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D A Eisner

Publications and source records attributed to D A Eisner.

At least 127 records · Page 7Linked to original sources
PubMed1984

Characterization of oscillations of intracellular calcium concentration in ferret ventricular muscle.

The photoprotein aequorin was injected into superficial cells of ferret papillary muscles. Tension and aequorin light (a function of intracellular [Ca2+]) were monitored. Increasing intracellular Ca concentration ([Ca2+]i), either by decreasing extracellular Na, or by inhibiting the Na pump with strophanthidin, produced spontaneous oscillations of [Ca2+]i and tension. Fourier analysis showed that these oscillations had frequencies of up to 3-4 Hz. If the muscle was stimulated in these conditions the Ca transient associated with the twitch was followed by a series of damped oscillations of [Ca2+]i which were accompanied by after-contractions. Under a given set of conditions the frequency of the stimulated oscillations was similar to that of the spontaneous oscillations. Manoeuvres which increase [Ca2+]i increased the frequency of both spontaneous and stimulated oscillations. Drugs which inhibit the function of the sarcoplasmic reticulum (caffeine and ryanodine) abolished both stimulated and spontaneous oscillations. The spontaneous oscillations during a Na-free contracture were unaffected by the Ca channel blocker D-600. When repetitive stimulation was begun the frequency and magnitude of the stimulated oscillations increased over several minutes. Increasing the frequency of stimulation increased the magnitude of the stimulated oscillations. It is concluded that the spontaneous oscillations of [Ca2+]i may be due to oscillatory Ca release from the sarcoplasmic reticulum. The similar properties of the spontaneous and stimulated oscillations suggest that the latter may be due to a synchronization of the former.

Aequorin↗
PubMed1984

The quantitative relationship between twitch tension and intracellular sodium activity in sheep cardiac Purkinje fibres.

Tension was measured in voltage clamped sheep cardiac Purkinje fibres while simultaneously measuring the intracellular Na activity (aiNa) with a recessed-tip, Na-selective micro-electrode. Inhibiting the Na-K pump either by exposing the preparation to a K-free solution or by adding the cardioactive steroid strophanthidin increased both aiNa and twitch tension and resulted in the development of tonic tension, after-contractions and a transient inward current (ITI). The increase of twitch tension was present at lower aiNa than that required to produce the other phenomena. The relationship between the magnitude of the twitch tension and aiNa was always non-linear. Twitch tension increased steeply with aiNa at first but the relationship flattened off at higher aiNa and tension eventually decreased. Over the steep range, the relationship between tension and aiNa could be represented as: twitch tension = b (aiNa)y where y had a mean value of 3.2. Changing membrane potential or [Ca2+]o changed b but had little effect on y. Mn (2 mmol/l) greatly decreased twitch tension but, at least initially, had little effect on tonic tension. The steep relationship between twitch tension and aiNa was seen, irrespective of whether the Na-K pump was inhibited either by exposure to K-free solution or to strophanthidin and whether the relationship was measured either when aiNa was increasing or after it had reached a steady state. The steep dependence of twitch tension on aiNa observed in the present work means that manoeuvres which produce even small changes of aiNa will have significant effects on contraction.

Animals↗
PubMed1983

Ca2+ ions can affect intracellular pH in mammalian cardiac muscle.

Although intracellular pH (pHi) has important effects on both the mechanical and electrical properties of cardiac muscle, the control of pHi in the heart is still poorly understood. One important determinant of pHi appears to be the transmembrane Na+ gradient. It has therefore been suggested that Na+-H+ exchange assists in the control of pHi in heart as has been proposed for other excitable cells. However, pHi and the intracellular Ca2+ concentration ([Ca2+]i) are interdependent in a variety of tissues and it has been shown recently that pHi can affect [Ca2+]i in cardiac muscle. As [Ca2+]i in cardiac muscle is also strongly influenced by the transmembrane Na+ gradient it is possible that the apparent Na+-dependence of pHi is secondary to changes in [Ca2+]i. Previous work in cardiac muscle has not been able to separate the effects of Na+-H+ exchange and [Ca2+]i on pHi (refs 4,5). Here we demonstrate in cardiac muscle that an increase in [Ca2+]i produces an intracellular acidification which cannot be ascribed to Na+-H+ exchange.

Animals↗
PubMed1983

Do calcium-activated potassium channels exist in the heart?

Changes of intracellular Ca concentration in cardiac muscle have significant effects on transmembrane currents and many of these effects can be accounted for by postulating the existence of Ca-activated K channels in the heart. However, the evidence that such channels exist is equivocal. This is partly because of technical problems, for example the difficulty of identifying an individual ionic current amongst the many currents that exist in the heart. An additional problem, however, is posed by the fact that other currents may also be modulated by Ca ions. It is important therefore to distinguish between these currents and those caused by Ca-activated, K-specific channels. In this review we consider the evidence for Ca activated currents in the heart and, in particular, we discuss whether or not these currents are carried exclusively by K ions.

Action Potentials↗
PubMed1983

Stimulation and inhibition by ATP and orthophosphate of the potassium-potassium exchange in resealed red cell ghosts.

The potassium:potassium (K-K) exchange through the sodium pump has been measured as the ouabain-sensitive 86Rb uptake by Na-free ghosts resealed to contain various concentrations of ATP, orthophosphate and K. The exchange is activated by increasing either internal or external K+ (Rb+) ion concentration. The activation curves can be described by simple Michaelis kinetics as: exchange = Vmax [K]/(Kapp + [K]). Increasing ATP concentration increases the apparent affinity for external K ions but decreases the apparent affinity for internal K (Ki+). Increasing [ATP] from 1 microM to 1 mM typically increases the Kapp for Ki+ from less than 1 mM to about 30 mM. Increasing ATP first activates the exchange but, after an optimal concentration is reached, further increase of ATP inhibits. The value of ATP concentration which gives the maximum flux depends on the internal and external K+ concentrations. The higher [Ki], the greater the optimal ATP concentration. Increasing external K (Rb) decreases the optimal ATP concentration. Increasing the concentration of orthophosphate (Pi) activates the exchange at high ATP but inhibits at low ATP concentration. A concentration of Pi which stimulates the exchange at high external K (Rb) can inhibit at low external K (Rb). These findings are in agreement with a consecutive or ping-pong model of the K-K exchange. We suggest that previous experiments have not shown the inhibitory effects of ATP and Pi because of the particular range of concentrations investigated.

Adenosine Triphosphate↗
PubMed1983

The control of tonic tension by membrane potential and intracellular sodium activity in the sheep cardiac Purkinje fibre.

Intracellular Na activity (aiNa) was measured with recessed-tip, Na-selective micro-electrodes in voltage-clamped sheep cardiac Purkinje fibres. Tension was measured simultaneously. aiNa was increased reversibly either by exposing the preparation to K-free, Rb-free solution of by adding the cardioactive steroid strophanthidin. An increase of aiNa produced an increase of tonic tension which was larger at depolarized membrane potentials. At sufficiently negative membrane potentials, changes of aiNa (over the range 6-30 mM) had no effect on tonic tension. Therefore, both an increase of aiNa and a depolarization are required to increase tonic tension. It is concluded that either a low level of aiNa or a large negative membrane potential is sufficient to maintain a low intracellular Ca concentration. Tonic tension was measured as a function of aiNa. At a given membrane potential the relationship can be described empirically by an equation of the form: tonic tension = b(aiNa)y, where y is a constant and b depends on membrane potential. In five experiments y was found to be 3.7 +/- 0.7 (mean +/- S.E.M.) over a range of potentials from -60 to -10 mV. Tonic tension was measured as a function of membrane potential. At a given aiNa the relationship can be described approximately as: tonic tension = k exp (aV), where a is a constant and k depends on aiNa. In five experiments a was found to be 0.06 +/- 0.01 mV-1 (mean +/- S.E.M.). A depolarization of 10 mV increases tonic tension by the same amount as does an increase of aiNa that is equivalent to a 3.7 mV change of the Na equilibrium potential, ENa. Hence ENa is nearly 3 times more effective than membrane potential in controlling tonic tension. During a prolonged depolarization (several minutes) the initial increase of tonic tension decays gradually. This is associated with a fall of aiNa. The relationship between tonic tension and aiNa is similar to that seen when aiNa is increased by inhibiting the Na pump. It is concluded that the fall of aiNa is responsible for the decay of tonic tension. The changes of tonic tension reported in this paper are consistent with the effects of aiNa and membrane potential on a voltage-dependent Na-Ca exchange. The possibility that a voltage-dependent Ca channel contributes to tonic tension is also discussed.

Animals↗
PubMed1983

The role of intracellular sodium activity in the anti-arrhythmic action of local anaesthetics in sheep Purkinje fibres.

The effects of lidocaine have been examined on the arrhythmogenic transient inward current (ITI) in voltage-clamped sheep cardiac Purkinje fibres. Tension and intracellular Na activity (aiNa) were measured simultaneously. The addition of lidocaine (200-300 microM) produced an immediate decrease of inward holding current and a gradual fall of aiNa. The relative magnitudes of the changes of current and aiNa were shown to be consistent with the outward shift of current representing principally a reduction of inward Na current. The Na pump was inhibited by reducing the external Rb concentration in a K-free solution. This produced an after-contraction and transient inward current (ITI) along with a rise of aiNa. The subsequent addition of lidocaine decreased the magnitude of ITI and the after-contraction while decreasing aiNa. Tetrodotoxin (TTX) had qualitatively similar effects to lidocaine on inward holding current, aiNa, ITI and the after-contraction. When aiNa was changed by (i) lidocaine, (ii) TTX or (iii) small changes of external Rb concentration, a hysteresis was seen in the relationship between aiNa and ITI or after-contraction. The hysteresis was similar to that previously found between aiNa and contraction (Eisner, Lederer & Vaughan-Jones, 1981). Despite this hysteresis, neither lidocaine nor TTX affected the relationship between magnitudes of ITI and the after-contraction. It is suggested that the fall of aiNa is a major factor in the reduction of ITI by lidocaine. These results are discussed in relation to the anti-arrhythmic actions of lidocaine.

Action Potentials↗
PubMed1983

The effects of low sodium solutions on intracellular calcium concentration and tension in ferret ventricular muscle.

Papillary muscles from the right ventricles of ferrets were micro-injected with the photoprotein aequorin. Both tension and the light emitted by the aequorin, which is a measure of the free intracellular Ca concentration [( Ca2+]i), were monitored. Exposure of the papillary muscle to a solution in which all the Na had been replaced by K (0 Na(K) solution) resulted in an increase in tension which subsequently slowly decreased. This contracture was associated with a large increase in [Ca2+]i followed by a decrease to a steady-state-level which was often significantly greater than that in Na-containing solutions. If choline, Li or Tris was used instead of K as a substitute for Na, both the contracture and the associated increase of [Ca2+]i were reduced. The effects of depolarization alone (by raising external K at constant Na concentration) were compared with those of Na removal alone (at constant external K concentration). Na removal contributes more than depolarization to the effects of a Na-free, K-containing solution on the contracture and rise of [Ca2+]i. Increasing intracellular Na concentration [( Na+]i), by exposure to strophanthidin (10 mumol/l), increased the magnitude of both the contracture and [Ca2+]i in 0 Na(K) solutions. Conversely, decreasing [Na+]i by exposure to a solution containing a decreased extracellular Na concentration [( Na+]o), decreased the contracture and [Ca2+]i. When contractures were produced by solutions with various [Na+]o, the size of the resulting contracture and [Ca2+]i were inversely related to [Na+]o. No contracture was seen unless [Na+]o was reduced to below 70 mmol/l. A decrease in the extracellular Ca concentration [( Ca2+]o) from 2 to 0.5 mmol/l or an increase to 8 mmol/l produced, respectively, large decreases and increases of the twitch and accompanying Ca transient. However, if [Ca2+]o was changed at the same time as Na was replaced by K there was little effect on either the contracture or the rise of [Ca2+]i. If [Ca2+]o was changed before replacing Na by K then increasing [Ca2+]o from 2 to 8 mmol/l decreased, and decreasing [Ca2+]o from 2 to 0.5 mmol/l increased, the rise of [Ca2+]i produced by replacing Na by K. The difference between this result and that obtained when [Ca2+]o was changed at the same time as Na was removed may be due to changes of [Na+]i produced by prolonged exposure to an altered [Ca2+]o.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1982

The effects of sodium pump activity on the slow inward current in sheep cardiac Purkinje fibres.

The effects of Na pump activity on the slow inward current, Isi, magnitude and twitch tension were investigated in sheep cardiac Purkinje fibres. A two-microelectrode voltage-clamp method was used, tension being measured simultaneously. Na pump activity was lowered either by reducing the extracellular K concentration, [K]O, or by applying the cardiotonic steroid strophanthidin. Reduction of [K]O from 4 to 0 mM leads to time-dependent increases in Isi magnitude and twitch tension. The increases of Isi and tension could be reversed by adding Tl, Rb, Cs or NH4 ions to the K-free superfusate. The actions of these ions are attributed to the known ability of these cations to activate the external site of the Na pump. This conclusion is supported by the observation that such activator cations do not reverse the increases in Isi and tension produced by strophanthidin. We conclude that the effects of low [K]O on Isi are mediated by Na pump inhibition. Similarly the Na pump inhibition produced by strophanthidin increases Isi and tension, although, in this case, other mechanisms may also contribute. Measurements of the activity of the electrogenic Na pump show that elevated intracellular Na ion concentration secondary to Na pump inhibition and not the instantaneous Na pump turnover rate mediates the increase in Isi magnitude.

Animals↗
PubMed1982

The dependence on heart rate of the human ventricular action potential duration.

For the human electrocardiogram, the relationship between QT interval and heart rate was examined in conditions where the heart rate was changed at different rates. The QT interval provides a measure of the ventricular action potential duration. For slow changes of heart rate, elicited by mild exercise, the dependence of QT interval on heart rate obtained when the heart rate was rising was the same as that obtained when the heart rate was falling. The QT interval was approximately proportional to 1/(heart rate)1/2. For the rapid transient changes of heart rate associated with respiration, the QT interval was approximately constant, independent of the instantaneous heart rate. For rapid sustained changes of heart rate, elicited by heavy exercise or immersion of the face in cold water, the changes in QT interval lagged behind the heart rate changes. Consequently the dependence of QT interval on heart rate obtained when the heart rate was increasing differed from the dependence obtained during a fall in heart rate. This time dependence of the relationship between QT interval and heart rate is similar to that seen for the relationship between action potential duration and stimulation rate in isolated pieces of mammalian ventricle.

Action Potentials↗
PubMed1982

Inhibition of the sodium pump by inorganic phosphate in resealed red cell ghosts.

1. Ouabain-sensitive Rb influx was measured into K-free resealed red cell ghosts. The effects of inorganic phosphate (Pi) were examined. 2. Phosphate decreased the magnitude of the influx. Increasing Pi lowered the apparent affinity for both ATP and external rubidium ions. The effects of Pi on the affinity for external Rb were greatest at low ATP concentrations. 3. In the nominal absence of phosphate, increasing ATP from 1 to 100 microM had little effect on the Rb influx from solutions of low (1 microM) rubidium concentrations. In the presence of Pi, ATP increased Rb uptake markedly, even from solutions of low Rb concentration. 4. The above interactions between Pi, ATP and external Rb are consistent with a consecutive scheme for the Na pump in which phosphate is released after potassium binds at the external surface and before ATP binds to release potassium ions to the internal solution. 5. Previous failures to find an effect of phosphate on either the affinity for ATP or that for external potassium (rubidium) ions are shown to be equally consistent with the model. The lack of change of apparent affinity is shown to result from the restricted range of concentrations used in these previous experiments.

Adenosine Triphosphate↗
PubMed1981

The effects of heart rate on the action potential of guinea-pig and human ventricular muscle.

1. On increasing the stimulation frequency of isolated pieces of guinea-pig ventricular muscle, the resting potential depolarizes, and the action potential duration and amplitude are reduced. On termination of the high frequency train of action potentials, these changes are reversed. 2. The resting potential changes are roughly exponential, with a time constant of the order of 10 sec, and are attributable to K+ accumulation in the extracellular space. They are not explicable in terms of known gating variables. 3. The action potential duration and amplitude recover much more slowly than the resting potential, after a high frequency train (half-time approximately 5 min). The time course of these recoveries is not exponential, and is slower after trains which produce more shortening of the action potential. The slow time course suggests that K+ accumulation is not the main cause of the changes in action potential shape. Furthermore, when a certain depolarization of the resting potential is produced by a high frequency train, there is a greater reduction of the action potential duration than that which occurs when the bathing [K+] is raised to produce the same depolarization (Reiter & Stickel, 1968). This is so even when a gradient of extracellular [K+] is induced in the preparation, to mimic non-uniform K+ accumulation. 4. Similarly, the shortening of the action potential produced by toxic doses or cardiotonic steroids is probably not the result of K+ accumulation. 5. The slow changes of the action potential shape produced by a high frequency train are not attributable to the effects of gating variables, nor (solely) to a rise in the intracellular Na concentration stimulating the electrogenic Na/K pump. The dye 3,3'-diethylthiadicarbocyanine, which blocks the Ca2+-activated K conductance in the erythrocyte, has no significant effect on the shape changes. 6. After a sudden change in heart rate, the QT interval of the human electrocardiogram (e.c.g.) changes slowly to a new equilibrium value. The time course of this change is similar to that of the action potential duration in guinea-pig ventricle following a change in stimulation frequency. These changes of the e.c.g. are probably not due to slow alterations of neural or hormonal factors extrinsic to the heart. In the whole heart, the effects on the ventricular action potential duration of changes in sympathetic or vagal tone, or of circulating catecholamines, can be largely accounted for by the changes of atrial driving frequency they produce.

Action Potentials↗
PubMed1981

The dependence of sodium pumping and tension on intracellular sodium activity in voltage-clamped sheep Purkinje fibres.

1. Intracellular Na activity (aiNa) was measured in sheep cardiac Purkinje fibres using a recessed-tip Na+-sensitive micro-electrode. The membrane potentials was controlled with a two-micro-electrode voltage clamp. Tension was measured simultaneously. 2. Removing external K produced a rise of aiNa and both twitch and tonic tension. On adding 4-10 mM-[Rb]0 to reactivate the Na-K pump aiNa and tension declined. An electrogenic Na pump current transient accompanied the fall of aiNa. 3. The half-time of decay of the electrogenic Na pump current transient was similar to that of aiNa, (mean tNa0.5/tI0.5 = 0.97 +/- 0.03 (S.E.M.; n = 28)). Following the re-activation of the Na-K pump, the electrogenic Na pump current transient was linearly related to aiNa. 4. The duration of exposure to K-free, Rb-free solutions was varied to change the level of aiNa. On subsequently re-activating the Na-K pump with 10 mM-[Rb]0, the ratio of the charge extruded to the total change of aiNa was constant. It is concluded that the fraction of Na extruded electrogenically is unaffected by changes of aiNa. About 26% of the total Na extrusion appeared as charge transfer. 5. The relationship between tonic tension and aiNa was usually different during Na-K pump inhibition in a K-free, Rb-free solution compared with the relationship during Na-K pump re-activation. In general, a given aiNa was associated with a greater level of tonic tension during Na-K pump inhibition compared with that during pump re-activation. A similar hysteresis was often seen between twitch tension and aiNa.

Animals↗