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A L Wit

Publications and source records attributed to A L Wit.

At least 55 records · Page 3Linked to original sources
PubMed1987

Arrhythmogenic actions of antiarrhythmic drugs.

Cardiac arrhythmias may result from abnormalities of impulse propagation or abnormalities of impulse initiation. When arrhythmias are initiated by antiarrhythmic drugs, the most common mechanisms appear to be conduction block or reentry, and abnormal impulse initiation, which may be triggered by afterdepolarizations. The effects of drugs on conduction may result from their actions on the fast sodium channel, the slow calcium channel or their ability to prolong repolarization. The extent to which a drug that depresses fast sodium or slow calcium entry will exert its toxic effects depends in large part on its binding characteristics to its channel receptor site. Such toxicity represents a continuum for the therapeutic effects of these drugs. The factors that control drug access to binding sites, including lipid solubility, molecular size and extent of ionization, are reviewed, as are the contributions to conduction abnormalities of drug-induced changes in repolarization. The mechanisms whereby drugs induce abnormalities of impulse initiation are still a matter of conjecture. Apparently, drugs that increase inward plateau currents or decrease repolarizing potassium ion currents carry increased risk. Moreover, there is evidence for the role of early after depolarizations occurring secondary to prolonged repolarization as a possible cause of arrhythmias, including torsades de pointes. The mechanisms whereby antiarrhythmic drugs may contribute to this type of tachyarrhythmia are reviewed.

Action Potentials↗
PubMed1987

Characteristics of a transient inward current that causes delayed afterdepolarizations in atrial cells of the canine coronary sinus.

Delayed afterdepolarizations and triggered activity occur in atrial cells of the canine coronary sinus in response to catecholamines. We studied the properties of the membrane current that causes the afterdepolarizations with the two-microelectrode voltage clamp technique in small preparations (about 0.5 x 1 mm). At a holding potential of -50 mV a transient inward current (TI) occurred after repolarization from a depolarizing step to between -40 and -20 mV in the absence of catecholamines. When the depolarizing pulse was made more positive or its duration increased the amplitude of the TI current increased and it reached peak amplitude faster. The current-voltage relationship of the TI current was studied by changing the voltage to which the membrane was repolarized after a depolarizing clamp pulse of fixed amplitude and duration. At repolarization levels positive to -30 mV there were current fluctuations without a distinct TI current. As the repolarization voltage was made more negative, a TI current occurred and its time to peak increased monotonically. The TI current amplitude increased and reached a maximum amplitude at around -60 to -70 mV, and then declined at more negative repolarization voltages. Norepinephrine increased the TI current while simultaneously augmenting the slow inward current. Elevating [Ca]0 increased the TI current amplitude. Caffeine (2 mM) increased the TI current amplitude, while caffeine (4 mM) increased and then decreased the current amplitude. The dependence of the TI current on the voltage and duration of the activating depolarizing step in these atrial cells are qualitatively similar to those of the TI current associated with digitalis toxicity in Purkinje fibers and ventricular muscle, although there are some quantitative differences. There is no distinct TI reversal in these atrial cells, similar to TI in ventricular muscle but dissimilar to TI in Purkinje fibers.

Animals↗
PubMed1987

Triggered activity in atrial fibres of canine coronary sinus: role of extracellular potassium accumulation and depletion.

1. Bursts of triggered activity can be induced in atrial fibres of the canine coronary sinus exposed to catecholamines. During a triggered burst there is an initial acceleration of rate accompanied by depolarization of the maximum diastolic potential (m.d.p.) followed by slowing of the rate and termination accompanied by hyperpolarization. 2. We have used extracellular K+-sensitive micro-electrodes (potassium ISE) to monitor extracellular K+ concentration ([K+]o) during and following triggered activity, while simultaneously measuring membrane potential with conventional intracellular micro-electrodes. 3. We found that the initial increase in rate during triggered activity is accompanied by increased [K+]o and depolarization. Later rate slowing and m.d.p. hyperpolarization is accompanied by decline of extracellular K+ accumulation. Following termination of triggered activity, extracellular K+ depletion occurred. 4. The decline of [K+]o and slowing of rate are known responses to enhanced Na+-K+ pump activation, as is the post-triggering depletion of extracellular K+. 5. Strophanthidin, which blocks the Na+-K+ pump, also blocks the [K+]o decline, the slowing of rate seen towards the end of the triggered episode, and the post-triggering depletion of extracellular K+. 6. Separate experiments studying the effects of elevated bath K+ and depolarizing current on triggering rate and delayed after-depolarization amplitude support our hypothesis that the rate profile of the triggered episode is to a large extent controlled by variations in m.d.p. subsequent to extracellular K+ accumulation and Na+-K+ pump activation.

Action Potentials↗
PubMed1987

Effects of reducing [Na+]o on catecholamine-induced delayed afterdepolarizations in atrial cells.

Atrial cells of the canine coronary sinus generate arrhythmogenic delayed afterdepolarizations (DADs) in the presence of catecholamines. We studied the direct effects of reducing extracellular Na+ concentration ([Na+]o) to determine whether it is an important charge carrier of the DADs. We also compared the effects of sucrose substitution and Li+ substitution to obtain some insight into the ionic mechanism mediating the DADs, because Li+ can substitute for Na+ in various Na+ channels but not in electrogenic Na+-Ca2+ exchange. Reducing [Na+]o for 2-5 min caused complicated changes in electrical and mechanical properties of coronary sinus cells. When Li+ was used as a substitute, there was initially a decrease in the DAD within 25 s. Action potential duration decreased, resting tension increased, and twitch tension decreased. After 85 s, a small delayed afterdepolarization reappeared, membrane potential depolarized, and the aftercontraction increased. When sucrose was used as a substitute similar changes occurred except membrane potential hyperpolarized. Some of these changes suggest an elevation in intracellular [Ca2+] and subsequent alterations in membrane properties. To distinguish the direct effect of reducing [Na+]o from these indirect effects, we used a fast-flow superfusion system and thin, small preparations (approximately 1 mm wide, 4 mm long, and 6-12 cell layers thick). Under such conditions, 2- to 3-s solution changes could modify extracellular [Na+] without significantly affecting intracellular ionic composition. Brief periods of [Na+]o reduction during the DAD caused a decrease in its amplitude and rate of depolarization when either sucrose or Li+ was used as a substitute for Na+, without the other changes in membrane potential which occur during prolonged [Na+]o reduction. These results suggest Na+ is an important charge carrier for the inward current causing DADs in coronary sinus cells, and the membrane system mediating DADs may be either electrogenic Na+-Ca2+ exchange or a combination of electrogenic Na+-Ca2+ exchange and some other mechanism such as cation channels permeable to Li+.

Animals↗
PubMed1987

Intracellular K+ activity, intracellular Na+ activity and maximum diastolic potential of canine subendocardial Purkinje cells from one-day-old infarcts.

The basis for the reduced maximum diastolic potential of canine cardiac subendocardial Purkinje fibers surviving one day after extensive transmural infarction was investigated, using double-barrel potassium and sodium ion-sensitive microelectrodes. The maximum diastolic potential of Purkinje fibers in infarct preparations from the left ventricular apex measured during the first hour of superfusion in a tissue bath was -50.1 +/- 13.7 mV, a value markedly reduced from the value in control Purkinje fibers from noninfarcted preparations (-85.0 +/- 4.5 mV). The intracellular potassium ion activity was reduced by 50.4 mM during this time (intracellular potassium ion activity equals 61.6 +/- 16.1 mM, as compared to control intracellular potassium ion activity of 112 +/- 19.8 mM). The potassium equilibrium potential was reduced by 16.0 mV (from -97.2 +/- 4.7 mV in controls to -81.2 +/- 6.9 mV), thus accounting for about one half of the reduction in the maximum diastolic potential. After 6 hours of superfusion, the maximum diastolic potential increased to -78.9 +/- 8.7 mV (still significantly less than control). The potassium equilibrium potential had largely recovered (-93.8 +/- 5.9 mV). The intracellular sodium ion activity of Purkinje fibers in the infarcts (15.6 +/- 6.9 mM) was elevated during the first hour of superfusion by 6.2 mM compared to control (9.4 +/- 2.6 mM), and this was only 12% as much as the initial intracellular potassium ion activity decrease. Sodium ion activity after 3-6 hours of superfusion was not significantly different than normal (12.1 +/- 4.9 mM). In conclusion, only a portion of the maximum diastolic potential changes can be explained by a reduction of the potassium equilibrium potential. It is likely that change(s) in the cell membrane sodium-potassium pump's function and in the membrane conductance are also involved. Furthermore, the lack of a compensatory increase in intracellular sodium ion activity accompanying the large reduction of intracellular potassium ion activity may be a consequence of the cellular acidosis, which is known to occur during myocardial ischemia.

Animals↗
PubMed1986

Characteristics of initiation and termination of catecholamine-induced triggered activity in atrial fibers of the coronary sinus.

We studied epinephrine-induced delayed afterdepolarizations and triggered activity in atrial fibers from the canine coronary sinus to determine whether their responses to cardiac pacing would aid in formulating a uniform set of guidelines for differentiating this triggered activity from other arrhythmogenic mechanisms. We used standard microelectrode techniques and compared the delayed afterdepolarizations and triggered activity with those occurring in ouabain-superfused Purkinje fibers. Like Purkinje fibers, the frequency of triggering in the coronary sinus and the coupling interval of the first triggered beat were related directly to the basic drive cycle length, and the delayed afterdepolarization amplitude and frequency of triggering were related to the coupling interval of premature stimuli (S2). However, unlike Purkinje fibers, the coupling interval of the delayed afterdepolarization and of the first triggered beat were independent of the S2. Once initiated, triggered activity in the coronary sinus followed one of four rhythm patterns: in all four, the minimum and equilibrium cycle lengths were independent of the initiating cycle length. Triggered activity was terminated by overdrive and S2 pacing, especially by long episodes of overdrive at short cycle length. The first escape beat after overdrive was linearly related to the overdrive cycle length, resulting in overdrive acceleration. The return cycle length after S2 was linearly related to the S2 coupling interval. Because delayed afterdepolarizations and triggered activity in the coronary sinus respond differently to pacing from those in ouabain-superfused Purkinje fibers, triggered activity in general may not be identified by a uniform set of guidelines.

Action Potentials↗
PubMed1985

The effects of caffeine and ryanodine on the electrical activity of the canine coronary sinus.

Cells of the coronary sinus of the canine heart can exhibit triggered activity which each action potential arises from a depolarizing after-potential that follows the previous action potential; an early after-hyperpolarization commonly precedes the delayed after-depolarization and both are increased in amplitude by the addition of noradrenaline. The delayed after-depolarization is thought to be caused by an inward current activated by a rise in intracellular Ca2+ that is, in turn, caused by Ca2+-induced release of Ca2+ from the sarcoplasmic reticulum (s.r.). The effects of caffeine and of ryanodine on the electrical activity of the coronary sinus were investigated because each of those agents is thought to affect the handling of intracellular Ca2+ by the s.r. The steady-state effect of exposure to 5 mM-caffeine is to cause the delayed after-depolarization to move much earlier in the cycle, and become too small to give rise to an action potential so that preparations cannot show triggered activity; moreover, if a burst of activity is in progress it is terminated by exposure to 5 mM-caffeine. Exposure to 0.5 mM-caffeine causes the delayed after-depolarization to move earlier in the cycle but to become larger so that triggered activity is more easily induced and longer lasting than in the absence of caffeine. Shortly after the addition (or wash-out) of 5 mM-caffeine the after-depolarization transiently resembles that seen in the presence of 0.5 mM-caffeine so that bursts of triggered activity may occur just after the addition or removal of 5 mM-caffeine. Exposure to 5 mM-caffeine abolishes early rapid repolarization (phase 1), shifts the plateau to a more positive level and retards the completion of repolarization. The effect on phase 1 is mimicked by exposure to solutions low in Cl-; the effect on the plateau is mimicked by exposure to 20 mM-tetraethylammonium (TEA); fibres exposed to solutions containing 20 mM-TEA and 21 mM-Cl- show action potentials very like those of fibres exposed to 5 mM-caffeine. If a fibre already exposed to a low Cl-, TEA-containing solution is then exposed to 5 mM-caffeine, no further change occurs in the action potential but the characteristic effects of caffeine on the after-depolarization appear. Exposure to ryanodine prevents the appearance of the delayed after-depolarization but leads to the appearance of an exceptionally long depolarizing after-potential that begins very early in diastole and, though waning, persists almost throughout diastole.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1985

Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts.

The electrophysiologic and anatomic basis for fractionated electrograms were investigated in superfused epicardial preparations from infarcted canine hearts. Fractionated bipolar electrograms were frequently recorded in preparations from infarcts 2 weeks to 18 months old but only rarely in preparations from 5-day-old infarcts. The fractionated electrograms were not caused by movement artifacts. They were not associated with depressed transmembrane resting or action potentials (which were found in the 5-day-old infarcts), but rather transmembrane potentials recorded in the vicinity of the bipolar electrodes were normal. Despite the normal transmembrane potentials, activation time in regions where fractionated electrograms occurred was prolonged. However, prolonged activation time by itself did not cause fractionation, since fractionated electrograms were not recorded from normal preparations in which conduction was markedly slowed by a superfusate containing 16 mM potassium and epinephrine. Unipolar electrograms recorded with glass microelectrodes (tip size 1 to 5 microns) showed that activation in regions where fractionated electrograms were recorded was inhomogeneous. Prepotentials were found preceding the upstrokes of some action potentials in regions where double potentials were recorded, suggesting the possibility of electrotonic transmission across high resistance or inexcitable gaps, but no electrotonic potentials were seen in regions with multicomponent fractionated electrograms. Fractionated electrograms were recorded in regions where infarct healing caused wide separation of individual myocardial fibers while distorting their orientation. The anatomic changes probably caused slow and inhomogeneous activation.

Action Potentials↗
PubMed1985

Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing.

Structural and electrophysiological properties of the epicardial muscle which survives on the surface of transmural infarcts of the canine heart (epicardial border zone) were studied at different times after occlusion of the left anterior coronary artery (LAD). Isolated preparations were superfused in vitro, transmembrane potentials recorded, and impulse propagation mapped. In preparations from subacute infarcts (1 and 5 days), resting potential, action potential amplitude, upstroke velocity, and duration were all significantly reduced. Well-defined directional differences in propagation occurred. Propagation was more rapid in the direction perpendicular to the left anterior coronary artery than in the direction perpendicular to the base of the heart, because of the uniform anisotropic structure of the surviving muscle fibers which were arranged in tightly packed bundles oriented perpendicular to the left anterior coronary artery. The only ultrastructural abnormalities found in these muscle fibers was an accumulation of large amounts of lipid droplets. As the infarcts healed, resting potential, action potential amplitude, and upstroke velocity returned to normal by 2 weeks, although action potential duration decreased further. Lipid droplets had disappeared, and connective tissue had invaded the epicardial border zone, separating the muscle bundles. By 2 months, action potentials were normal, but the muscle fibers were widely separated and disoriented by the connective tissue (parallel bundles no longer were found). In these regions with a nonuniform anisotropic structure, the well-defined directional differences in impulse propagation were lost. However, activation was very slow, perhaps because of diminished connections between cells. The persistence of slow conduction in healed infarcts may contribute to the occurrence of chronic arrhythmias.

Animals↗
PubMed1985

Electrophysiological basis for antiarrhythmic drug action.

Arrhythmias result from abnormalities of impulse initiation or impulse conduction or a combination of both. Abnormal impulse initiation results from either automaticity or triggered activity. Automaticity can further be subdivided into (1) automaticity caused by the normal automatic mechanism (a normal property of cardiac cells in the sinus node, in some parts of the atria, in the atrioventricular junctional region, and in the His-Purkinje system) and (2) automaticity caused by an abnormal mechanism (resulting from a decrease in membrane potential of cardiac fibers, which normally have a high level of membrane potential). Triggered activity is caused by afterdepolarizations, which are second depolarizations that occur either during repolarization (referred to as early afterdepolarizations) or after repolarization is complete or nearly complete (referred to as delayed afterdepolarizations). Abnormal impulse conduction results in reentrant excitation. Usually a combination of slowed conduction and unidirectional conduction block provides the conditions necessary for reentry to occur.

Action Potentials↗
PubMed1984

Mechanisms for atrial arrhythmias associated with cardiomyopathy: a study of feline hearts with primary myocardial disease.

The cellular electrophysiologic and structural characteristics of arrhythmic and non-arrhythmic atria isolated from feline hearts with spontaneously occurring cardiomyopathy were studied. The animals were divided into three groups according to the degree of left atrial enlargement: mild (group I), moderate (group II), and severe (group III). The right atria were of relatively normal size. Microelectrode recordings showed that inexcitable cells were present in both left and right atria of all groups but were most numerous in the left atria of group III animals. Most inexcitable cells had low resting membrane potentials. There was also a significant reduction in resting membrane potentials, maximum rate of phase 0 depolarization, and action potential amplitude of excitable cells in left atria of animals in groups II and III, whereas action potentials of excitable cells in the right atria were normal. Acetylcholine or norepinephrine often restored excitability to cells that originally did not generate action potentials. Norepinephrine also caused slow-response action potentials as well as abnormal automaticity and triggered activity due to delayed afterpotentials. The diseased atria showed marked structural abnormalities, which were most pronounced in group III cats, including large amounts of interstitial fibrosis, cellular hypertrophy and degeneration, and thickened basement membranes. Therefore electrophysiologic abnormalities and concurrent changes in cell structure may be involved in the genesis of atrial tachyarrhythmias caused by cardiomyopathy.

Acetylcholine↗
PubMed1984

The time course of action potential repolarization affects delayed afterdepolarization amplitude in atrial fibers of the canine coronary sinus.

The effects of changing the time course of action potential repolarization on the amplitude and coupling interval of delayed afterdepolarizations were studied in small preparations of coronary sinus atrial fibers exposed to catecholamines. Repolarization was accelerated or retarded by current pulses passed through an intracellular microelectrode in the depolarizing or repolarizing direction. Acceleration of repolarization decreased the amplitude of delayed afterdepolarizations, prolonged their coupling interval to the action potential upstroke, and prevented triggered activity. Prolonging the time for repolarization increased afterdepolarization amplitude, shortened the coupling interval, and caused triggered activity. The afterdepolarization amplitude and coupling interval had a linear relationship to the duration of the action potential plateau. In some preparations, the action potential plateau increased spontaneously at stimulation rates that caused afterdepolarization amplitude to increase and triggering to occur, and this may have contributed to the occurrence of triggering. The effects of action potential repolarization on delayed afterdepolarizations suggest that pharmacological agents such as antiarrhythmic drugs which alter action potential duration should influence afterdepolarizations. Drugs which shorten action potential duration might prevent triggered activity from occurring, whereas drugs which prolong duration might cause triggering.

Action Potentials↗
PubMed1983

Pathophysiologic mechanisms of cardiac arrhythmias.

Arrhythmias result from abnormalities of impulse initiation or impulse conduction or a combination of both. Abnormal impulse initiation results from either automaticity or triggered activity. Automaticity can further be subdivided into (1) automaticity caused by the normal automatic mechanism (a normal property of cardiac cells in the sinus node, in some parts of the atria, in the atrioventricular junctional region, and in the His-Purkinje system) and (2) automaticity caused by an abnormal mechanism (resulting from a decrease in membrane potential of cardiac fibers, which normally have a high level of membrane potential). Triggered activity is caused by afterdepolarizations, which are second depolarizations that occur either during repolarization (referred to as early afterdepolarizations) or after repolarization is complete or nearly complete (referred to as delayed afterdepolarizations). Abnormal impulse conduction results in reentrant excitation. Usually a combination of slowed conduction and unidirectional conduction block provides the conditions necessary for reentry to occur. Slow conduction and block may result from a decrease in the resting potential and velocity of depolarization of the action potential or may be a consequence of the anisotropic structure of cardiac muscle, in which case resting potential and action potential upstroke velocity may be normal.

Action Potentials↗
PubMed1983

Electropharmacology of antiarrhythmic drugs.

Cardiac arrhythmias may be caused by abnormalities of impulse initiation, impulse propagation, or a combination of the two. The specific mechanisms that may induce arrhythmias are reviewed, as are the means whereby antiarrhythmic drugs might be expected to modify arrhythmias. The cellular electrophysiologic effects of the following antiarrhythmic drugs are discussed: quinidine, procainamide, disopyramide, lidocaine, tocainide, mexiletine, phenytoin, beta-blocking and slow-channel-blocking drugs, aprindine, bretylium, ethmozin, and amiodarone. A knowledge of the similarities and differences of their actions on the determinants of conduction, on repolarization and refractoriness, on automatic mechanisms, and on afterdepolarizations, when considered in the context of the mechanism of clinically occurring tachyarrhythmias, may provide the correct framework for the choice of an appropriate agent for the control of an individual disorder of rhythm. However, it is emphasized that neither the precise mechanism of various dysrhythmias nor the fundamental basis for the salutary action of antiarrhythmic compounds is completely understood.

Action Potentials↗
PubMed1983

Comparison of the direct effects of nifedipine and verapamil on the electrical activity of the sinoatrial and atrioventricular nodes of the rabbit heart.

We compared the effects of nifedipine and verapamil on the rabbit sinus and atrioventricular nodes. Both drugs slowed the rate of impulse initiation by sinus node cells. Verapamil exerted a greater negative chronotropic effect at low concentrations, but at higher concentrations verapamil and nifedipine were equipotent. Nifedipine also reduced the amplitude of sinus node action potentials and the Vmax of phase O, effects which are identical to those previously described for verapamil. Both drugs slowed AV nodal conduction and prolonged refractory periods, but verapamil was more potent than nifedipine. Nifedipine reduced the amplitude of AV nodal action potentials and Vmax of phase O the same as verapamil. Nifedipine and verapamil, therefore, have nearly identical direct effects on the nodes. The failure of nifedipine to depress AV nodal conduction in situ and abolish reentrant AV nodal tachycardia is probably a result of the decreased sensitivity of the AV node to nifedipine compared to verapamil.

Animals↗