Cromakalim (BRL 34915) restores in vitro the membrane potential of depolarized human skeletal muscle fibres

The purpose of the present study was to analyze the effects of cromakalim (BRL 34915), a potent drug from a new class of drugs characterized as K+ channel openers, on the electrical activity of human skeletal muscle. Therefore, intracellular recordings were used to measure the effects of cromakalim on the membrane potential and input conductance of fibres from human skeletal muscle biopsies. Cromakalim in a concentration above 1 mol/l induced an increase in membrane K+ conductance. This effect resulted in a membrane hyperpolarization. The magnitude of this polarization depended on the difference between resting and K+ equilibrium potential. The effect had a rapid onset and was quickly reversible after washing. Fibres from two patients with hyperkalaemic periodic paralysis showed an excessive membrane depolarization during and also after exposure to an slightly elevated extracellular K+ concentration. In the latter situation, cromakalim repolarized the fibres to the normal resting potential. Tolbutamide (1 mmol/l) and Ba2+ (3 mmol/l) strongly antagonized the effect of cromakalim. The data show that cromakalim hyperpolarizes depolarized human skeletal muscle fibres maintained in vitro. The underlying mechanism is probably an activation of otherwise silent, ATP-regulated K+ channels. Such an effect may be of therapeutic benefit in a situation in which a membrane depolarization causes muscle paralysis

Adynamia episodica hereditaria with myotonia: A non-inactivating sodium current and the effect of extracellular pH

To study the mechanism of periodic paralysis, we investigated the properties of intact muscle fibers biopsied from a patient who had adynamia episodica hereditaria with electromyographic signs of myotonia. When the potassium concentration in the extracellular medium, [K]e, was 3.5 mmol/l, force of contraction, membrane resting potential, and intracellular sodium activity were normal, but depolarizing voltage clamp steps revealed the existence of an abnormal inward current. This current was activated at membrane potentials less negative than -80 mV, reached a maximum within 50 msec, and was not inactivated with time. The inward current was completely and reversibly blocked by tetrodotoxin, which indicates that it was carried by sodium ions. In a solution containing 9 mmol/l potassium, normal muscle would depolarize to -63 mV and yet be capable of developing full tetanic force upon stimulation. The muscle from the patient depolarized to -57 mV and became inexcitable, i.e., it was paralyzed. A contracture did not develop. Lowering of the extracellular pH did not influence the resting potential, but it effectively antagonized or prevented the paralytic effect of high [K]e by changing the inactivation characteristics of the sodium channels. Hydrochlorothiazide, which had a therapeutic effect on the patient, did not prevent paralysis in vitro. An abnormal rise of the intracellular sodium activity was recorded when the extracellular potassium concentration was raised to 10 mmol/l

Familial hyperkalemic periodic paralysis caused by a de novo mutation in the sodium channel gene SCN4A

Familial hyperkalemic periodic paralysis (HYPP) is an autosomaldominant channelopathy characterized by transient and recurrent episodes of paralysis with concomitant hyperkalemia. Mutations in the skeletal muscle voltage-gated sodium channel gene SCN4A have been reported to be responsible for this disease. Here, we report the case of a 16-year-old girl with HYPP whose mutational analysis revealed a heterozygous c.2111C>T substitution in the SCN4A gene leading to a Thr704Met mutation in the protein sequence. The parents were clinically unaffected and did not have a mutation in the SCN4A gene. A de novo SCN4A mutation for familial HYPP has not previously been reported. The patient did not respond to acetazolamide, but showed a marked improvement in paralytic symptoms upon treatment with hydrochlorothiazide. The findings in this case indicate that a de novo mutation needs to be considered when an isolated family member is found to have a HYPP phenotype

Pathophysiological Role of Omega Pore Current in Channelopathies

In voltage-gated cation channels, a recurrent pattern for mutations is the neutralization of positively charged residues in the voltage-sensing S4 transmembrane segments. These mutations cause dominant ion channelopathies affecting many tissues such as brain, heart, and skeletal muscle. Recent studies suggest that the pathogenesis of associated phenotypes is not limited to alterations in the gating of the ion-conducting alpha pore. Instead, aberrant so-called omega currents, facilitated by the movement of mutated S4 segments, also appear to contribute to symptoms. Surprisingly, these omega currents conduct cations with varying ion selectivity and are activated in either a hyperpolarized or depolarized voltage range. This review gives an overview of voltage sensor channelopathies in general and focuses on pathogenesis of skeletal muscle S4 disorders for which current knowledge is most advanced

Enhancement of K+ conductance improves in vitro the contraction force of skeletal muscle in hypokalemic periodic paralysis

An abnormal ratio between Na+ and K+ conductances seems to be the cause for the depolarization and paralysis of skeletal muscle in primary hypokalemic periodic paralysis. Recently we have shown that the k+ channel opener cromakalim hyperpolarizes mammalian skeletal muscle fibers. Now we have studied the effects of this drug on the twitch force of muscle biopsies from normal and diseased human skeletal muscle. Cromakalim had little effect on the twitch force of normal muscle whereas it strongly improved the contraction force of fibers from patients suffering from hypokalemic periodic paralysis. Recordings of intracellular K+ and Cl- activities in human muscle and isolated rat soleus muscle support the view that cromakalim enhances the membrane K+ conductance (gK+). These data indicate that K+ channel openers may have a beneficial effect in primary hypokalemic periodic paralysis

On the sensitivity of surface NMR in the presence of electrical conductivity anomalies

The surface-NMR tomography technique is based on the principles of electromagnetic induction and proton spin dynamics. Electromagnetic fields emitted by large surface current-driven loops are employed to locate and quantify groundwater reservoirs. The oscillating magnetic fields interact with proton spins of water molecules in the electrically conductive subsurface. To study the influence of changing subsurface electrical properties on the nuclear spin response, we consider the spin magnetization as a virtual magnetic dipole receiver. The numerical solutions for the electric and magnetic fields of the transmitter and the virtual receiver in 3-D heterogeneous ground are based on the finite-element method. We explicitly compute the frequency-domain electromagnetic sensitivities for separate spin magnetizations in a groundwater aquifer to study the distortion of the NMR response because of electrical heterogeneities in the medium. Analyses of entire pulse moment sequences yield the cumulative sensitivities to electrical conductivity and water-content variations in the subsurface. We illustrate the influence of conductivity on NMR responses using a limited number of models. From these models we found that electrical conductivity anomalies in the shallow subsurface (<50 m) having values =0.1 S m-1 and volumes with linear dimensions in the order of our loop size (i.e. edge length 100 m) can have a strong influence on the NMR response and ought to be taken into account in the inversion of surface-NMR data. The effect increases non-linearly with increased body size, increased conductivity contrast and decreased anomaly dept