[Diabetic cardiomyopathy and rhythm disorders].
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Animals↗
Biomedical subjects
E Coraboeuf
Publications and source records attributed to E Coraboeuf.
Age-related changes of action potential plateau shape in isolated human atrial fibers.
Because the frequency of atrial arrhythmia increases dramatically with age in humans, we investigated age-related changes of cellular electrical activity in human atrial fibers, utilizing standard microelectrode techniques. Twenty-four atrial samples, uniformly exhibiting fast responses, were selected. Patients were in two different age groups: 10.0 +/- 7.0 mo and 54.4 +/- 9.7 yr. Although mean maximum diastolic electrical potential did not significantly differ, the two groups showed marked dissimilarities in action potential (AP) shape. Adult-type APs always exhibited an initial notch followed by a low-level prolonged plateau, whereas APs of the young were more triangular and had a short plateau approaching zero potential. 4-Aminopyridine (0.5 mM) markedly increased the level of the adult AP plateau without suppressing the initial notch, which disappeared after further addition of caffeine (10 mM). The simultaneous action of the two drugs changed an adult-type AP into a young type. The drug effects were much less marked in young atria. Our results suggest that an age-related increase in transient outward currents can account for the differences in plateau shape described. Moreover, age-related differences in plateau configuration in response to a period of rest suggest a faster repriming kinetic of these currents in adults.
4-Aminopyridine↗
[Cellular electrophysiology of abnormal automaticity foci].
Foci of abnormal automaticity are the result of either 1) an abnormal pacemaker discharging spontaneously in the absence of an initiating stimulation usually arising in the midst of depolarised myocardial fibres but also from zones of physiological subsidiary automaticity normally inhibited during sinus rhythm, or 2) automatic activity triggered by an initiating stimulus related to oscillating after-depolarisation or early after-depolarisation. Oscillating after-depolarisation, the clinical expression of which was thought initially to be limited to digitalis toxicity, can arise in any experimental situation associated with calcium overload of the cell. Early after-depolarisation which often occurs during the terminal phase of the action potential of the Purkinje fibres, arises under different experimental conditions to those giving rise to oscillating after-depolarisation. Cellular electrophysiological techniques demonstrate the mechanism responsible for abnormal automaticity and the sites of action of antiarrhythmic drugs. Close collaboration between cellular electrophysiologists and clinicians is necessary to establish the responsibility of mechanisms demonstrated in vitro in the genesis of clinical arrhythmias.
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[The variability in the duration of human atrial action potentials increases with age].
35 human atrial samples, presenting electrophysiological characteristics within "normal" limits, were studied in vitro. 19 were sampled from adult patients and 16 were sampled from very young patients. Maximum diastolic potential did not significantly differ between adult and young, either in mean value or in variability. Action potential duration increased with age, particularly during the earliest years of life. The variability of action potential duration, which is considered as an arrhythmogenic factor, is greater in the adult.
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Automaticity of ventricular fibers induced by low concentrations of barium.
The effects of low concentrations of Ba have been studied on dog Purkinje fibers and on guinea pig left ventricular epicardium. In both tissues, Ba induces diastolic depolarization at a membrane potential more negative than -80 mV. This effect becomes clearly detectable at concentrations as low as 10-20 microM in Purkinje fibers bathed in 5.4 mM K Tyrode solution and around 100 microM in ventricular epicardium. In both tissues the Ba-induced depolarization is blocked in a dose-dependent manner by low concentrations of Cs (0.5-5 mM) as is the normal pacemaker current (if) in Purkinje fibers. In ventricular muscle the Ba-induced depolarization develops at the same rate whether the tissue is at rest or depolarized by repetitive stimulation. The maximum (initial) slope of diastolic depolarization is insensitive to D 600, La, and 4-aminopyridine, increased by tetraethylammonium chloride, decreased by tetrodotoxin, and almost entirely suppressed by Na removal. Experimental data and reconstruction of electrical activity suggest that in ventricular muscle the Ba-induced diastolic depolarization results to a large extent from the unmasking of a small pacemaker inward current, mainly carried by Na ions and similar to the pacemaker current of Purkinje fibers. Unmasking of the depolarizing effect of the pacemaker current is very likely due to the decrease by Ba of the inward going rectification. Steady-state inward Na current flowing through the Na window can increase the diastolic depolarization. Residual Cs-insensitive, Ba-induced diastolic depolarization may result from a time-dependent blockade of the background K conductance like the one described in skeletal muscle.
4-Aminopyridine↗
Simulation of potassium accumulation in clefts of Purkinje fibers: effect on membrane electrical activity.
Purkinje fiber action potentials and concomitant intercellular cleft [K] variations were reconstructed by using modified McAllister, Noble & Tsien (1975) equations including the pump current, ip, and the pacemaker current, if. Three different mean cleft widths were chosen: 40, 200 and 1000 nm. Assuming a cylindrical arrangement of the cells in the bundle, the cleft [K] gradient across the bundle was calculated by using the radial cylindrical diffusion equation. The effects of varying several parameters (cleft width, tortuosity, ip and if) were studied in conditions corresponding to two different values of [K] in the bulk solution, namely 2.7 and 5.4 mM. The shortening influence on the action potential of the systolic increase in cleft [K] was detectable only in the case of the smallest cleft width. Reduction in electrogenic pump activity led to alterations of the electrical activity which depended on the cleft width. The evolution of the intercellular [K] during each action potential and the following diastolic period was normally biphasic; a small reaccumulation during the late part of the diastole was induced by the K component of the if current. Experimentally determined intercellular [K] variations described in the literature exhibit a monophasic evolution. Such a monophasic evolution could be reproduced after reduction of both if and the transient outward K current and suppression of the negative slope of the ik1-Em relationship. In this case the amplitude of the cyclic change in intercellular [K] was approximately equal to 0.2 mM (for a 200 nm cleft width), a value much lower than that experimentally recorded. Possible reasons for this discrepancy are discussed. A simplified three compartment model for K diffusion was also used. Results obtained with the two models demonstrated that the simplified model can be used as a reasonable approximation of the more complex radial diffusion model, with a reduction in computation time reaching 80% or more.
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Studies on slow cardiac action potentials occurring in potassium-rich media as a simulation of the early phase of myocardial infarction. Influence of potassium-conductance blockers and antiarrhythmic drugs.
In the acute phase of myocardial infarction, a marked intracellular potassium loss and the lack of intact coronary circulation are known to result in extracellular hyperpotassemia partially depolarizing the damaged cells. To simulate these conditions, isolated guinea pig papillary muscles were superfused with K+-rich Tyrode solution, the minimal norepinephrine concentration required to trigger slow action potentials (SR) was measured, and the characteristics of SR were studied with glass microelectrodes. The threshold norepinephrine concentration was found to be about 1.04 x 10(-6)M. This threshold concentration was decreased by substances inhibiting the outward potassium currents (4-aminopyridine, tetraethylammonium, cesium); the SR duration and the maximal rate of depolarization were increased by them. Lidocaine and procainamide have no influence on these parameters. Phenytoin and the Mg2+ ion were found to have a marked inhibitor effect by increasing the threshold norepinephrine concentration and decreasing the maximal rate of depolarization of SR.
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Existence of two transient outward currents in sheep cardiac Purkinje fibers.
Voltage clamp analysis of the transient outward (positive dynamic) current was performed in sheep Purkinje fibers at a pulse frequency of 1/min. 4-aminopyridine (4-AP, 1 mM) suppressed most of the transient outward current, thus revealing the slow inward current, isi, and an associated brief outward current ibo. The long lasting component of the current suppressed by 4-AP was labelled ilo. In the presence of 4-AP, ibo was suppressed either by caffeine 10 mM or when Sr was substituted for Ca, both conditions making isi clearly detectable. Mn ions suppressed both isi and ibo. Current decay was a monoexponential process for ibo (tau = 12 ms) and a two exponential process for ilo (tau 1 = 80-100 ms, tau 2 = 250-400 ms). The peak amplitude-Em relationships were different for the two currents. It was shown that the reversal potential of ilo was not measurable by the usual method probably because of the too fast activation-deactivation kinetics of the current. It is concluded that not one but two transient outward currents with different electrophysiological and pharmacological characteristics exist in the sheep Purkinje fiber. The reason of the caffeine-sensitivity of ibo is discussed.
4-Aminopyridine↗
Role of adrenocortical hormones on the ontogenesis of ventricular action potential of rat myocardium.
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Action Potentials↗
Effect of tetraethylammonium, 4-aminopyridine, cesium and magnesium on slow responses in the guinea pig papillary muscle.
Having inactivated the sodium conductance by K-rich media, propagated slow responses were triggered by local electrical stimulation after addition of catecholamines. We determined the smallest noradrenaline concentration eliciting slow responses (noradrenaline threshold) and it was found to be 1.04 X 10(-6) mol . litre-1 +/- 0.25. The rate of rise and the amplitude of cardiac slow responses increase with the external concentration in calcium, however their development is also influenced by altering potassium conductances. Substances inhibiting gK: tetraetylammonium, 4-aminopyridine and cesium increased the maximal rate of rise and the duration of slow responses and except for the latter compound, decreased the noradrenaline threshold. On the other hand Mg ions exerted an inhibitory effect on slow responses since they markedly decreased the maximal rate of depolarisation and increased the noradrenaline threshold in spite of a very small increase in the duration of slow responses. The effect of Mg ions can be explained by an inhibition of the slow inward current.
4-Aminopyridine↗
The site of gating in the ventricular conducting system of rabbit, dog and monkey hearts.
The longest action potential durations of the ventricular conducting system were found at about two thirds of the distance along each false tendon in dog and monkey hearts. In the rabbit heart, this area which corresponds to the gating mechanism - was found in the middle part of the bundle branches; therefore the number of gates is much smaller in the rabbit than in other 2 species.
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Computer simulation of acidosis-induced abnormal repolarization and repetitive activity in dog Purkinje fibers.
Equations described by Mc Allister et al. (1975) were used to simulate the abnormal repolarization phase of the action potential (early after depolarization or hump), which often occurs in isolated dog Purkinje fibers submitted to acid media and can result in re-excitation. The development of humps was simulated by modifying the īK2-Em relationship in such a way that the resulting repolarizing current was increased at low membrane potential and decreased at higher (more negative) membrane potential. Beyond a certain size, humps triggered single, or multiple re-excitations. Hump size was very sensitive to small changes in īK2 and iK1, moderately sensitive to changes in īx1 and almost insensitive to changes in ix2. Negative shifts in the s infinity-Em relationship induced slowing of the basic frequency and only a small decrease in hump size. Decreasing gsi and gNa exerted inhibitory effects on hump development, the latter effect being larger than the former. The steady-state inward sodium current resulting from the overlap of m infinity-Em and h infinity-Em relationships appeared of particular importance in the development of humps.
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Acidosis-induced abnormal repolarization and repetitive activity in isolated dog Purkinje fibers.
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Action Potentials↗
Effect of tetrodotoxin on action potentials of the conducting system in the dog heart.
Tetrodotoxin (TTX) shortens Purkinje fiber action potential duration (APD) at concentrations (greater than or equal to 3.3 x 10(-8) M) lower than that at which the maximum rate of rise decreases (approximately 10(-6) M). The shortening effect of TTX occurs either at low or high driving rate and is much greater in Purkinje fibers than in bundle branch and muscle fibers. As a result, at a TTX concentration of 1.3 x 10(-6) M, the APD is no longer statistically different all along the conducting system, i.e., the gating mechanism described by Myerburg et al. (Circ. Res. 26: 361-378, 1970) is suppressed. It is concluded that this gating mechanism is attributable, at least in part, to the existence of a TTX-sensitive inward sodium current lengthening the plateau of the Purkinje fiber action potential. Our experimental results and reconstruction of Purkinje fiber action potentials suggest that this current, which is more sensitive to TTX than the normal rapid sodium current, flows through a background sodium conductance or/and a small proportion of sodium channels with no inactivation mechanism (or inactivation mechanism different from normal). The importance of this finding for the mechanism of action of antiarrhythmic drugs is pointed out.
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Arrhythmogenic effects of sodium palmitate on canine subendocardial Purkinje fibres as evidenced by recording transmembrane action potentials [proceedings].
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Action Potentials↗
Electrophysiological and inotropic effects of natural amino-deoxyglyco-cardenolides.
The electrophysiological, inotropic and chronotropic effects of the two first natural amino-dexoyglyco-cardenolides, mitiphylline and holarosine B, were studied. Mitiphylline has qualitatively the same properties as those of common cardiac glycosides but is more potent; holarosine B has a similar action on cardiac electrophysiological parameters of the guinea pig heart but is less potent. The difference in activity between these two compounds could be attributed to the configuration in 5-and 17-positions of the genins. Holarisone B has the particularity of increasing the action potential plateau amplitude and its duration in rat heart; this could be part of the role of the aminosugar moiety.
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Ionic basis of electrical activity in cardiac tissues.
Cardiac electrical events are described in terms of membrane physiology. The concept that cardiac membranes possess specific ionic channels controlled by gates bearing electrical charges is discussed. When open, these channels permit ions to cross the membrane, giving rise to passive inward (depolarizing) and outward (repolarizing) currents. Two different inward and four or five different outward currents appear to be responsible for the development of cardiac electrical activity; both inward currents appear to be controlled by activation and inactivation variables, whereas outward currents are essentially controlled by activation variables and/or inward-going rectifiers. The potential range in which the different currents activate and inactivate (or are limited by inward-going rectification), and the kinetics of activation and inactivation processes explain the development of electrical activity in normal cardiac tissues and in partially depolarized fibers. In addition to passive ionic currents, electrogenic active transport participates in the development of electrical phenomena. The conductance of the membrane for potassium ions and the electrical coupling between cardiac cells depend on the intracellular concentration of calcium ions.
Animals↗
Staircase in frog ventricular muscle. Its dependence on membrane excitation and extracellular ionic composition.
Staircase was studied in frog ventricle strip preparations where it was possible to alter extracellular ionic composition extremely rapidly in the diastolic interval between beats. Several findings strongly indicate that staircase in this tissue is a result of progressively increasing calcium influx per beat, rather than a beat-by-beat augmentation of an intracellular calcium pool which contributes to activation. After a steady state of force development, the very next beat could be graded, from approximately zero force to the steady state value attained during the staircase progression, by grading the calcium concentration of a new Ringer's solution switched to perfuse the muscle in the diastolic period immediately before that beat. Also, action potentials, elicited during the "quiescent" period in the virtual absence of contraction (in 0.025 mm calcium Ringer's solution), markedly increase force development and accelerate the staircase seen upon return to normal Ringer's solution. Staircase is augmented and accelerated by prior exposure of the muscle, during the quiescent period, to calcium-poor media and markedly suppressed by prior exposure to sodium-poor media. Tetrodotoxin, in a dose that markedly slows the action potential upstroke, has no effect on staircase. Finally, staircase is seen to occur during a train of depolarizations (by voltage clamp) to inside positive levels greater than the equilibrium potential for sodium. It is concluded that changes in intracellular sodium concentration will alter the staircase response and may contribute to its genesis, but that this cannot be the sole cause of staircase.
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