A Three-State Multi-Ion Kinetic Model for Conduction Properties of ClC-0 Chloride Channel

A three-state, multiion kinetic model was proposed to enable the conduction properties of the mammalian channel ClC-0 to be well characterized. Using this rate-theory based model, the current-voltage and conductance-concentration relations were obtained. The five parameters needed were determined by fitting the data of conduction experiments of the wild-type ClC-0 and its K519C mutant. The model was then tested against available calculation and simulation data, and the energy differences between distinct chloride-occupancy states computed agreed with an independent calculation on the binding free energies solved by using the Poisson-Boltzmann equation. The average ion number of conduction and the ion passing duration calculated closely resembled the values obtained from Brownian dynamics simulations. According to the model, the decrease of conductance caused by mutating residue K519 to C519 can be attributed to the effect of K519C mutation on translocation rate constants. Our study sets up a theoretical model for ion permeation and conductance in ClC-0. It provides a starting point for experimentalists to test the three-state model, and would help in understanding the conduction mechanism of ClC-0.     

Inference of motor unit recruitment order in voluntary and electrically elicited contractions

The relationship between surface myoelectric signal parameters and the level of voluntary or electrically elicited contractions was studied in 32 experiments on the tibialis anterior muscle of 22 healthy human subjects. Contractions were performed at 20 and 80% of the maximum voluntary contraction torque. Two levels of stimulation current were used, yielding, respectively, a maximum M wave and an M wave approximately 30% of the maximum. A four-bar electrode probe was used to detect single- and double-differential signals from which mean and median frequency of the power spectrum and average muscle fiber conduction velocity were estimated. Measurements obtained from voluntary contractions showed a positive correlation between contraction levels and both conduction velocity and spectral parameters. Conduction velocity increased by 21.2 +/- 10.9% when voluntary contraction level increased from 20 to 80% of the maximal value. Spectral parameters increased by similar amounts. Tetanic electrical stimulation was applied to a muscle motor point for 20 s via surface electrodes. Rectangular current pulses with 0.1-ms width and frequencies of 20, 25, 30, 35, and 40 Hz were used. Four types of behavior were observed with increasing stimulation level: 1) the two spectral parameters and conduction velocity both increased with stimulation in 15 experiments, 2) the two spectral parameters decreased and conduction velocity increased in 8 experiments, 3) the two spectral parameters and conduction velocity both decreased in 6 experiments, and 4) the two spectral parameters increased and conduction velocity decreased in 3 experiments. Conduction velocity increased with increasing stimulation current in 72% of the experiments, indicating a recruitment order similar to that of voluntary contractions, although it decreased in the other 28% of the cases, indicating a reverse order of recruitment. Contrary to what is observed in direct stimulation of nerves, motor units are not in general recruited in reverse order of size during electrical stimulation of a muscle motor point. This discrepancy may be the result of geometric factors or a lack of correlation between axonal branch diameter and the diameter of the parent motoneuron axon. Changes of conduction velocity and spectral parameters in opposite directions may be the result of the combined effect of the motor unit recruitment order and of the different tissue filtering function associated with the geometric location of the recruited motor units within the muscle.     

Bistable nerve conduction

It has been demonstrated experimentally that slow and fast conduction waves with distinct conduction velocities can occur in the same nerve system depending on the strength or the form of the stimulus, which give rise to two modes of nerve functions. However, the mechanisms remain to be elucidated. In this study, we use computer simulations of the cable equation with modified Hodgkin-Huxley kinetics and analytical solutions of a simplified model to show that stimulus-dependent slow and fast waves recapitulating the experimental observations can occur in the cable, which are the two stable conduction states of a bistable conduction behavior. The bistable conduction is caused by a positive feedback loop of the wavefront upstroke speed, mediated by the sodium channel inactivation properties. Although the occurrence of bistable conduction only requires the presence of the sodium current, adding a calcium current to the model further promotes bistable conduction by potentiating the slow wave. We also show that the bistable conduction is robust, occurring for sodium and calcium activation thresholds well within the experimentally determined ones of the known sodium and calcium channel families. Since bistable conduction can occur in the cable equation of Hodgkin-Huxley kinetics with a single inward current, i.e., the sodium current, it can be a generic mechanism applicable to stimulus-dependent fast and slow conduction not only in the nerve systems but also in other electrically excitable systems, such as cardiac muscles.     

Conduction velocity and excitability of A and C fibers of cat mesenteric nerves

The conduction velocity and excitability of fibers running from the mesenteric into the splanchnic nerves were studied in experiments on cats. Among the A fibers of these nerves there were shown to be: 1) fibers with an excitation threshold of 0.06–0.10 V (stimulus duration 0.1 msec) and a maximal conduction velocity of 48–85 m/sec; 2) fibers with an excitation threshold of 0.3–0.7 V, impulses of which form up to five waves in the composition of the action potential, with maximal conduction velocities of between 8–10 and 33–39 m/sec; 3) fibers with an excitation threshold of over 1 V and a conduction velocity of between 1.8 and 7 m/sec. The excitation threshold of the group C fibers was 6–8 V. Impulses of these fibers form a low-amplitude wave in the composition of the action potential of the mesenteric and splanchnic nerves with a conduction velocity of 1.0–1.8 m/sec, several waves of higher amplitude with a conduction velocity of 0.5–1.2 m/sec, and several low-amplitude waves with a conduction velocity of 0.35–0.55 m/sec. The results of experiments with different combinations of arrangement of the stimulating and recording electrodes on the mesenteric and splanchnic nerves indicate that sympathetic postganglionic C fibers of the mesenteric nerves occur only in the second group, whereas afferent C fibers occur in all three of the groups distinguished.Institute of Normal and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 7, No. 3, pp. 272–278, May–June, 1975.     

Optical measurement of conduction in single demyelinated axons

Demyelination was initiated in Xenopus sciatic nerves by an intraneural injection of lysolecithin over a 2-3-mm region. During the next week macrophages and Schwann cells removed all remaining damaged myelin by phagocytosis. Proliferating Schwann cells then began to remyelinate the axons, with the first few lamellae appearing 13 d after surgery. Action potentials were recorded optically through the use of a potential-sensitive dye. Signals could be detected both at normal nodes of Ranvier and within demyelinated segments. Before remyelination, conduction through the lesion occurred in only a small fraction of the fibers. However, in these particular cases we could demonstrate continuous (nonsaltatory) conduction at very low velocities over long (greater than one internode) lengths of demyelinated axons. We have previously found through loose patch clamp experiments that the internodal axolemma contains voltage-dependent Na+ channels at a density approximately 4% of that at the nodes. These channels alone, however, are insufficient for successful conduction past the transition point between myelinated and demyelinated regions. Small improvements in the passive cable properties of the axon, adequate for propagation at this site, can be realized through the close apposition of macrophages and Schwann cells. As the initial lamellae of myelin appear, the probability of success at the transition zone increases rapidly, though the conduction velocity through the demyelinated segment is not appreciably changed. A detailed computational model is used to test the relative roles of the internodal Na+ channels and the new extracellular layer. The results suggest a possible mechanism that may contribute to the spontaneous recovery of function often seen in demyelinating disease.     

Mechanism of facilitation of conduction in Purkinje fibers with sequential pacing

Clinical studies have demonstrated that retrograde conduction of a premature beat through the His-Purkinje system can be facilitated by atrioventricular sequential pacing. Several possible mechanisms of facilitation have been proposed. No studies, however, have shown the occurrence of this phenomenon or its mechanism in isolated Purkinje fibers. The present study demonstrated that facilitation of conduction of a premature beat can indeed occur in isolated canine Purkinje fibers during sequential pacing. When a premature beat showed conduction delay during unidirectional pacing, its conduction consistently improved during sequential pacing. This improvement of conduction was related to a greater membrane recovery of a portion of the Purkinje fiber, i.e., the portion that was pre-excited by the sequential mode of stimulation. These findings suggest that an important mechanism of the facilitation of conduction observed clinically may be similar; i.e., pre-excitation and consequent earlier recovery from refractoriness of portions of the His-Purkinje system during atrioventricular sequential pacing.     

On the mechanisms of arrhythmias in the myocardium of mXinalpha-deficient murine left atrial-pulmonary veins

We have previously shown that left atrial-pulmonary vein tissue (LA-PV) can generate reentrant arrhythmias (atrial fibrillation, AF) in wild-type (mXinalpha+/+) but not in mXinalpha-null (mXinalpha-/-) mice. With the present experiments, we investigated the arrhythmogenic activity and the underlying mechanisms in mXinalpha+/+ vs. mXinalpha-/- LA-PV. Electrical activity and conduction velocity (CV) were recorded in LA-PV by means of a MED64 system. CV was significantly faster in mXinalpha+/+ than in mXinalpha-/- LA-PV and it was increased by 1 muM isoproterenol (ISO). AF could be induced by fast pacing in the mXinalpha+/+ but not in mXinalpha-/- LA-PV where automatic rhythms could occur. ISO increased the incidence of AF in Xinalpha+/+ whereas it increased that of automatic rhythms in mXinalpha-/- LA-PV. In LA-PV with the right atrium attached (RA-LA-PV), automatic rhythms occurred in all preparations. In mXinalpha+/+ RA-LA-PV simultaneously treated with ISO, strophanthidin and atropine, the incidence of the automatic rhythm was about the same, but AF increased significantly. In contrast, in mXinalpha-/- RA-LA-PV under the same condition, the automatic rhythm was markedly enhanced, but still no AF occurred. Conventional microelectrode techniques showed a longer APD(90) and a less negative maximum diastolic potential (MDP) in mXinalpha-/- than mXinalpha+/+ LA-PV tissues. Whole-cell current clamp experiments also showed a less negative MDP in mXinalpha-/- vs. mXinalpha+/+ LA-PV cardiomyocytes. The fact that AF could be induced by fast pacing under several conditions in mXinalpha+/+ but not in mXinalpha-/- LA-PV preparations appears to be due to a slower CV, a prolonged APD(90), a less negative MDP and possibly larger areas of conduction block in mXinalpha-/- myocardial cells. In contrast, the non-impairment of automatic and triggered rhythms in mXinalpha-/- preparations may be due to the fact that the mechanisms underlying these rhythms do not involve cell-to-cell conduction.     

Contraction of collecting lymphatics: organization of pressure-dependent rate for multiple lymphangions

The paper describes the extension of a previously developed model of pressure-dependent contraction rate to the case of multiple lymphangions. Mechanical factors are key modulators of active lymphatic pumping. As part of the evolution of our lumped-parameter model to match experimental findings, we have designed an algorithm whereby the time until the next contraction depends on lymphangion transmural pressure in the contraction just completed. The functional dependence of frequency on pressure is quantitatively matched to isobaric contraction experiments on isolated lymphatic segments. When each of several lymphangions is given this ability, a scheme for their coordination must be instituted to match the observed synchronization. Accordingly, and in line with an experiment on an isolated lymphatic vessel segment in which we measured contraction sequence and conduction delay, we took the fundamental principle to be that local timing can be overridden by signals to initiate contraction that start in adjacent lymphangions, conducted with a short delay. The scheme leads to retrograde conduction when the lymphangion chain is pumping against an adverse pressure difference, but antegrade conduction when contractions occur with no or a favourable pressure difference. Abolition of these conducted signals leads to chaotic variation of cycle-mean flow-rate from the chain, diastolic duration in each lymphangion, and inter-lymphangion delays. Chaotic rhythm is also seen under other circumstances. Because the model responds to increasing adverse pressure difference by increasing the repetition rate of contractions, it maintains time-average output flow-rate better than one with fixed repetition rate.     

Muscle fatigue: conduction or mechanical failure?

It is well documented that repeated voluntary activity or electrical stimulation of skeletal muscle results in a decline in force production or power output. However, the precise physiological causes of "muscle fatigue" are not yet well understood. It is conceivable that the mechanism(s) may lie either in the conduction of action potentials in the central and peripheral nervous systems or in the transformation of the electrical event into mechanical force production by the muscle itself. In fact, none of the components of the electrical pathway from generation of impulses in the brain to their conduction over the neuron and the excitable membranes of the muscle can as yet be ruled out as potential contributors to the fatigue process. Relative to that on conduction failure, more information exists concerning the possibility that a defect in the excitation contraction coupling process in skeletal muscle, e.g., intracellular acidosis, inadequate supply of energy for contraction, or a disruption in Ca2+ homeostasis may also be significant in compromising force production following sustained activity. Despite this, the amount of conflicting data derived from these experiments has hindered the resolution of this question. In the future more attention must be given to such issues as the type of activity used to elicit fatigue and the fiber composition of the muscles studied. This is imperative as these factors clearly impact the nature of correlations between the biochemical and physiological events in muscle that are required to support prospective fatigue mechanisms.     

Functional mathematical model of dual pathway AV nodal conduction

Dual atrioventricular (AV) nodal pathway physiology is described as two different wave fronts that propagate from the atria to the His bundle: one with a longer effective refractory period [fast pathway (FP)] and a second with a shorter effective refractory period [slow pathway (SP)]. By using His electrogram alternance, we have developed a mathematical model of AV conduction that incorporates dual AV nodal pathway physiology. Experiments were performed on five rabbit atrial-AV nodal preparations to develop and test the presented model. His electrogram alternances from the inferior margin of the His bundle were used to identify fast and slow wave front propagations. The ability to predict AV conduction time and the interaction between FP and SP wave fronts have been analyzed during regular and irregular atrial rhythms (e.g., atrial fibrillation). In addition, the role of dual AV nodal pathway wave fronts in the generation of Wenckebach periodicities has been illustrated. Finally, AV node ablative modifications have been evaluated. The model accurately reproduced interactions between FP and SP during regular and irregular atrial pacing protocols. In all experiments, specificity and sensitivity higher than 85% were obtained in the prediction of the pathway responsible for conduction. It has been shown that, during atrial fibrillation, the SP ablation significantly increased the mean HH interval (204 ± 39 vs. 274 ± 50 ms, P < 0.05), whereas FP ablation did not produce significant slowing of ventricular rate. The presented mathematical model can help in understanding some of the intriguing AV node mechanisms and should be considered as a step forward in the studies of AV nodal conduction.     

Electrophysiological effects of the aqueous extract of Averrhoa carambola L. leaves on the guinea pig heart

This work aims to describe some electrophysiological changes promoted by the aqueous extract (AEx) from Averrhoa carambola leaves in guinea pig heart. The experiments were carried out on isolated heart or on right atrium-ventricle preparations. In 6 hearts, the extract induced many kinds of atrioventricular blocks (1st, 2nd, and 3rd degrees); increased the QT interval from 229+/-23 to 264+/-19 ms; increased the QRS complex duration from 27+/-3.1 to 59+/-11 ms, and depressed the cardiac rate from 136+/-17 to 89+/-14b pm. Furthermore, it decreased the conduction velocity of atrial impulse (17+/-3%); reduced the intraventricular pressure (86+/-6%), and increased the conduction time between the right atrium and the His bundle (27+/-6.5%). The conduction time from the His bundle to the right ventricle was not altered. Atropine sulfate did not change either the electrocardiographic parameters or the intraventricular pressure effects promoted by the A. carambola AEx. Based on these results, the popular use of such extracts should be avoided because it can promote electrical and mechanical changes in the normal heart.     

原核基因组的进化方向和癌／正常细胞的熵产生

本文评述了理论生物学的两个基础实验。一是用离子束辐照加速大肠杆菌进化的方法研究原核基因组的进化方向,证明进化中的缺失偏好性和编码信息量扩增律不矛盾。二是提出用导热法测量细胞的熵产生,比较研究了癌细胞和正常细胞的熵产生和外加电场的关系,证明在一定强度的电场作用下正常细胞的熵产生可以明显超过癌细胞,从而实现改变两类细胞间熵流方向的目的。     

Bioelectric properties of frog sciatic nerves during exposure to stationary magnetic fields

The bioelectric properties of frog sciatic nerves have been measured during exposure to homogeneous, stationary magnetic fields. The action potential amplitude, conduction velocity, absolute refractory period and relative refractory period were found to be unaffected by a continuous 4-h exposure to perpendicular or parallel 2.0 T (1 T equal 10(4) G) magnetic fields. These parameters also remained unchanged during a 1-h post-exposure period. The conduction velocity was similarly found to be unchanged when the field was applied continuously for 17 h. Exposure of sciatic nerves to a 1.0-T field led to no alteration in the threshold for neural excitation. The absence of magnetic field effects on nerve electrical activity observed in the present experiments contrasts with the positive findings reported previously by other investigators. These discrepancies may be attributable to an inadequate control of ambient temperature in the earlier studies.     

Proton conduction in lecithins. III. Nature of charge carriers

The nature of charge carriers was studied in hydrated lecithin using different techniques. The current-voltage characteristics confirmed the ionic nature of conduction. Attempts to determine the charge mobility were unsuccessful. From measurements of the thermovoltage at different hydration levels the charge carrier was found to be positive. The value of the thermo electromotive force (thermo e.m.f.) depends on the phase state of the lipid but is independent of its water content. The mechanism of charge generation is discussed. The activation energy of conduction does not reflect the phase change directly. Its dependence on water content is attributed to charge mobility which involves the motion of the head groups. Electrolysis experiments were carried out and the amount of hydrogen evolved was determined by gas chromatography. A proton mechanism of conduction is suggested.     

经颅磁刺激在大脑皮质研究中的应用和进展

经颅磁刺激（TMS）是一种能够在脑中感应聚焦电流,瞬间调制大脑皮质的无创方法,在临床研究、基础神经学和诊治疾病等方面有许多应用。通过记录运动皮质诱发电位（MEPs),TMS已经或将成为探测脑下运动路径传导、评价皮质兴奋性、皮质映射和研究皮质塑性的常规工具。TMS能够主动干预脑功能,这种特性使它成为研究正常人脑－行为关系的独特技术,可以建立脑活动与任务完成之间的因果关系,探索脑功能连接。近年来的许多实验又表明,TMS在运动紊乱和精神疾病方面有潜在的治疗作用,但达到临床应用还有一定距离。     

Effects of stochastic channel gating and distribution on the cardiac action potential

Ion channels exhibit stochastic conformational changes determining their gating behavior. In addition, the process of protein turnover leads to a natural variability of the number of membrane and gap junctional channels. Nevertheless, in computational models, these two aspects are scarcely considered and their impacts are largely unknown. We investigated the effects of stochastic current fluctuations and channel distributions on action potential duration (APD), intercellular conduction delays (ICDs) and conduction blocks using a modified ventricular cell model (Rudy et al.) with Markovian formulations of the principal ion currents (to simulate their stochastic open-close gating behavior) and with channel counts drawn from Poisson distributions (to simulate their natural variability). In single cells, APD variability (coefficient of variation: 1.6% at BCL=1000 ms) was essentially caused by stochastic channel gating of I_Ks, persistent I_Na and I_Ca,L. In cell strands, ICD variability induced by stochastic channel gating and Poissonian channel distributions was low under normal conditions. Nonetheless, at low intercellular coupling levels, Poissonian gap junctional channel distribution resulted in a large ICD variability (coefficient of variation >20%), highly heterogeneous conduction patterns and conduction blocks. Therefore, the stochastic behavior of current fluctuations and channel distributions can contribute to the heterogeneity of conduction patterns and to conduction block, as observed previously in experiments in cardiac tissue with altered intercellular coupling.     

Electrophysiological characteristics of the aortic baroceptors

The presence in the left aortic nerve of rabbits of medullated and nonmedullated fibres with conduction velocities of 12--30 m/s and 0.9--1.2 m/s, respectively, was demonstrated. In experiments on the isolated aortic arch preparation the electrophysiological characteristics of the aortic baroceptors with the medullated and non-medullated fibres were studied by means of a selective block of conduction in these fibers. Baroceptors with the non-medullated fibers had a higher threshold pressure and a wider functional range.     

猫冠状动脉缺血与再灌注对房室传导的影响

急性下壁心肌梗塞常引起房室传导功能障碍,然而这种障碍与心肌缺血的内在联系并不很清楚,本实验在去植物性神经传出纤维的猫上进行,通过模板匹配方法从Ｈｉｓ束电图检测Ａ,Ｈ,Ｖ波并测量两心房间期（ＡＡ）,心房波与Ｈｉｓ波间期（ＡＨ）,Ｈｉｓ波与心室波间期（ＨＶ）和心房波与心室波间期（ＡＶ）。结果如下：结扎右冠状动脉后,２０只动物的ＡＨ间期１４只出现增加（Ａ组）６只未出现增加（Ｂ组）对Ｂ组进行快速心房起博和     

Mechanism of conduction block in amphibian myelinated axon induced by biphasic electrical current at ultra-high frequency

The mechanism of axonal conduction block induced by ultra-high frequency (≥20 kHz) biphasic electrical current was investigated using a lumped circuit model of the amphibian myelinated axon based on Frankenhaeuser-Huxley (FH) equations. The ultra-high frequency stimulation produces constant activation of both sodium and potassium channels at the axonal node under the block electrode causing the axonal conduction block. This blocking mechanism is different from the mechanism when the stimulation frequency is between 4 kHz and 10 kHz, where only the potassium channel is constantly activated. The minimal stimulation intensity required to induce a conduction block increases as the stimulation frequency increases. The results from this simulation study are useful to guide future animal experiments to reveal the different mechanisms underlying nerve conduction block induced by high-frequency biphasic electrical current.