https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1957.sp005808

The action of calcium on the electrical properties of squid axons

To obtain information concerning the time course and instantaneous distribution of the excitatory process of the normal human heart, studies were made on isolated human hearts from seven individuals who died from various cerebral conditions, but who had no history of cardiac disease. Measurements were made from as many as 870 intramural terminals. In the isolated human hearts three endocardial areas were synchronously excited 0 to 5 msec after the start of the left ventricular activity potential. These areas increased rapidly in size during the next 5 to 10 msec and became confluent in 15 to 20 msec. The left ventricular areas first excited were (1) high on the anterior paraseptal wall just below the attachment of the mitral valve; (2) central on the left surface of the interventricular septum and (3) posterior paraseptal about one third of the distance from apex to base. The last part of the left ventricle to be activated usually was the posterobasal area. Endocardial activation of the right ventricle wa...

Total Excitation of the Isolated Human Heart

The properties of Na channels of the node of Ranvier are altered by neutral, amine, and quaternary local anesthetic compounds. The kinetics of the Na currents are governed by a composite of voltage- and time-dependent gating processes with voltage- and time-dependent block of channels by drug. Conventional measurements of steady-state sodium inactivation by use of 50-ms prepulses show a large negative voltage shift of the inactivation curve with neutral benzocaine and with some ionizable amines like lidocaine and tetracaine, but no shift is seen with quaternary OX-572. However, when the experiment is done with repetitive application of a prepulse-testpulse waveform, a shift with the quaternary cations (applied internally) is seen as well. 1-min hyperpolarizations of lidocaine- or tetracaine-treated fibers restore two to four times as many channels to the conducting pool as 50-ms hyperpolarizations. Raising the external Ca++ concentration also has a strong unblocking effect. These manipulations do not relieve block in fibers treated with internal quaternary drugs. The results are interpreted in terms of a single receptor in Na channels for the different drug types. Lipid-soluble drug forms are thought to come and go from the receptor via a hydrophobic region of the membrane, while charged and less lipid-soluble forms pass via a hydrophilic region (the inner channel mouth). The hydrophilic pathway is open only when the gates of the channel are open. Any drug form in the channel increases the probability of closing the inactivation gate which, in effect, is equivalent to a negative shift of the voltage dependence of inactivation.

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Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction.

A mathematical model of the cardiac ventricular action potential is presented. In our previous work, the membrane Na+ current and K+ currents were formulated. The present article focuses on processes that regulate intracellular Ca2+ and depend on its concentration. The model presented here for the mammalian ventricular action potential is based mostly on the guinea pig ventricular cell. However, it provides the framework for modeling other types of ventricular cells with appropriate modifications made to account for species differences. The following processes are formulated: Ca2+ current through the L-type channel (ICa), the Na(+)-Ca2+ exchanger, Ca2+ release and uptake by the sarcoplasmic reticulum (SR), buffering of Ca2+ in the SR and in the myoplasm, a Ca2+ pump in the sarcolemma, the Na(+)-K+ pump, and a nonspecific Ca(2+)-activated membrane current. Activation of ICa is an order of magnitude faster than in previous models. Inactivation of ICa depends on both the membrane voltage and [Ca2+]i. SR is divided into two subcompartments, a network SR (NSR) and a junctional SR (JSR). Functionally, Ca2+ enters the NSR and translocates to the JSR following a monoexponential function. Release of Ca2+ occurs at JSR and can be triggered by two different mechanisms, Ca(2+)-induced Ca2+ release and spontaneous release. The model provides the basis for the study of arrhythmogenic activity of the single myocyte including afterdepolarizations and triggered activity. It can simulate cellular responses under different degrees of Ca2+ overload. Such simulations are presented in our accompanying article in this issue of Circulation Research.

A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes.

A mathematical model of the membrane action potential of the mammalian ventricular cell is introduced. The model is based, whenever possible, on recent single-cell and single-channel data and incorporates the possibility of changing extracellular potassium concentration [K]o. The fast sodium current, INa, is characterized by fast upstroke velocity (Vmax = 400 V/sec) and slow recovery from inactivation. The time-independent potassium current, IK1, includes a negative-slope phase and displays significant crossover phenomenon as [K]o is varied. The time-dependent potassium current, IK, shows only a minimal degree of crossover. A novel potassium current that activates at plateau potentials is included in the model. The simulated action potential duplicates the experimentally observed effects of changes in [K]o on action potential duration and rest potential. Physiological simulations focus on the interaction between depolarization and repolarization (i.e., premature stimulation). Results demonstrate the importance of the slow recovery of INa in determining the response of the cell. Simulated responses to periodic stimulation include monotonic Wenckebach patterns and alternans at normal [K]o, whereas at low [K]o nonmonotonic Wenckebach periodicities, aperiodic patterns, and enhanced supernormal excitability that results in unstable responses ("chaotic activity") are observed. The results are consistent with recent experimental observations, and the model simulations relate these phenomena to the underlying ionic channel kinetics.

A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction.

There is evidence suggesting that the onset of electrical activity in nerve and muscle depends on a specific permeability increase of the surface membrane which allows sodium ions to enter the fibre at a high rate (for references, see Hodgkin, 1951). Furthermore, it has been shown for the giant axon of the squid (Hodgkin & Huxley, 1952 a) that the amount by which the sodium permeability increases during activity (or depolarization) depends on the value of the potential difference which had been acting on the surface membrane before the depolarization. The present experiments were undertaken in order to look for a similar effect in mammalian Purkinje fibres. By means of a feedback circuit the 'resting' potential could be chosen at will; its effect was observed on certain features of the action potential which are thought to be indicative ofthe sodium permeability, namely the upstroke velocity and the size of the 'overshoot'.

The effect of the cardiac membrane potential on the rapid availability of the sodium-carrying system

Calcium ions and local anaesthetics are said to 'stabilize' excitable membranes. This statement is based on the findings that in the presence of these agents (i) stronger currents are needed to stimulate the tissues, (ii) spontaneous rhythms are slowed or suppressed, (iii) conduction of impulses may be blocked, and (iv) the resting potential remains practically unchanged (for references, see Fleckenstein & Hardt, 1952; Brink, 1954). The present paper describes the action of calcium ions and local anaesthetics on the magnitude of the diastolic membrane potential, the rate of rise and ' overshoot' of the action potential, the threshold potential and the membrane resistance of mammalian Purkinje fibres. A knowledge of such data may contribute to an understanding of the mode of action of these 'stabilizing' agents. METHODS

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1955.sp005379

Effects of calcium ions and local anaesthetics on electrical properties of Purkinje fibres

The aim of the present work was to measure the myoplasm resistance and the membrane resistance and capacity in Purkinje fibres of the mammalian heart. A knowledge of these characteristics is important in any discussion of cardiac excitation and conduction, and may also be of interest to those concerned with the movement of ions through cell membranes. The theoretical method employed was similar in principle to that introduced by Hodgkin & Rushton (1946). This is based on the assumption that a single fibre can be regarded as a cable-like structure with a core of well-conducting protoplasm and a thin surface membrane having a high resistance and a large capacity per unit area. In the present case the analysis was simplified by keeping the fibre in a large volume of saline and using internal electrodes to apply current and to record potential. This has the advantage that fewer independent measurements are needed in order to determine the basic constants of the fibre. The equations of cable theory are usually applied to a uniform fibre of infinite length, while the fibres of the cardiac syncytium fuse with one another at distances of less than 1 mm. The difficulties arising from this situation were reduced by using single fibres in the Purkinje system of the kid which were found to be free from interconnexions for a length of a few mm and by making use of a phenomenon characteristic for heart muscle, the 'healing-over' of cut surfaces. THEORY

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1952.sp004799

The electrical constants of Purkinje fibres.

1. The passive electrical properties of muscle bundles obtained from the right ventricle of sheep or calf hearts were determined. Preparations were kept in silicon oil; through extracellular electrodes constant current pulses were made to flow between the ends of the bundles.2. Using micro-electrodes for potential recording, the following data were obtained: (i) a space constant of 880 mu; (ii) a membrane time constant of 4.4 msec; (iii) a ratio of intra-to-extracellular longitudinal resistance of 3.5: 1; (iv) a conduction velocity of 0.75 m/sec.3. The intracellular specific resistance (R(i)) in the longitudinal direction was 470Omega cm, corresponding to 3 times R(i) of Purkinje fibres or 9 times the specific resistance of Tyrode solution.4. A calculation of specific membrane resistance (R(m)) and capacity (C(m)) was up against uncertainties in estimating the surface area. Taking morphological data as obtained by light microscopy, R(m) works out at 9100Omega cm(2), C(m) 0.81 muF/cm(2). Electron micrographs suggest that the true surface membrane might be either larger (T-tubules) or smaller (tight junctions between parallel fibres) than the surface area as seen by the light microscope.5. The apparently small value of C(m) seems to indicate that the flow of current between ;outside' and ;inside' is restricted to only a fraction of the fibre surface, while a considerable part of the contact area between parallel fibres is of the low-resistance type. This would provide for functional connexions not only at the level of intercalated disks, but also along parallel-running fibres.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1970.sp009256

Electrical constants of trabecular muscle from mammalian heart

Microcapillaries with an external tip diameter of 0 5p. (Ling & Gerard, 1949) can be inserted into single fibres of the cardiac syncytium and may be used to record resting and action potentials. The technique has so far been applied to the frog ventricle (Woodbury, Hecht & Christopherson, 1951) and to 'false tendons' of the dog and kid heart (Draper & Weidmann, 1951). The conductive system of the kid contains typical Purkinje fibres which are larger in diameter (40-lOOup.) than ordinary heart muscle fibres and which are only slightly contractile. In this preparation it is possible to insert two microelectrodes into the same fibre and to leave them intracellular for many minutes. Polarizing current can be applied through one electrode and the change in membrane potential -resulting from current flow recorded through the other electrode. The present paper contains an account of experiments designed to investigate the cardiac action potential by applying suitable pulses of current at various stages in the cardiac cycle.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1951.sp004667

Silvio Weidmann

Papers

The effect of the cardiac membrane potential on the rapid availability of the sodium-carrying system

Effects of calcium ions and local anaesthetics on electrical properties of Purkinje fibres

The electrical constants of Purkinje fibres.

Electrical constants of trabecular muscle from mammalian heart

Effect of current flow on the membrane potential of cardiac muscle.