Showing papers by "David A. Eisner published in 1979"

The steady-state TTX-sensitive ("window") sodium current in cardiac Purkinje fibres

Abstract: Voltage clamp experiments on isolated sheep Purkinje fibres showed an increase of the steady state outward membrane current, over the potential range -65mV to -15 mV, in the presence of tetrodotoxin (TTX, 3.10(-5 M). This "window" current is considered to be the steady state component of the fast sodium current (INa), resulting from the crossover of the activation and inactivation curves which govern the opening of the sodium channel. TTX had no significant effect on the reversal potential, activation curve, kinetics or instantaneous I-V relationship of the pacemaker current IK2. The window found in these experiments extends to potentials well into the range of the action potential plateau. Consequently small changes of the steady state INa might have large effects on the action potential duration. The effects of TTX and local anaesthetics are discussed in this context.

Inotropic and arrhythmogenic effects of potassium-depleted solutions on mammalian cardiac muscle.

Abstract: 1. We have investigated the electrical and mechanical effects of reducing the bathing K concentration, K0, over the range from 4-0 mM in guinea-pig papillary muscle and in sheep Purkinje fibres. 2. In papillary muscle, reducing K0 to zero produces a negative shift in the resting potential and an initial increase in action potential duration. An increase of twitch tension ensues, followed by a reduction in actin potential duration and, eventually, an increase in tonic tension. This increase in tonic tension is often accompanied by a decrease of twitch tension. Finally, transient depolarizations and after contractions are produced. 3. In voltage clamped Purkinje fibres, K0 reduction decreases the slope conductance at the more negative potentials and reduces the pace-maker current, iK2. Twitch tension increases rapidly and voltage dependent tonic tension develops. After even very short exposures to very low K0 (1 mM and below), an oscillatory transient inward current and accompanying aftercontraction can be seen. The oscillatory transient inward current and aftercontraction are similar to those described for cardiotonic steroid intoxication by Kass, Lederer, Tsien & Weingart (1978). 4. Prolonged exposure to 0 K0 leads to the development of a slow current ‘creep'. This current is activated by depolarization and has a reversal potential of -6.7 +/- 3.5 mV. The development of this creep current is accompanied by an increasing ‘creep’ in tonic tension with the same time course. On repolarization both the current creep and creep in tension recover with time courses still similar to each other. 5. Fluctuations appear in both the tension and current records during exposure to low K0. The tension and current fluctuations have similar principal frequencies (about 1 Hz). 6. Ca0 removal, substituting Ba0 for Ca0 or adding Mn0 (2 mM) can each remove the transient inward current, aftercontraction, fluctuations of current and tension, and creep current as well as the increase of twitch and tonic tension. 7. Replacing Ca0 by Sr0 leads to an increased inotropic effect of low K0 with altered kinetics and appears to abolish the transient inward current, aftercontraction and fluctuations of current and tension. 8. It is concluded that Ca1 plays a central role in the inotropic and arrhythmogenic effects of low K0. Possible mechanisms of Ca1 control are discussed in light of the results that have been presented.

The role of the sodium pump in the effects of potassium‐depleted solutions on mammalian cardiac muscle

Abstract: 1. Mammalian Purkinje fibres and ventricular muscle are significantly affected by exposure to low K solutions (Eisner & Lederer, 1979). Such exposure produces two classes of effects. ;Early' effects, developing over tens of seconds include (in ventricular muscle) a more negative resting potential and a lengthening of the action potential. In Purkinje fibres the principal ;early' effect is a decrease in slope conductance. ;Late' effects develop over minutes. In ventricular muscle such effects include a shortening of the action potential, an increase in twitch and tonic tension, and the development of transient depolarizations and aftercontractions. The late effects in Purkinje fibres are the increase in twitch tension and voltage dependent tonic tension, the development of transient depolarizations and the underlying oscillatory transient inward currents, the appearance of aftercontractions accompanying the transient depolarizations or transient inward currents, and the development of a slow ;creep' in both current and tension.2. The rate of development of early effects is consistent with the time taken to change the bathing K concentration, K(o). However the time course of onset of the late effects (including the positive inotropy) is too slow to be explained by the time taken to change K(o).3. The late effects of reducing K(o) from 4 to 0 mM can be prevented by including appropriate concentrations of the activator cations of the Na pump (Tl, Rb, Cs, NH(4) or Li) in the 0 K(o) bathing solution. Similarly the late effects of 0 K(o), once established, can be reversed by adding these cations to the 0 K(o) superfusing solution.4. The order of potency of these cations to remove the effects of 0 K(o) was found to be: Tl > K approximately Rb > NH(4) approximately Cs > Li. This is similar to the order of efficacy shown to activate the external K site of the Na pump in nerve and other tissue (Rang & Ritchie, 1968).5. Strophanthidin (10(-5)M) produces qualitatively similar electrical and mechanical effects as those seen in 0 K(o). However, the effects of strophanthidin are not reversed by the activator cations. Furthermore, in the presence of strophanthidin (10(-5)M), these cations do not reverse the effects of 0 K(o).6. In voltage-clamped Purkinje fibres, returning to a solution of 4 mM-K(o) after exposure to 0 K(o) produces a transient increase in outward current. Similarly, during exposure to 0 K(o) the addition of activator cations also produces a transient increase of outward current. The ability of these ions to develop this outward transient current is correlated with their ability to remove the inotropic and arrhythmogenic effects of 0 K(o).7. The transient outward current produced by activator cations in 0 K(o) is blocked by strophanthidin (10(-5)M). We conclude that the outward current transient reflects activation of an electrogenic Na pump. Furthermore, we find that, as in other tissues, the activator cations can substitute for K(o) in activating the Na-K pump.8. The reversal of inotropic and arrhythmogenic effects of 0 K(o) by activator cations indicates that such effects result from Na pump blockade. No additional explanation (e.g. Ca/K exchange) need be invoked.

Voltage clamp and tracer flux data: effects of a restricted extra-cellular space.

Abstract: In the original Hodgkin & Huxley analysis of the membrane currents in squid giant axon, the time dependence of the currents was attributed to voltage-dependent changes in the permeability of the membrane to the ions involved. According to this theoretical framework, the time constants for the rate of change of current should be unique functions of the membrane potential, and should be independent of the previous history of the voltage and current flowing. In recent years, however, there has been increasing awareness of the fact that, for many physiological preparations, the space just outside the cell membrane is not in good diffusive contact with the bulk extra-cellular fluid perfusing the preparation. Consequently, when current flows across the cell membrane, there are changes in the ion concentrations in this so-called ‘restricted extra-cellular space’ (RECS).

Thick slurry bevelling: a new technique for bevelling extremely fine microelectrodes and micropipettes.

Abstract: A simple, inexpensive and rapid bevelling method is described. A settled slurry of 0.05 μm alumina powder in saline is used as the grinding surface. The bevelling process is continuous and reproducible over a wide range of electrode resistances.

Membrane potential and ion concentration stability conditions for a cell with a restricted extracellular space.

Abstract: For an isolated membrane, the resting (zero current) potential is stable if the slope conductance is positive, and is unstable if the slope conductance is negative. Recent work suggests that the properties of many preparations are influenced by the presence of an extracellular space that is not in good diffusive contact with the bulk extracellular fluid. Ionic current flow across the membrane changes the ion concentrations in this space. These concentration changes affect the stability of the membrane potential. Even if the slope conductance is negative, the presence of the extracellular space can confer stability on the resting potential. Conversely, even if the slope conductance is positive, the extracellular space can produce instability of the resting potential. Evaluation of the relevant parameters for cardiac Purkinje fibres, from published experimental data, suggests that concentration changes in the extracellular space may play a significant role in determining when an action potential is initiated.