barchi 1978) generates an unstable state from which the further turn-off of potassium conductance (sustained by the persistently high [K + ]o) easily elicits repetitive firing activity. A complex two-phase effect of the intra-arterial administration of KC1 upon the excitability of dystrophic myotonic muscles was observed. At low KC1 infusion concentration a depression of muscular hyperexcitability was noted, while the further increase of the amount of infused KC1 sustained spontaneous myotonic electrical activity. It is known that increasing [K ÷ ]o worsens myotonia (Bryant 1973; Barchi 1975; Griggs et al. 1978) and, therefore, an improvement of myotonic symptoms associated with a moderate increase of [K + ]o seems a paradoxical and hardly conceivable result. Actually, the phenomenon has recently been reported in experimental myotonia in vitro (Birnberger and Klepzig 1979; Iyer et al. 1981). This result has been tentatively explained as the effect of the sudden depolarization produced by the increase of [K + ]o which may make the muscle incapable of repetitive discharges (Iyer et al. 1981). This explanation does not account for the worsening of myotonia that we observed for higher [K + ]o, Repetitive discharges of the unstable dystrophic myotonic fibers seem to be triggered either by the rhythmic turning-off of potassium conductance channels or by an increase of sodium permeability (Hofmann and De Nardo 1968; Bryant 1973; Lipiky 1979; Roses et al. 1979). In both cases the increase of potassium conductance associated with a small increment of [K +]o, could well counteract the enhancement of depolarizing forces that sustains repetitive discharges. A further increase of [K ÷]o would, finally, lead to a functional block of potassium conductance channels with an impairment of repolarizing forces, and the triggering of myotonic repetitive after-potentials will be more likely (Bryant 1973; Barchi 1975).
256 A f t e r t a u r i n e t r e a t m e n t , p o l y p h a s i c r e s p o n s e s to indirect electrical s t i m u l a t i o n were m o r e difficult to elicit in n o r m a l muscles, albeit they were still present in 6 o u t o f 9 t r e a t e d subjects. T h e i n c r e a s e d p o t a s s i u m c o n d u c t a n c e which p r o b a b l y underlies p o l y p h a s i c r e s p o n s e s can even be e n h a n c e d by t a u r i n e a c t i o n on p o t a s s i u m c h a n n e l s b u t the h y p e r p o l a r i z a t i o n a n d the increase o f c h l o r i d e c o n d u c t a n c e prom o t e d b y the a m i n o acid ( G r u e n e r et al. 1976; Izumi et al. 1978) w o u l d call for a m o r e p r o n o u n c e d i n c r e m e n t o f [K*],,. On the o t h e r h a n d , p o t a s s i u m - i n d u c e d repetitive d i s c h a r g e s were n o t l o n g e r r e c o r d e d after t a u r i n e at the p l a s m a p o t a s s i u m c o n c e n t r a t i o n s effective before t r e a t m e n t . In this case the t a u r i n e - i n d u c e d increase o f p o t a s s i u m c o n d u c t a n c e w o u l d selectively c o u n t e r a c t the p o s t u l a t e d m e c h a n i s m for triggering repetitive firing. T h e d e p r e s s a n t a c t i o n o f this a m i n o acid has recently been shown to be a s s o c i a t e d with the increase o f the defective m e m b r a n e perm e a b i l i t y to p o t a s s i u m a n d c h l o r i d e ions o f d y s t r o p h i c m y o t o n i c muscles (Durelli et al. 1982). B o t h E M G a n d clinical signs o f m y o t o n i a were d e c r e a s e d after t a u r i n e a n d d i m i n i s h e d f u r t h e r with a small i n c r e m e n t o f [K+],,. T h e latter, in fact, w o u l d sustain an increase o f p o t a s s i u m c o n d u c t a n c e p o t e n t i a t i n g t a u r i n e effects. Finally, in the presence o f this a m i n o acid the triggering o f m y o t o n i c repetitive firing r e q u i r e d a m o r e p r o n o u n c e d increase o f [K ÷ ]o since t a u r i n e a c t i o n on m e m b r a n e c o n d u c t a n c e s shunts a n d d e l a y s the d e p o l a r i z i n g effects o f e x t r a c e l l u l a r p o t a s s i u m . REFERENCES Adrian, R. H. and S. H. Bryant (1974) On the repetitive discharge in myotonic muscle fibers, J. Phy,shd. (Lond.), 240: 505-515. Adrian, R.H. and W.H. Freygang (1962a) The potassium and chloride conductance of frog muscle membrane, J. Physiol. (Lond.), 163: 61--103. Adrian, R.H. and W.H. Freygang (1962b) Potassium conductance of frog muscle membrane under controlled voltage, J. Physiol. ( Lond. ), 163:104-114. Adrian, R.H. and M.W. Marshall (1976) Action potentials reconstructed in normal and myotonic muscle fiber, J. Physiol. (Lond.), 258:125 143. Adrian, R.H., W.K. Chandler and A.L. Hodgkin (1968) Voltage clamp experiments in striated muscle fibers, J. gen. Physiol., 51(2): 1885-1925. Adrian, R. H., W.K. Chandler and A.L. Hodgkin (1970) Slow changes in potassium permeability in skeletal muscle, J. Physiol. (Lond.), 208: 645-668. Barchi, R.L. (1975) Myotonia - - An evaluation of the chloride hypothesis, Arch. Neurol. (Chic.), 32: 175-180. Birnberger, K. L. and M. Klepzig (1979) Influence of extracellular potassium and intracellular pH on myotonia, J. Neurol., 222: 23-35. Bryant, S.H. (1973) The electrophysiology of myotonia with a review of congenital myotonia of goats. In : J. E. Desmedt (Ed.), New Developments in Eleetromyography and Clinical Neurophysiology, Vol. 1, Karger, Basel, pp. 420-450. Buchthal, F. and L. Engbaek (1957) Propagation velocity of intracellularly recorded action potentials in striated frog muscle fibers, Aeta physiol, scand., (Suppl. 145): 42. Desmedt, J.E. (1964) Observations sur la r~action myotonique en stimulo-d~tection, Rev. neurol. (Paris), 110: 324-336. Durelli, L. and R. Mutani (1979) Myotonia, potassium and taurine ..... A preliminary report, J. neurol. Sci., 42: 103-109. Durelli, L., R. Mutani, F. Fassio, A. Satta and E. Bartoli (1982) Taurine and the hyperexcitable human muscle ..... Effects of taurine upon the potassium-induced hyperexcitability of dystrophic myotonic and normal muscles, Ann. Neurol.,:l 1:258 266. Eisenberg, R.S. and P.W. Gage (1969) Ionic conductance of the surface and transverse tubular membranes of frog sartorius fibers, J. gen. Physiol., 53 : 279-297.
257 Falk, G. and J. F, Landa (1960) Effects of potassium on frog skeletal muscle in a chloride-deficient medium, Amer. J. Physiol., 198: 1225-1231. Freygang, W.H., P.A. Goldstein and D.C. Hellam (1964) The after-potential that follows trains of impulses in frog muscles, J. gen. Physiol., 47: 929-952. Furman, R. E. and R.L. Barchi (1978) The pathophysiology of myotonia produced by aromatic carboxylic acids, Ann. Neurol., 4: 357-365. Griggs, R. C., R.T. Moxley, J. E. Riggs and W.K. Engel (1978) Effects of acetazolamide on myotonia, Ann. Neurol., 3:531 537. Gruener, R., H. Bryant, D. Markowitz, R. Huxtable and R. Bressler (1976) Ionic actions of taurine on nerve and muscle membranes - - Electrophysiologic studies. In: R. Huxtable and A. Barbeau (Eds.), Taurine, Raven Press, New York, pp. 225 242. Harper, P.S. (1979) The electrophysiological basis of myotonia. In: P.S. Harper (Ed.), Myotonic Dystrophy, Saunders, Philadelphia, pp. 274-290. Hille, B. and D.T. Campbell (1976) An improved vaseline gap voltage clamp for skeletal muscle fibers, J. gen. Physiol., 67: 265-293, Hodgkin, A. L. and P. Horovicz (1959) The influence of potassium and chloride ions on the membrane potential of single muscle fibers, J. Physiol. (Lond.), 148: 127-160. Hofmann, W.W. and G. L. De Nardo (1968) Sodium flux in myotonic muscular dystrophy, Amer. J. Physiol., 214: 33(~336. Horovicz, P., P.W. Gage and R.S. Eisenberg (1968) The role of the electrochemical gradient in determining potassium fluxes in frog striated muscle, J. gen. Physiol., 51(2): 1935-2035. Iyer, V.G., N.A. Ranish and G.M. Fenichel (1981) Ionic conductance and experimentally induced myotonia, J. neurol. Sci., 49: 159-164. Izumi, K., T. T. Ngo and A. Barbeau (1978) Metabolic modulation in central nervous system by taurine. In: A. Barbeau and R.J. Huxtable (Eds.), Taurine and Neurological Disorders, Raven Press, New York, pp. 137 149. Lewis, I. (1966) Trial of diazepam in myotonia A double blind single cross-over study, Neurology (Minneap.), 16: 831-836. Leyburn, P. and J. N. Walton (1959) The treatment of myotonia - - A controlled clinical trial, Brain, 82: 81-89. Lipicky, R.J. (1979) Myotonic syndromes other than myotonic dystrophy. In: P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 40 (Diseases of Muscle, Part l),North-Holland Publ. Comp.,Amsterdam, pp. 533 571. Lorkovi6, H. (1976) Effect of sodium ions on the voltage-current relationships in rat muscles, Arch. intern. Physiol. Biochim., 84: 838-849. Munsat, T. L. (1967) Therapy of myotonia, Neurology (Minneap.), 17: 359-367. Nakajima, S., S. Iwasaki and K. Obata (1962) Delayed rectification in frog's skeletal muscle membrane, J. gen. Physiol., 46: 97-115. Roses, A.D., P.S. Harper and E.H. Bossen (1979) Myotonic muscular dystrophy. In: P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 40 (Diseases o[' Muscle, Part 1), North-Holland Publ. Comp., Amsterdam, pp. 485 532. Shanes, A. M. (1958a) Electrochemical aspects of physiological and pharmacological action in excitable cells, Part 1 (The resting cell and its alteration by extrinsic factors), Pharmaeol. Rev., 10: 59-164. Shanes, A. M. (1958b) Electrochemical aspects of physiological and pharmacological action in excitable cells, Part 2 (The action potential and excitation), Pharmacol. Rev., 10:165 273.