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Biomedical subjects

S J Noble

Publications and source records attributed to S J Noble.

14 recordsLinked to original sources
PubMed1977

Membrane currents underlying activity in frog sinus venosus.

1. The spontaneous electrical activity of small strips of muscle from the sinus venosus region of the heart of Rana catesbeiana was investigated using the double sucrose gap technique. The voltage clamp was used to record the ionic currents underlying the pace-maker depolarization and the action potential.2. The records of spontaneous electrical activity are very similar to those obtained from the sinus venosus using micro-electrodes. Moreover, the pace-maker activity is almost completely insensitive to tetrodotoxin (TTX) at 2.0 x 10(-6) g/ml., which suggests that the pace-maker responses can be classified as primary, as opposed to follower pacing.3. In response to short rectangular depolarizing voltage clamp pulses, only one inward current is activated. This current is almost completely insensitive to TTX but can be blocked by manganese ions. It appears, therefore, to be equivalent to the slow inward (Ca(2+)/Na(+)) current, I(si), of other cardiac tissues. The threshold for I(si) is near to the maximum diastolic potential, indicating that it must be activated during the pace-maker depolarization.4. Interruption of the normal pace-maker depolarization by rapid activation of the voltage clamp circuit reveals the time-dependent decay of outward current. This current reverses between -75 and -90 mV and, therefore, is probably carried mainly by potassium ions.5. Outward current decay is not a simple exponential, and Hodgkin-Huxley analysis suggests that two distinct components of outward current may be present. One of these is activated in the potential range of the pace-maker depolarization and the other at more positive potentials. Both outward currents reach full, steady-state activation at about zero mV, i.e. within the ;plateau' range of the sinus action potential.6. These results are compared with other recently published voltage clamp data from the rabbit sino-atrial node.7. A hypothesis for the generation of pace-maker activity is presented which involves (i) decay of outward current and (ii) activation of the slow inward current, I(si).

Action Potentials↗
PubMed1976

Identification of the pace-maker current in frog atrium.

1. The nature and interactions of the membrane currents underlying induced pace-maker activity in frog atrial muscle have been investigated using a double sucrose gap technique. 2. The membrane current which controls the speed of the atrial pacemaker depolarization (the pace-maker current, ip), is shown to be an outward current activated within the plateau potential range of a normal action potential. The subsequent deactivation of ip at more negative potentials unmasks the depolarizing action of time-independent inward membrane currents so that a pace-maker potential can result. 3. The deactivation of ip over a limited potential range (between about -30 and -60 mV) can be reliably recorded by switching on the voltage clamp during an induced pace-maker depolarization. 4. Investigation of the time and voltage-dependent behaviour of ip over a much wider potential range is less straightforward. How ip can be separated from other components of outward current present in the decay tails following square voltage clamp depolarizations is described. 5. The majority of such current decay tails contain three components of outward current. It appears that two of these components, one of which is ip, are true Hodgkin-Huxley conductance systems chiefly carrying potassium ions. 6. The nature of the third current, which decays very slowly at moderate membrane potentials (about -40 mV), is discussed and reasons are briefly given for considering it to result from the accumulation of potassium ions in extracellular spaces. Preliminary evidence that potassium depletion occurs at potentials negative to the resting potential of the trabeculum is also presented. 7. Because of the obvious complexities involved, a quantitative analysis of the atrial outward currents is not attempted here but forms the subject of a following paper (Brown, Clark & Noble, 1976a).

Animals↗
PubMed1976

Analysis of pace-maker and repolarization currents in frog atrial muscle.

1. A quantitative analysis of the time-dependent component of outward membrane current in atrial wall trabeculae from Rana catesbeiana and Rana ridibunda has been carried out using a double sucrose gap technique. 2. Separation of the different components of delayed outward current was hampered by the sigmoid onset of one of the outward current systems ixfast and by the development of potassium ion accumulation which prevented current activation from reaching a steady state at positive membrane potentials. Semilogarithmic analysis of positive current decay tails recorded immediately following square voltage clamp depolarizations was therefore used to separate the two membrane conductance components ixfast and ixslow and the third component, attributable to potassium ion accumulation, which was almost invariably present in the tails. 3. It is shown that inaccuracies in this method of semilogarithmic separation of components caused by visual assessment of the i3 (accumulation) line are minor compared with the large changes in the time constants of ixfast and more especially of ixslow which would result from ignoring the potassium accumulation component. 4. Such semilogarithmic separation of the three components of outward current gave separate activation curves for each of the two membrane conductance components, ixfast and ixslow. 5. Measurement of 'total' activation curves in which all components of outward current were represented could be made more easily and fairly reliably. The position and shape of these activation curves on the voltage axis were found to closely resemble those obtained by three component separation. It is therefore suggested that such a simplified analysis reflects the properties of the individual currents sufficiently well for it to be of use in preliminary studies of, for example, drug action. 6. The kinetic properties of the atrial outward currents have been investigated over a wide potential range. Because of the presence of potassium ion accumulation, an indirect method of obtaining the average value of 1/gamma for outward current decay at negative potentials had to be employed. 7. It is shown that some degree of inward-going rectification is associated with the outward current systems of frog atrium. 8. The possible reasons for the differences between the analysis presented here and those presented earlier by us (Brown & Noble, 1969a, b) and by Ojeda & Rougier (1974) are discussed.

Animals↗
PubMed1976

Potassium accumulation and depletion in frog atrial muscle.

1. In atrial wall trabeculae of Rana catesbeiana and R. ridibunda very slowly decaying membrane currents have been consistently observed in decay tails following voltage clamp depolarizing and hyperpolarizing pulses. It is not thought that these currents are carried by time-dependent conductance channels but rather result from potassium ion accumulation or depletion. 2. Since voltage clamp techniques generally impose a non-physiological situation on the membranes of excitable cells, evidence that potassium ion accumulation occurs in unclamped atrial tissue is presented. 3. When potassium ions accumulate, the reversal potentials for both atrial delayed conductance mechanisms, ixfast and ixslow, should be shifted in a positive direction, the magnitude of the shifts being a function of the charge transferred during depolarization. Experiments have been performed to test this prediction quantitatively, and as a result, a simple accumulation model is developed. 4. A second important effect of accumulation should be upon the time-independent potassium conductance, iK1. It was found that this effect produces current tails whose decay becomes exponential when the amount of accumulation is small. The time constant of this exponential is shown to be equal to the time constant of decay of accumulation, tauacc. 5. One of the most important assumptions in the accumulation model is that the iK1(Em) relations for different values of [K]O 'cross-over' one another as they do in skeletal muscle and mammalian Purkinje tissue. Experimental verification of this assumption is presented. This 'cross-over' effect allows current changes due to accumulation to show an apparent 'reversal potential' and so to appear like a conductance mechanism. 6. Potassium depletion is shown to occur during hyperpolarizing pulses. This depletion process must be allowed for in a direct kinetic analysis of the pace-maker current, ixslow, at potentials negative to the resting potential (ER).

Action Potentials↗
PubMed1976

The influence of non-uniformity on the analysis of potassium currents in heart muscle.

1. A method is described for determining the space constant gamma of heart muscle strips using a sucrose gap technique. 2. The average value of gamma for frog atrial trabeculae was found to be nearly 700 mum. This value is nearly twice the length of the test gap (400 mum). Near the resting potential, the voltage non-uniformity should be about 10%. This was confirmed experimentally by comparing the membrane voltages recorded across the current-passing and voltage-recording sucrose gaps. 3. The non-uniformity during large depolarizations was calculated using a computer model. This model includes the inward-going rectification displayed by iK1 and the delayed rectification that occurs following depolarizations beyond -40mV. A single component of delayed rectification was included. 4. It is shown that even very large non-uniformities have relatively small effects on the shape of the activation curve and on the time course of onset or decay of current. 5. It is comcluded that the fast component of current decay described in a previous paper (Brown, Clark & Noble, 1976b) is not attributable to a non-uniformity artifact.

Action Potentials↗
PubMed1976

Changes in membrane currents in bullfrog atrium produced by acetylcholine.

1. A double sucrose-gap voltage-clamp technique has been used to study the effects of acetylcholine on the membrane currents in atrial trabeculae of the bullfrog, Rana catesbeiana. 2. The second, or slow inward (Ca2+/Na+) current, was found to be markedly reduced by concentrations of acetylcholine greater than approximately 2-0 X 10(-8)M. The resulting decrease in net calcium entry provides a straightforward explanation for the negative inotropic action of acetylcholine in atrial muscle. 3. Measurements of membrane resistance near the resting potential showed that relatively high doses of acetylcholine (approximately 10(-7) M) decrease membrane resistance by about twofold. This effect is shown to be the result of an increase in a time-independent background current which appears to be carried mainly by potassium ions. 4. Using appropriate pharmacological techniques, it has been possible to demonstrate: (i) that the peak slow inward current is reduced to about half its initial value before any significant increase in background current occurs; (ii) that even when a sufficient dose of acetylcholine to produce an increase in background current is used, the background current shows inward-going rectification and cannot account for the observed reduction in the slow inward current. 5. No consistent change was observed in the degree of activation of the time-dependent outward membrane currents after application of concentrations of acetylcholine which produced large decreases in the peak slow inward current. 6. These results are discussed in relation to previous electro-physiological and radioisotope studies of the mechanism of the negative inotropic effect of acetylcholine in cardiac muscle.

Acetylcholine↗
PubMed1975

Adrenergic control of cardian pacemaker currents.

Pacemaker activity in atrial muscle and in Purkinje fibres is generated by a time-dependent decay of potassium current that allows the membrane to be depolarized to the threshold for action potential initiation. The kinetics of the pacemaker potassium currents in these two parts of the heart are sufficiently different to indicate that they correspond to different membrane structures. This conclusion is strengthened by the discovery that the mechanisms of acceleration produced by adrenaline are also quite different. In Purkinje fibres, the activation threshold for the potassium current is shifted in a depolarizing direction with no change in maximum amplitude. This voltage shift is adequate by itself to explain the acceleration. In atrial fibres the pacemaker potassium current is increased in amplitude with no shift in threshold. By itself, this action of adrenaline would slow pacemaker activity and the acceleration in this case is dependent on a large increase in the current attributable to calcium ions. The roles of cyclic 3',5'-AMP and of intracellular calcium ions in mediating the pacemaker actions of adrenaline will also be discussed.

Animals↗