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Biomedical subjects

D Noble

Publications and source records attributed to D Noble.

At least 91 records · Page 5Linked to original sources
PubMed1991

Effects of i.v. lignocaine on psychological performance and subjective state in healthy volunteers.

In order to assess the effects of different doses of lignocaine on performance, nine healthy volunteers aged 21-34 yr received i.v. infusions of saline, low and high dose lignocaine (mean plasma concentrations 0.92 and 1.78 micrograms ml-1, respectively) in a double-blind randomized order. The Digit-Symbol Substitution Test (DSST) and Visual Analogue Scales (VAS) were performed repeatedly and a battery of performance tests once. The median (lower, upper quartile) number of correct responses for the DSST during the infusion period was: placebo 69 (67, 77); low 74 (71, 80); high 66 (61, 75) (P less than 0.001, General Linear Models; all pairwise comparisons P less than 0.05). None of the measures in the full battery showed any significant changes. VAS showed that subjects felt more interested (P less than 0.05), drowsy (P less than 0.01), dizzy, tense, abnormal, drunk and muzzy (P less than 0.001) with lignocaine than with placebo. These results confirm that lignocaine can produce acute performance effects (both improvements and impairments). Subjects were clearly aware of the presence of lignocaine, suggesting that subjective reports may be a useful indicator of its CNS effects.

Adult↗
PubMed1991

Side by side.

Explore the source record for details and available documents.

Hospital Bed Capacity, 100 to 299↗
PubMed1990

A model of the single atrial cell: relation between calcium current and calcium release.

The hypothesis that calcium release from the sarcoplasmic reticulum in cardiac muscle is induced by rises in free cytosolic calcium (Fabiato 1983, Am. J. Physiol 245) allows the possibility that the release could be at least partly regenerative. There would then be a non-linear relation between calcium current and calcium release. We have investigated this possibility in a single-cell version of the rabbit-atrial model developed by Hilgemann & Noble (1987, Proc. R. Soc. Lond. B 230). The model predicts different voltage ranges of activation for calcium-dependent processes (like the sodium-calcium exchange current, contraction or Fura-2 signals) and the calcium current, in agreement with the experimental results obtained by Earm et al. (1990, Proc. R. Soc. Lond. B 240) on exchange current tails, Cannell et al. (1987, Science, Wash. 238) by using Fura-2 signals, and Fedida et al. (1987, J. Physiol., Lond. 385) and Talo et al. (1988, Biology of isolated adult cardiac myocytes) by using contraction. However, when the Fura-2 concentration is sufficiently high (greater than 200 microM) the activation ranges become very similar as the buffering properties of Fura-2 are sufficient to remove the regenerative effect. It is therefore important to allow for the buffering properties of calcium indicators when investigating the correlation between calcium current and calcium release.

Animals↗
PubMed1989

Calcium movements during each heart beat.

Transsarcolemmal calcium movements are closely related to force generation in the heart. It is important to understand the transport pathways that control these movements of calcium across the sarcolemmal membrane. In the normal, beating heart, sodium-calcium exchange appears to be an important mechanism for the extrusion of calcium from the cell. The kinetics of this exchange are dependent upon the characteristics of the cell action potential. Calcium efflux via sodium-calcium exchange may be sufficient to balance calcium entry through calcium channels during the action potential.

Action Potentials↗
PubMed1989

Sodium-calcium exchange during the action potential in guinea-pig ventricular cells.

1. Slow inward tail currents attributable to electrogenic sodium-calcium exchange can be recorded by imposing hyperpolarizing voltage clamp pulses during the normal action potential of isolated guinea-pig ventricular cells. The hyperpolarizations return the membrane to the resting potential (between -65 and -88 m V) allowing an inward current to be recorded. This current usually has peak amplitude when repolarization is imposed during the first 50 ms after the action potential upstroke, but becomes negligible once the final phase of repolarization is reached. The envelope of peak current tail amplitudes strongly resembles that of the intracellular calcium transient recorded in other studies. 2. Repetitive stimulation producing normal action potentials at a frequency of 2 Hz progressively augments the tail current recorded immediately after the stimulus train. Conversely, if each action potential is prematurely terminated at 0.1 Hz, repetitive stimulation produces a tail current much smaller than the control value. The control amplitude of inward current is only maintained if interrupted action potentials are separated by at least one full 'repriming' action potential. These effects mimic those on cell contraction (Arlock & Wohlfart, 1986) and suggest that progressive changes in tail current are controlled by variations in the amplitude and time course of the intracellular calcium transient. 3. When intracellular calcium is buffered sufficiently to abolish contraction, the tail current is abolished. Substitution of calcium with strontium greatly reduces the tail current. 4. The inward tail current can also be recorded at more positive membrane potentials using standard voltage clamp pulse protocols. In this way it was found that temperature has a large effect on the tail current, which can change from net inward at 22 degrees C to net outward at 37 degrees C. The largest inward currents are usually recorded at about 30 degrees C. It is shown that this effect is attributable predominantly to the temperature sensitivity of activation of the delayed potassium current, iK, whose decay can then mask the slow tail current at high temperatures. 5. Studies of the relationship between the tail current and the membrane calcium current, iCa, have been performed using a method of drug application which is capable of perturbing iCa in a very rapid and highly reversible manner. Partial block of iCa with cadmium does not initially alter the size of the associated inward current tail. When iCa is increased by applying isoprenaline, the percentage augmentation of the associated tail current is much greater but occurs more slowly.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1988

The effects of prenylamine on single ventricular myocytes of guinea-pig.

1. The action of prenylamine, an antianginal drug, was studied in single ventricular guinea-pig myocytes. In concentrations of 10-50 microM, prenylamine significantly (P less than 0.01) shortened action potentials, and significantly (P less than 0.001) reduced the inward calcium current by 29% to 76% (n = 7). This effect was also present in the presence of adrenoceptor-blockade (with phentolamine and propranolol), and was thus not due to indirect changes in endogenous catecholamine action. 2. Prenylamine did not affect the steady state level of current at the end of long pulses, and does therefore not act by changing time-dependent outward currents. Since the resting potential in the unclamped mode is unchanged during gross changes in action potential duration, it is also unlikely that there are any changes in the background, time-independent potassium conductance. 3. It is concluded that prenylamine has a direct effect on cardiac calcium channels, not mediated by adrenoceptor activation.

Animals↗
PubMed1988

On the mechanism of isoprenaline- and forskolin-induced depolarization of single guinea-pig ventricular myocytes.

1. Isoprenaline (10 nM to 1 microM) and forskolin (0.6-100 microM) depolarized single guinea-pig myocytes studied in vitro. Under voltage clamp both agents caused an inward current to flow. 2. These effects were abolished by propranolol (100 nM) and the beta1-antagonist metoprolol (100-200 nM), but not by the beta2-agonist [corrected] salbutamol (1 microM). 3. The interaction of isoprenaline with forskolin, caffeine or isobutylmethylxanthine (IBMX) on current amplitude was as expected if all of these drugs were causing inward current by increasing intracellular levels of cyclic adenosine monophosphate (cyclic AMP). Low concentrations of forskolin (less than 600 nM) or IBMX (less than 20 microM) potentiated the effect of isoprenaline, whereas isoprenaline caused no further inward current in cells in which high concentrations of forskolin (600 nM-100 microM) or IBMX (20 microM-1 mM) were already evoking maximum inward current. 4. Isoprenaline-induced inward current was reduced 30-50% by acetylcholine (10-30 microM). This action of acetylcholine was blocked by atropine (100 nM). 5. The effect of isoprenaline on holding current was critically dependent on temperature. The onset of the current was delayed and its amplitude reduced as the myocyte was cooled from 37 degrees C to ambient temperature (22-24 degrees C). 6. Isoprenaline-induced inward current was not affected by the potassium channel blockers barium (2 mM) or tetraethylammonium (TEA; 10-20 mM). The amplitude of the inward current did not vary as a function of [K+]o. 7. The inward current was not affected by the calcium channel blockers cadmium 1 mM, or nifedipine (10 microM), or when internal calcium was reduced by including EGTA in the recording electrode filling solution. 8. The amplitude of the current was also unaffected by caesium (5 mM), which blocks the hyperpolarization-activated, non-specific channel if, or by strophanthidin (10 microM) which blocks the Na+-K+ pump. It was unchanged by substitution of external chloride by isethionate. 9. The inward current was absent when external sodium was replaced by the impermeant ion tetramethylammonium (TMA). 10. Isoprenaline- and forskolin-induced inward currents were associated with an increase in both membrane chord conductance and noise. The increase in conductance was most readily measured at potentials where the inwardly rectifying potassium channel, iK1, was small, or when iK1 was blocked by the addition of barium (2 mM).(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1988

Reversal potential of the calcium current in bull-frog atrial myocytes.

1. Voltage clamp recordings of the calcium current (ICa) in single myocytes which were enzymatically isolated from bull-frog atrium show that a genuine reversal of the current flowing through Ca2+ channels can be recorded (ef. Reuter & Scholz, 1977; Lee & Tsien, 1982, 1984; Campbell, Giles & Shibata, 1988c). In normal 2.5 mM [Ca2+]0 Ringer solution this apparent reversal potential (Erev) is near +50 mV, a value well below the predicted thermodynamic Ca2+ equilibrium potential (ECa). 2. None the less, Erev shifts with variations in extracellular divalent ion concentrations (Ca2+, Sr2+ and Ba2+) according to the predictions of a Nernstian divalent cation electrode, i.e. approximately 29 mV per 10-fold change in the external concentration of divalent ion. 3. The existing theoretical analysis of this Erev has been extended in order to clarify its interpretation with regard to the selectivity characteristics of ICa. 4. The apparent reversal potential is analysed using a form of the constant field equation which has been modified to include (i) simultaneous monovalent and divalent cation movements and (ii) the presence of a surface potential (V'). This equation can be solved to yield an explicit expression for Erev. The effects of V' on apparent permeability ratios for the Ca2+ channel Erev are demonstrated. 5. In combination, our experimental results and calculations suggest that: (i) previous estimates of V' which were used to describe permeability (P) ratios of Ca2+ channels in various cardiac preparations may be in error, (ii) in normal [Ca2+]o the PNa/PCa ratio is very small, and (iii) PCa/PK must be greater than 1000. An analysis of the relative selectivity of the channel for divalent cations compared to K+ shows that PCa greater than PSr greater than PBa, assuming that PK remains the same after the divalent substitutions. 6. The Ca2+ channel in bull-frog atrial cells is thus much more selective for Ca2+ ions than had previously been estimated; in particular, inward flow of monovalent cations (e.g. Na+) through these channels does not contribute significantly to the observed ICa. The physiological implications of this high selectivity for Ca2+ ions are discussed.

Action Potentials↗
PubMed1988

Use-dependent reduction and facilitation of Ca2+ current in guinea-pig myocytes.

1. Action potentials, calcium currents (iCa) and cell contraction have been recorded from single guinea-pig myocytes during periods of stimulation from rest. Voltage clamp was carried out using a single microelectrode. Cell contraction was measured optically. All experiments were performed at 18-22 degrees C. 2. An inverse relationship was observed between cell contraction and action potential duration or iCa. Mixed trains of action potentials and voltage clamp pulses preserved this relationship. Long voltage clamp pulses induced negative 'staircases' of iCa and positive 'staircases' of cell contraction. A facilitation of iCa was observed during repetitive stimulation with clamp pulses of 100 ms duration or less and was accompanied by a decrease in cell contraction. 3. The voltage dependence of inward current staircases was found to depend on Ca2+ entry rather than membrane voltage for long voltage clamp pulses and was not affected by 30 mM-TEA or 50 microM-TTX. Current reduction was greatest at 0 mV (P less than 0.05) when iCa was largest. Changes in cell contraction during pulse trains showed a similar voltage dependence. The time constant of current staircases was only mildly voltage dependent. 4. Interference with normal cellular mechanisms for Ca2+ uptake and release by strontium, 1-5 mM-caffeine and 1 microM-ryanodine increased current staircases and could abolish iCa facilitation with short clamp pulses. 5. Variations in the level of Ca2+-dependent inactivation of iCa can explain many features of the changes in iCa during stimulation after rest. Long clamp pulses (or action potentials) may increase cell Ca2+ loading and inhibit iCa. Short clamp pulses reduce available Ca2+ for cell contraction and this may reflect a lowered myoplasmic Ca2+ level which allows facilitation of iCa.

Action Potentials↗
PubMed1988

Mechanism of the use dependence of Ca2+ current in guinea-pig myocytes.

1. The mechanism of the use-dependent reduction and facilitation of the calcium current (iCa) in single guinea-pig myocytes described by Fedida, Noble & Spindler (1988) has been examined by varying [Ca2+]o, [Ca2+]i and iCa. 2. Moderate enhancement of [Ca2+]i and [Ca2+]i changes produced by increasing [Ca2+]o reduces iCa and enhances the use-dependent reduction. 3. Intracellular calcium overload, produced by reducing [Na+]o, greatly reduces iCa and almost totally eliminates the use-dependent variations. 4. Use-dependent reduction of iCa is also smaller after substituting external Ba2+ ions for Ca2+ ions. 5. When [Ca2+]i is buffered by intracellular EGTA sufficient to eliminate other [Ca2+]i-dependent processes, such as contraction and Na+-Ca2+ exchange, some use-dependent reduction of iCa remains, although the effect is smaller. Use-dependent facilitation of iCa is more prominent in the presence of internal EGTA. 6. The facilitation of iCa is abolished by Ba2+ replacement of Ca2+ and by the beta-adrenoceptor agonist isoprenaline. This suggests that the facilitation is mediated by Ca2+ entry itself rather than membrane voltage. Facilitation is evident as a delay of current relaxation, even in the presence of internal EGTA.

Action Potentials↗
PubMed1987

Experimental and theoretical work on excitation and excitation-contraction coupling in the heart.

A combination of experimental and theoretical work has been used to investigate the movements of calcium during cardiac excitation. In addition to calcium entry through several types of calcium channel, calcium efflux occurs to balance the entry during each cycle of activity. Measurements of net membrane calcium movements have been made with the right time resolution by Don Hilgemann in Los Angeles by investigating fast extracellular calcium transients. This work shows that, in mammalian cardiac cells, net calcium exit occurs quite early during repolarization and is nearly complete by the time the resting potential is re-established. These results correlate very well indeed with measurements made in the Oxford laboratory of calcium-activated inward current in single cardiac myocytes. Both approaches are consistent with the view that calcium efflux occurs largely through the sodium-calcium exchange process. Modelling of this process in equations developed recently with Dario DiFrancesco, Susan Noble and Don Hilgemann succeeds in reproducing both the ionic current changes and the fast extracellular calcium transients.

Animals↗
PubMed1987

The control of calcium current reactivation by catecholamines and acetylcholine in single guinea-pig ventricular myocytes.

The time course of reactivation of the calcium current in isolated single cardiac cells is complex. The rising phase is sigmoid and there is an overshoot. Catecholamines increase the initial rate of reactivation but reduce or abolish the overshoot. This combination of effects results in a 'crossover', so that the net effect of adrenaline depends on the pulse interval used. Acetylcholine not only reduces the current amplitude, it also substantially slows recovery. At short intervals the effect of acetylcholine is therefore very large. Agents that increase intracellular cyclic AMP levels affect the amplitude of the current but do not have a large effect on the reactivation time course. It is suggested that the autonomic transmitters exert their effects by controlling the local calcium concentration near the inner surface of the channels. This is supported by the fact that there are natural variations in reactivation time course between different cells and that these are correlated with their calcium loading, as judged by other electrophysiological criteria, such as the speed of calcium current inactivation and the presence of the calcium-dependent slow inward current.

Acetylcholine↗
PubMed1987

Excitation-contraction coupling and extracellular calcium transients in rabbit atrium: reconstruction of basic cellular mechanisms.

Interactions of electrogenic sodium-calcium exchange, calcium channel and sarcoplasmic reticulum in the mammalian heart have been explored by simulation of extracellular calcium transients measured with tetramethylmurexide in rabbit atrium. The approach has been to use the simplest possible formulations of these mechanisms, which together with a minimum number of additional mechanisms allow reconstruction of action potentials, intracellular calcium transients and extracellular calcium transients. A 3:1 sodium-calcium exchange stoichiometry is assumed. Calcium-channel inactivation is assumed to take place by a voltage-dependent mechanism, which is accelerated by a rise in intracellular calcium; intracellular calcium release becomes a major physiological regulator of calcium influx via calcium channels. A calcium release mechanism is assumed, which is both calcium- and voltage-sensitive, and which undergoes prolonged inactivation. 200 microM cytosolic calcium buffer is assumed. For most simulations only instantaneous potassium conductances are simulated so as to study the other mechanisms independently of time- and calcium-dependent outward current. Thus, the model reconstructs extracellular calcium transients and typical action-potential configuration changes during steady-state and non-steady-state stimulation from the mechanisms directly involved in trans-sarcolemmal calcium movements. The model predicts relatively small trans-sarcolemmal calcium movements during regular stimulation (ca. 2 mumol kg-1 fresh mass per excitation); calcium current is fully activated within 2 ms of excitation, inactivation is substantially complete within 30 ms, and sodium-calcium exchange significantly resists repolarization from approximately -30 mV. Net calcium movements many times larger are possible during non-steady-state stimulation. Long action potentials at premature excitations or after inhibition of calcium release can be supported almost exclusively by calcium current (net calcium influx 5-30 mumol kg-1 fresh mass); action potentials during potentiated post-stimulatory contractions can be supported almost exclusively by sodium-calcium exchange (net calcium efflux 4-20 mumol kg-1 fresh mass). Large calcium movements between the extracellular space and the sarcoplasmic reticulum can take place through the cytosol with virtually no contractile activation. The simulations provide integrated explanations of electrical activity, contractile function and trans-sarcolemmal calcium movements, which were outside the explanatory range of previous models.

Animals↗
PubMed1987

Life threatening complication of high-frequency jet ventilation.

High-frequency jet ventilation is being increasingly used as an alternative to conventional methods of ventilation in both anaesthesia and intensive care. We report a case of severe respiratory obstruction as a complication of high-frequency jet ventilation. Patients with bleeding diathesis, including patients on haemodialysis, may particularly be at risk.

Airway Obstruction↗
PubMed1987

Inward current related to contraction in guinea-pig ventricular myocytes.

1. A component of inward current has been identified in isolated guinea-pig ventricular cells that is closely correlated with the contraction of the cell and not with the rapidly activated calcium current. This is a delayed current most clearly seen as a current 'tail' after 50-200 ms depolarizing pulses. At 22 degrees C the delayed current has a maximum amplitude of approximately 0.5 nA at -40 mV (consistently 10-20% of the peak amplitude of the calcium current) and decays with a half time of approximately 150 ms. 2. Paired-pulse protocols show that at pulse intervals (300-400 ms) at which the calcium current is nearly fully reprimed, the delayed component is very small. It recovers over a time course of several seconds, as does the contraction. Adrenaline speeds the decay of the delayed current (approximately 50%) and similarly accelerates cell relaxation. Adrenaline also shortens the recovery time of both the contraction and the delayed current. 3. During long trains of repetitive pulses, the delayed current amplitude follows that of the contraction 'staircase'. The half-time of the decay of the current 'tail' also matches that of contraction and suggests that both may reflect the time course of the underlying intracellular calcium transient. 4. The half-time of decay of the delayed current is only moderately voltage dependent over the potential range -80 to 0 mV. The amplitude of the delayed current normally reaches a minimum around -20 mV and increases at more negative potentials. 5. The voltage dependence and kinetics of decay of the current show that it should flow and decay largely during the action potential plateau and repolarization rather than during diastole. 6. Diffusion of high concentrations of EGTA into cells abolishes the delayed current and cell contraction. Under these conditions the fast calcium current is increased and its inactivation delayed. 7. When calcium is replaced by strontium, the delayed current amplitude is greatly reduced even though the contraction is larger and slower. 8. The results are consistent with the hypothesis that the delayed inward current is activated by the intracellular calcium transient. It may be carried by the sodium-calcium exchange process and/or by calcium-activated non-specific channels (especially when interal calcium is elevated by reduction of external sodium). 9. In the presence of 1 microM-ryanodine, the calcium current is greatly reduced, whereas the delayed current is not significantly altered.

Action Potentials↗
PubMed1987

The arrhythmogenic transient inward current iTI and related contraction in isolated guinea-pig ventricular myocytes.

1. The arrhythmogenic transient inward current, iTI, and contractions were recorded in isolated guinea-pig ventricular myocytes, after exposure to strophanthidin or low external K+ (0.5 mM), using a single-microelectrode voltage-clamp technique and an optical measure of contraction. 2. The inward current, iTI, and after-contraction occurred on repolarization after a depolarizing pre-pulse. Longer pre-pulses to more positive potentials increased the size and reduced the latency of iTI. Oscillatory currents and contractions also occurred during pulses to positive potentials. 3. The voltage dependence of iTI was studied by repolarizing to different potentials after a constant depolarizing pulse. Inward currents preceded after-contractions at all potentials. The iTI was maximal at about -50 mV, diminishing in magnitude at more negative and positive potentials. It remained inward at potentials up to +47 mV. The contraction exhibited a similar voltage dependence. The current-voltage relation varied in the same cell with longer exposure to glycosides. Thus, the voltage dependence of iTI reflected not only that of an underlying ionic mechanism but also the effects of potential on intracellular Ca2+ oscillations which trigger iTI. 4. Uniformity of internal Ca2+ transients was achieved by clamping to different potentials at the peak of an inward current. The iTI remained inward at positive potentials. An inward tail current, seen on repolarizing during iTI at the end of a depolarizing pre-pulse, progressively increased at negative potentials. This voltage dependence may be close to that of the Ca2+-activated inward current responsible for iTI. 5. Replacement of Na+ by Li+ initially increased the magnitude of iTI, but further exposure abolished the inward current, while the after-contractions continued to increase. The potential dependence of iTI was not affected by exposure to zero Na+. Replacement of Ca2+ by Sr2+ also abolished iTI and the after-contraction, but the main effect was to slow their occurrence. 6. The voltage dependence of the Ca2+-activated inward current in guinea-pig ventricular myocytes leads us to favour electrogenic Na-Ca exchange current as a major component of iTI, under our experimental conditions.

Action Potentials↗
PubMed1986

Relationship between the transient inward current and slow inward currents in the sino-atrial node of the rabbit.

In low K+ (0.3 mM) solutions rabbit sinus node preparations show the oscillatory transient inward current, iTI, already recorded in these conditions in Purkinje and ventricular preparations. The time course of iTI closely resembles that of the slow component of the slow inward current (isi) previously reported by us (Brown, Kimura, Noble, Noble & Taupignon, 1984a) in rabbit sinus node, when recorded near its threshold (-40 mV). When the duration of voltage-clamp steps is varied there is a strong correlation between the 'envelope' of isi amplitudes on depolarization and the time course of iTI on hyperpolarization. Although oscillations of iTI become smaller near 0 mV, there is no potential at which the current records are completely flat, suggesting that there is no simple reversal potential. 75% substitution of Na+ by Li+ greatly reduces both iTI and slow isi in about the same proportion. Reducing the activity of the Na-K exchange pump by the amount expected in 0.3 mM-K+ solutions is sufficient to induce oscillatory iTI in a computer model of the sino-atrial node (Noble & Noble, 1984). The model reproduces the current as variations in the Na-Ca exchange current dependent on intracellular Ca2+ concentration ([ Ca]i). The model was also used to test the alternative hypothesis that the slow inward currents might be generated by [Ca]i-activated non-specific cation channels. It is shown that this would distort the shape of the repolarization phase of the action potential. It is concluded that the experiments and computations are consistent with the hypothesis that a large fraction of iTI and the slow component of isi could both be generated by Na-Ca exchange and that only a relatively small fraction might be generated by non-specific channels.

Action Potentials↗