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D Noble

Publications and source records attributed to D Noble.

At least 109 records · Page 6Linked to original sources
PubMed1986

The relationship between the transient inward current (TI) and other components of slow inward current in mammalian cardiac muscle.

When rabbit sino-atrial node preparations and isolated guinea-pig ventricular cells are subjected to Na-K pump blockade (either by reducing external K+ by a factor of 10: sinus node; or by the presence of 10(-7) M ouabain: ventricular cells) they develop oscillatory transient inward currents of the kind already recorded in Purkinje fibres and ventricular muscle strands. The time course of these transient currents, generally known as TI's, closely resembles that of the slow component of second inward current (isi,2) previously reported by us as occurring in rabbit sinus node when recorded near its threshold (-40 mV). Moreover, we have found that, under voltage clamp conditions, the 'envelope' of isi currents activated by depolarization from negative membrane potentials matches the outline of the iTI which develops during the initial hyperpolarization. In the sinus node, oscillations of iTI become smaller near O mV but are never flat and there is no clear cut reversal potential, whilst in ventricular cells oscillations and contractions cease at very positive membrane potentials (+35 mV) without the TI current ever becoming net outward. Replacing 75% of the external Na+ with Li+ reduces isi and iTI in the node by about the same proportion strongly suggesting that both are carried by a Na-Ca exchange mechanism. This idea is supported by reproducing the conditions of Na-K pump block in a computer model of the sinus node activity++, when oscillatory currents are generated by variations in activity of the Na-Ca exchange mechanism triggered by fluctuating levels of intracellular calcium. The same model when used to test the hypothesis that isi,2 might be carried by a non-specific ion channel showed that considerable distortion of the action potential would then occur. From the experimental and computed results it is concluded that the majority of isi,2 and iTI currents are both mediated by Na-Ca exchange.

Animals↗
PubMed1986

Ionic mechanisms controlling the action potential duration and the timing of repolarization.

The T wave of the electrocardiogram is determined by differential repolarization times in different parts of the ventricle. A better fundamental understanding of this must depend on a more complete account of the membrane processes involved in repolarization. This paper deals with four processes that have been investigated or re-investigated recently. The results are illustrated by using the DiFrancesco-Noble (1985) model and its recent modifications: The potassium-dependence of the inward rectifier current, iK1 has a strong role to play in determining action potential duration and pacemaker activity in Purkinje tissue, but has a negligible role to play in sinoatrial node tissue. The potassium-dependence of other currents plays a minor role. Activation of the sodium-potassium pump current can significantly shorten the action potential and suppress pacemaker activity. The sodium-calcium exchange current can generate a small slow component of the second inward current, called i(si),a. In action potentials, such as that of rat ventricle and rabbit atrium, which show a long slow final phase of repolarization, this exchange current plays the major role in the timing of repolarization. Calcium-dependent inactivation of the calcium current may underly the strong inverse correlation between action potential duration and contraction. Recent experiments on single ventricle cells show that this phenomenon almost certainly underlies the 'staircases' of inward current and action potential duration during long trains of action potentials.

Action Potentials↗
PubMed1984

A new calcium current underlying the plateau of the cardiac action potential.

A small and very slow inward calcium current has been identified in isolated single ventricular cells using TTX and Cd2+ to block the sodium and fast calcium currents. Activation requires about 300 ms at the threshold potential of -60 mV, decreasing to 80 ms at the peak current voltage of -30 mV. Inactivation is five to ten times longer. Half steady-state activation and inactivation are at -50 and -45 mV respectively. The current is distinctively different in both its kinetics and pharmacology from the conventional calcium current described in single heart cells. It is proposed that it contributes significant current to help maintain a major portion of the long ventricular action potential.

Action Potentials↗
PubMed1984

A model of sino-atrial node electrical activity based on a modification of the DiFrancesco-Noble (1984) equations.

DiFrancesco & Noble's (1984) equations (Phil. Trans. R. Soc. Lond. B (in the press.] have been modified to apply to the mammalian sino-atrial node. The modifications are based on recent experimental work. The modified equations successfully reproduce action potential and pacemaker activity in the node. Slightly different versions have been developed for peripheral regions that show a maximum diastolic potential near --75 mV and for central regions that do not hyperpolarize beyond --60 to --65 mV. Variations in extracellular potassium influence the frequency of pacemaker activity in the s.a. node model very much less than they do in the Purkinje fibre model. This corresponds well to the experimental observation that the node is less sensitive to external [K] than are Purkinje fibres. Activation of the Na-K exchange pump in the model by increasing intracellular sodium can suppress pacemaker activity. This phenomenon may contribute to the mechanism of overdrive suppression.

Action Potentials↗
PubMed1984

The slow inward current, isi, in the rabbit sino-atrial node investigated by voltage clamp and computer simulation.

The properties of the slow inward current, isi, in the sino-atrial (s.a.) node of the rabbit have been investigated using two microelectrodes to apply voltage clamp to small, spontaneously beating, preparations. Many of the experimental results can be closely simulated using the computer model of s.a. node electrical activity (Noble & Noble 1984) which has been developed from models of Purkinje fibre activity (Noble 1962; DiFrancesco & Noble 1984). Comparison of the computed reconstructions with experimental results provides a test of the validity of the modelling. Experiments using paired depolarizing clamp pulses show that inactivation of isi is calcium-entry dependent although, unlike the inactivation of Ca2+ currents in some other systems, it also shows some voltage-dependence. Re-availability (recovery from inactivation) of isi in s.a. node is much slower than inactivation at the same potential, showing that isi is not controlled by a single first order process. This very slow recovery from inactivation of isi in the s.a. node and the slow time course of its activation and inactivation at voltages near threshold (-40 to -50 mV) can be closely modelled by assuming that there are two components of 'total isi': a fast inward current, iCa,f' representing the 'gated' fraction and a second, slower, inward current component, iNaCa which, we propose, is caused by the sodium-calcium exchange that ensues when the initial Ca2+ -entry triggers the release of stored intracellular Ca2+. When repetitive trains of clamp pulses are given, a 'staircase' of isi magnitude is seen which can be increasing ('positive') or decreasing ('negative') according to the potential level and frequency of the pulse train given. When computer reconstructions of such staircases are made, it is found that the positive staircases (which, in contrast to negative staircases, imply that more complex processes than simple inactivation are present) can be closely simulated by a model which incorporates slower processes (suggested Na-Ca exchange current) in the total isi in addition to the gated current component.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

The ionic currents underlying pacemaker activity in rabbit sino-atrial node: experimental results and computer simulations.

The membrane currents underlying the pacemaker depolarization have been investigated in rabbit s.a. node preparations using the two-microelectrode voltage clamp technique. Many of the experimental results have been simulated using a computer model of s.a. node electrical activity. Changes of three time-dependent membrane currents which could contribute to pacemaker depolarization are found to occur in the relevant potential range: decay of the potassium current, iK, and activation of the inward current, if, and of the slow inward current, isi. The contribution of if activation to the pacemaker depolarization ranges from nil to an appreciable part depending on the preparation; when Cs (1 mM) blocks if, it nevertheless does not prevent pacemaking. In the model, holding the if activation variable at zero slows but does not stop pacemaking; doubling if conductance and shifting its activation curve by 15 mV in the positive direction causes a 15% faster rate of pacemaking. The slow time course of re-availability of isi must be allowed for when determining the isi threshold. A voltage clamp protocol designed to mimic as closely as possible an action potential followed by a pacemaker depolarization gives an estimate of isi threshold at the potential level of the last third of the pacemaker depolarization. This has been confirmed in experiments in which the voltage clamp was switched on at different points in the pacemaker depolarization. In the computer simulation, 'blocking' isi depolarizes the membrane to the zero current level (close to the potential reached at the end of a pacemaker depolarization) and stops the generation of action potentials. The decay of iK contributes to the pacemaker depolarization; with both our own model and that of K. Yanagihara, A. Noma and H. Irisawa, Jap. J. Physiol. 30, 841-857 (1980) 'blocking' iK decay abolishes pacemaker activity. Computations of extracellular K+ concentration changes compared with iK decay in a cylindrical model allow re-assessment of the interpretation of K+ concentration measurements during pacemaking made by J. Maylie, M. Morad and J. Weiss, J. Physiol., Lond. 311, 167-178 (1981).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Effect of nitroglycerin on the electrical changes of early or subendocardial ischaemia evaluated by monophasic action potential recordings.

Intracavitary recording of monophasic action potentials (MAP) is a sensitive means of detecting the electrophysiological effects of early or subendocardial ischaemia. The effects of nitroglycerin (NTG) on the MAP was evaluated during pacing-induced angina in seven patients with localised, reversible ischaemia. Recordings from the ischaemic zone demonstrated a decrease in MAP amplitude and an abnormal rate-corrected shortening of MAP repolarisation. The "control" right ventricular MAP showed only the expected rate-dependent decrease in duration throughout the pacing stress test. The ischaemic MAP were unchanged following the intracoronary administration of NTG (100 micrograms). In contrast, intravenous NTG (200 to 300 micrograms) produced a normalisation of MAP amplitude and duration in spite of continuous pacing at the angina-provoking rate. These changes were preceded by a fall in aortic pressure (from mean 123/84 to 96/62) and subsequent lowering of the rate-pressure product. The major beneficial effects of NTG on the early electrical changes of pacing-induced ischaemia are thus related to decreased oxygen demand due to reduction in cardiac preload.

Action Potentials↗
PubMed1984

Differential effects of ischaemia and hyperkalaemia on myocardial repolarization and conduction times in the dog.

The role of increased extracellular K+ concentration ([K+]o) in the production of the early electrophysiological changes induced by myocardial ischaemia, was evaluated by recordings of monophasic action potentials and the paced endocardial evoked response. Changes in the duration of local repolarization and conduction time were evaluated during ischaemia, K+ infusion and hypoxia. Raising [K+]o levels in systemic arterial blood from 3.4 +/- 0.5 mmol l-1 to 5.9 +/- 1.5 mmol l-1 produced a similar shortening of repolarization as was seen during ischaemia. Prolongation of conduction time occurred only when the [K+]o levels rose to 8.8 +/- 1.3 mmol l-1. The conduction time slowing during acute ischaemia was always greater and occurred at lower [K+]o levels than that produced by K+ infusion at rates equivalent to the post-ischaemic myocardial venous effluent. Monophasic action potential amplitude and upstroke velocity were reduced in ischaemia but not markedly affected by the increase in [K+]o. Absolute reduction in repolarization time during K+ infusion was more marked at the apex than at the base in the epicardial recordings. The superimposition of hypoxia on hyperkalaemia resulted in marked slowing of repolarization and conduction time. Many but not all of the early electrophysiological abnormalities of acute ischaemia in the intact heart can be related to raised [K+]o.

Action Potentials↗
PubMed1983

Study of the electrophysiological effects of early or subendocardial ischaemia with intracavitary electrodes in the dog.

The early electrophysiological patterns of regional subendocardial ischaemia were studied by using the paced endocardial evoked response and simultaneous endocardial monophasic action potential recordings in 16 experiments in open chested dogs. Ischaemia was produced by transient (1-3 min) coronary artery occlusion. Regional subendocardial isochaemia caused asynchronous activation due to differential conduction delay and shortened repolarization as evaluated by the duration of the paced evoked response from 175 +/- (SD) 18.7 ms to 167 +/- 16 ms (P less than 0.001). These changes occurred within 60 s of occlusion and reversed rapidly after release of the occlusion. In simultaneous endocardial monophasic action potentials there was a decrease in plateau amplitude and the duration of repolarization shortened from 180 +/- (SD) 21.2 ms to 167 +/- 20.4 ms (P less than 0.001). The delay in endocardial activation after 2 min ischaemia was 5.5 ms, which is considerably shorter than the conduction delay previously reported in the subepicardial layers. The calcium-channel blocking drug verapamil (infused at 0.4 mg/kg) altered the rate at which shortening of repolarization and asynchronous activation occurred during ischaemia in six experiments. These experiments suggest that intracavitary electrodes could provide earlier and more sensitive detection of regional subendocardial ischaemia and may permit the assessment of therapy on the early electrical changes in the intact heart.

Action Potentials↗
PubMed1983

The effects of low concentrations of cardiotonic steroids on membrane currents and tension in sheep Purkinje fibres.

1. Simultaneous measurements of voltage-clamp currents and tension were made in shortened sheep Purkinje fibres exposed to various concentrations of strophanthidin, ouabain and digoxin.2. In 5.4 mM-K moderate doses (mean 2.4 x 10(-7)M) of the drugs produced an inward shift of the current-voltage relationship at very negative potentials, consistent with an increase in cleft K concentration (Cohen, Daut & Noble, 1976b), which was always accompanied by an increase in tension. This change, which has been attributed to Na-K pump inhibition, was often better correlated with an increase in voltage-dependent tonic tension than in twitch tension.3. Exposure to dihydro-ouabain gave a monotonic increase in tension but a delayed increase in inward current. This suggests (cf. Lee, Kang, Sokol & Lee, 1980) that minor changes in pump activity may not always change the current-voltage relationship.4. Low concentrations of strophanthidin (5 x 10(-9) to 5 x 10(-7) M) produced an outward current shift at very negative potentials, this change becoming smaller with a more rapid onset and reversing on increasing the dose. This change is attributed to pump stimulation.5. The outward current shift was often associated with a negative inotropic effect, which always reversed either spontaneously or on removal of the drug.6. The alternative response at a narrower dose range (1 x 10(-8) to 2 x 10(-7) M) was an increase in twitch (not tonic) tension, termed the low-dose positive inotropic effect.7. After a low concentration of cardiotonic steroid had given an early negative inotropic effect the bulk Ca concentration was reduced and the drug re-applied. The low-dose positive inotropic mechanism was then observed.8. Outward current shifts and negative inotropy were also obtained with low concentrations of the clinically used glycosides digoxin and ouabain.9. Low concentrations of strophanthidin applied to externally stimulated sheep ventricular trabeculae produced negative inotropy with lengthening of the action potential duration. Positive inotropy and action potential shortening occurred with higher doses.10. A computer model of ionic currents and distributions in Purkinje fibres satisfactorily reproduced the changes in membrane currents and ionic gradients observed with cardiotonic steroids. The only perturbations capable of explaining our results were Na pump stimulation and inhibition.11. It is concluded that cardiotonic steroids possess two inotropic mechanisms. The first is a low-dose positive inotropic mechanism causally unrelated to changes in sodium pump activity and possibly a direct release of a membrane-associated calcium fraction. Should this mechanism be unavailable then net pump stimulation at low doses will produce negative inotropy. The second mechanism is the well known Na-lag process.

Animals↗
PubMed1983

Intracardiac electrode detection of early ischaemia in man.

We have evaluated an intracardiac technique for the study of the electrophysiological patterns of early or subendocardial ischaemia in man. Simultaneous recordings of the paced endocardial evoked response and monophasic action potentials were obtained during pacing stress testing in 10 patients with reversible myocardial ischaemia. Early patterns of change occurred in both these recordings in response to regional ischaemia. Abnormal rate corrected shortening of the local repolarisation time in the paced endocardial evoked response from the left ventricular ischaemic zone diverging from control non-ischaemic values by a mean of 10.6% was paralleled by decreases in the simultaneous paced monophasic action potentials duration. A differential delay in the local activation time and conduction was also documented by the paced endocardial evoked response and monophasic action potential electrodes. Non-ischaemic control zones showed no changes in the pattern of activation and repolarisation. Disparate repolarisation times and asynchronous activation within the myocardium were thus consistently demonstrated during regional ischaemia. These changes in the endocardial paced evoked response and monophasic action potentials always preceded the appearance and regression of the clinical ischaemia. Intracavitary recordings may thus provide earlier and more sensitive detection of regional ischaemia during cardiac catheterisation or coronary artery surgery. The study of the patterns of activation and response could permit the assessment of interventions on the early electrical changes of ischaemia, and may bridge the gap between in vitro studies and the electrophysiological studies performed upon the intact heart.

Action Potentials↗
PubMed1983

The role of nitrates on regional subendocardial ischaemia--studies with endocardial monophasic action potentials during pacing-induced angina.

Intracavitary recording of monophasic action potentials (MAP) is a sensitive means of detecting the electrophysiological effects of early or subendocardial ischaemia. The effect of nitroglycerin on the MAP was evaluated during pacing-induced angina in seven patients with localized, reversible ischaemia. Recordings from the ischaemic zone demonstrated a decrease in MAP amplitude and an abnormal rate-corrected shortening of MAP repolarization. The "control" right ventricular MAP showed only the expected rate-dependent decrease in duration throughout the pacing stress test. The ischaemic MAP were unchanged following the intracoronary administration of 100 micrograms nitroglycerin. In contrast, 200-300 micrograms intravenous nitroglycerin produced a normalization of MAP amplitude and duration in spite of continuous pacing at the angina-provoking rate. These changes were preceded by a fall in aortic pressure (from mean 123/84 to 96/62) and subsequent lowering of the rate-pressure product. The major beneficial effects of nitroglycerin on the early electrical changes of pacing-induced ischaemia are thus related to decreased oxygen demand due to cardiac unloading.

Action Potentials↗