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C Antzelevitch

Publications and source records attributed to C Antzelevitch.

At least 91 records · Page 5Linked to original sources
PubMed1994

High [Ca2+]o-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium. Phase 2 reentry.

BACKGROUND: Elevated intracellular calcium activity is thought to play an important role in arrhythmia induction, particularly during ischemia and reperfusion. Delayed after-depolarization-induced triggered activity and intracellular communication problems are thought to be responsible. METHODS AND RESULTS: Increased extracellular calcium levels and rapid pacing are interventions known to elevate intracellular calcium activity. The present study, conducted using standard microelectrode techniques, was designed to compare the effects of increased [Ca2+]o (1.8 to 5.4 mmol/L) in isolated canine ventricular epicardial and endocardial tissues and to test the hypothesis that elevated intracellular calcium activity contributes to arrhythmogenesis in working ventricular myocardial tissues by promoting electrical heterogeneity. High [Ca2+]o caused a slight abbreviation of action potential duration (APD90) in endocardium but more dramatic rate-dependent and dynamic changes in epicardium. Under steady-state conditions, epicardium displayed a marked abbreviation of APD90 at fast rates but no significant changes at slow rates. A significant augmentation of phase 1 was evident at the faster stimulation rates. Vmax and conduction velocity were only slightly reduced. The marked abbreviation of the epicardial response at the factor rates was due to loss of the action potential dome. Recovery of the dome after deceleration was not synchronous throughout the preparation. As a consequence, a sudden slowing of rate caused marked dispersion of repolarization among neighboring epicardial sites, giving rise to ectopic activity via a phase 2 reentry mechanism. These effects of high [Ca2+]o were mimicked by exposure of the preparations to low [Na+]o. Electrical homogeneity was restored and arrhythmias were abolished after addition of the Ito blocker 4-aminopyridine 1 mmol/L. 4-Aminopyridine also eliminated the differential response of epicardium and endocardium to high [Ca2+]o. CONCLUSIONS: Our data demonstrate the induction of marked electrical heterogeneity and reentrant activity by high [Ca2+]o and rapid stimulation, conditions known to elevate [Ca2+]i. The results suggest that increased intracellular calcium activity, as occurs during ischemia and reperfusion, may contribute to the development of electrical inhomogeneity in the ventricle and thus to the genesis of ventricular arrhythmias through a mechanism other than triggered activity, namely, phase 2 reentry. Our data point to an increase in net outward current as the underlying mechanism for the calcium-induced changes. Our results also suggest that the presence of a prominent transient outward current (Ito) in epicardium sensitizes that tissue to the effects of high calcium. Finally, the results suggest that Ito blockers can reverse high calcium-induced electrical heterogeneity and thus can exert antiarrhythmic actions.

Action Potentials↗
PubMed1993

Drug-induced afterdepolarizations and triggered activity occur in a discrete subpopulation of ventricular muscle cells (M cells) in the canine heart: quinidine and digitalis.

INTRODUCTION: Oscillations of membrane potential that attend or follow the cardiac action potential and depend on preceding transmembrane activity for their manifestation are known as afterdepolarizations. Early afterdepolarizations (EADs) interrupt or retard repolarization of the cardiac action potential, whereas delayed afterdepolarizations (DADs) arise after full repolarization. EADs and DADs can give rise to spontaneous action potentials or triggered activity believed to be responsible for a variety of cardiac arrhythmias. Recent studies from our laboratory have highlighted differences in the electrophysiology and pharmacology of three functionally distinct myocardial cell types found in the canine ventricle. Epicardial, M region, and endocardial tissues and cells show distinct, sometimes opposite, responses to a variety of drugs, including those capable of inducing EADs and DADs. METHODS AND RESULTS: In the present study, we used standard microelectrode techniques to examine the pharmacologic response of these cellular subtypes to therapeutic levels of quinidine and toxic levels of digitalis. Quinidine readily produced prominent EADs and EAD-induced triggered activity in tissue preparations from the M region (deep subepicardium), but not in those from epicardium, endocardium, or deep subendocardium of the canine ventricle. Acetylstrophanthidin produced prominent DADs in M cell preparations and subendocardial Purkinje fibers but only minute DADs, if any, in epicardium, endocardium, or deep subendocardium. DAD-induced triggered activity was observed to arise only in Purkinje and M cells and never in myocardial tissues from the epicardial, endocardial, or deep subendocardial regions of the ventricular wall. CONCLUSION: We conclude that EADs, DADs, and triggered activity caused by therapeutic levels of quinidine and toxic levels of digitalis are limited to or much more readily induced in a select population of cells in the deep subepicardial (M cell) region of the canine ventricle in addition to the Purkinje system of the heart.

Animals↗
PubMed1993

Flecainide-induced arrhythmia in canine ventricular epicardium. Phase 2 reentry?

BACKGROUND: We recently reported that sodium channel block can produce opposite effects on action potential duration (APD) and refractoriness in epicardial versus endocardial tissues of the canine ventricle. In addition, strong sodium channel current inhibition was found to cause loss of the action potential dome in epicardium but not endocardium, thus inducing a marked dispersion of repolarization and refractoriness between epicardium and endocardium as well as among neighboring epicardial sites. The marked heterogeneity that evolves under these conditions provides a substrate for the development of arrhythmias. Flecainide was found to induce extrasystolic activity more readily than other sodium blockers. The present study contrasts the electrophysiological actions of flecainide in canine ventricular epicardium and endocardium and examines the characteristics of flecainide-induced arrhythmias in epicardial sheets of canine ventricle. METHODS AND RESULTS: Standard microelectrode techniques were used. Flecainide (10-20 microM) produced either prolongation or marked abbreviation of APD in epicardium but only minor changes in the APD of endocardium. Marked abbreviation of APD in epicardium was due to loss of the action potential dome (plateau phase). Arrhythmias displaying characteristics of reentry could be readily induced in flecainide-treated preparations either by increasing the stimulation rate or by introduction of extrastimuli. Flecainide-induced slowing of conduction, more accentuated at the faster stimulation rates, appeared to act synergistically with the drug-induced dispersion of repolarization to generate reentry in these relatively small sheets of epicardium. 4-Aminopyridine, a transient outward current (Ito) blocker, reversed the flecainide-induced marked abbreviation of APD in epicardium and abolished reentrant activity in all cases. Flecainide failed to induce reentry in preparations pretreated with 4-aminopyridine. CONCLUSIONS: Our data suggest that the presence of a prominent Ito in epicardium contributes the development of marked electrical heterogeneity in the ventricle after exposure to flecainide. Flecainide-induced dispersion of repolarization, especially when accompanied by prominent conduction delays, results in extrasystolic activity via a mechanism that we have termed "phase 2 reentry." Our results also suggest a role for Ito blockers in the treatment of reentrant arrhythmias.

4-Aminopyridine↗
PubMed1993

Pinacidil-induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues. Does activation of ATP-regulated potassium current promote phase 2 reentry?

BACKGROUND: Pinacidil is known to augment a time-independent outward current in cardiac tissues by activating the ATP-regulated potassium channels. Activation of this current, IK-ATP, is thought to be responsible for increased potassium permeability in ischemia. The contribution of IK-ATP activation to arrhythmogenesis and the role of activation of this current in suppression of arrhythmias are areas of great interest and debate. Because electrical depression attending myocardial ischemia is more accentuated in ventricular epicardium than in endocardium, we endeavored to contrast the effects of pinacidil-induced IK-ATP activation on the electrophysiology of canine ventricular epicardium and endocardium. METHODS AND RESULTS: Standard microelectrode techniques were used. Pinacidil (1 to 5 mumol/L) produced a marked dispersion of repolarization and refractoriness in isolated canine ventricular epicardium as well as between epicardium and endocardium. In endocardium, pinacidil abbreviated action potential duration (APD90) and refractoriness by 8.0 +/- 2.3%. In epicardium, the effects of pinacidil were nonhomogeneous. At some sites, pinacidil induced an all-or-none repolarization at the end of phase 1 of the action potential, resulting in 55.5 +/- 8.7% abbreviation of APD90 and refractoriness. Adjacent to these were sites at which the dome was maintained with only minor changes in APD and refractoriness. Extrasystolic activity displaying features of reentry was observed in isolated sheets of epicardium (63.2%) after exposure to pinacidil (1 to 5 mumol/L) but never in its absence. Dispersion of repolarization and ectopic activity was most readily induced in epicardium by a slowing of the stimulation rate in the presence of pinacidil. Electrical homogeneity was restored and arrhythmias abolished after washout of pinacidil or addition of either a transient outward current blocker, 4-aminopyridine, or a blocker of the ATP-regulated potassium channels, glybenclamide. CONCLUSIONS: Our data suggest that the activation of IK-ATP can produce a marked dispersion of repolarization and refractoriness in epicardium as well as between epicardium and endocardium, leading to the development of extrasystolic activity via a mechanism that we have called phase 2 reentry. The available data also suggest that blockade of the transient outward current and/or the ATP-regulated potassium channels may be useful antiarrhythmic interventions under ischemic or "ATP depleted" conditions.

Action Potentials↗
PubMed1993

Differences in the electrophysiological response of canine ventricular epicardium and endocardium to ischemia. Role of the transient outward current.

BACKGROUND: Acute ischemia is known to produce more severe electrophysiological disturbances in canine ventricular epicardium than endocardium, although the mechanism for the differential sensitivity is still unresolved. Recent studies have demonstrated the presence of a prominent transient outward current (Ito) in ventricular epicardium but not endocardium. The present study was designed to test the hypothesis that the differential sensitivity of these two tissues to ischemia results, at least in part, from a more prominent Ito in epicardium than in endocardium. METHODS AND RESULTS: Isolated canine ventricular epicardial and endocardial tissues and myocytes were studied by standard microelectrode techniques. Simulated ischemia (hyperkalemia, hypoxia, and acidosis) abolished the action potential plateau and caused a 50% to 60% shortening of action potential duration in epicardium but only a 10% to 20% shortening in endocardium. 4-Aminopyridine, an Ito inhibitor, restored the plateau in epicardium and reduced the dispersion of action potential duration between epicardium and endocardium. Stimulation protocols that minimized the contribution of Ito, such as acceleration of the stimulation rate or introduction of early premature beats, produced a paradoxical prolongation of the epicardial response caused by restoration of the action potential dome. Thus, ischemia-induced dispersion of repolarization was greatly diminished at rapid rates and after premature beats. Similar results were obtained in tissues and myocytes obtained from the same myocardial layers, suggesting that the differential sensitivities of epicardium and endocardium to ischemia are largely a result of inherent differences in cellular properties. CONCLUSIONS: Our data suggest that the presence of a prominent Ito in epicardium but not endocardium contributes importantly to the selective electrical depression of epicardium by simulated ischemia. The repolarizing influence of Ito serves to amplify the ischemia-induced changes in inward (ICa and INa) and outward (calcium-activated) currents. By facilitating loss of the dome in epicardium, Ito contributes to the development of a marked dispersion of repolarization between normal and ischemic epicardium and between epicardium and endocardium, thereby providing the electrophysiological substrate for the genesis of reentrant arrhythmias.

4-Aminopyridine↗
PubMed1993

Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle.

Recent studies from our laboratory involving syncytial preparations have delineated electrophysiological distinctions between epicardium, endocardium, and a unique population of cells in the deep subepicardial to midmyocardial layers (M region) of the canine ventricle. In the present study, we used standard microelectrode, single microelectrode switch voltage-clamp, and whole-cell patch-clamp techniques to examine transmembrane action potentials, steady-state current-voltage relations, and the 4-aminopyridine-sensitive transient outward current (Ito1) in myocytes enzymatically dissociated from discrete layers of the free wall of the canine left ventricle. Action potential characteristics of myocytes isolated from the epicardium, M region, and endocardium were very similar to those previously observed in syncytial preparations isolated from the respective regions of the ventricular wall. A prominent spike and dome was apparent in myocytes from epicardium and the M region but not in myocytes from endocardium. Action potential duration-rate relations were considerably more pronounced in cells isolated from the M region. Current-voltage relations recorded from cells of epicardial, M region, and endocardial origin all displayed an N-shaped configuration with a prominent negative slope-conductance region. The magnitude of the inward rectifier K+ current (IK1) was 392 +/- 86, 289 +/- 65, and 348 +/- 115 pA in epicardial, M region, and endocardial myocytes, respectively, when defined as steady-state current blocked by 10 mM Cs+. Similar levels were obtained when IK1 was defined as the steady-state difference current measured in the presence (6 mM) and absence of extracellular K+. Ito1 was significantly greater in epicardial and M region myocytes than in endocardial myocytes. At a test potential of +70 mV (holding potential, -80 mV), Ito1 amplitude was 4,203 +/- 2,370, 3,638 +/- 1,135, and 714 +/- 286 pA in epicardial, M region, and endocardial cells, respectively. No significant differences were observed in the voltage dependence of inactivation of Ito1 in the three cell types. The time course of reactivation of Ito1 was slower in cells from the M region compared with either epicardial or endocardial cells. Our data suggest that prominent heterogeneity exists in the electrophysiology of cells spanning the canine ventricular wall and that differences in the intensity of the transient outward current contribute importantly, but not exclusively, to this heterogeneity. These findings should advance our understanding of basic heart function and the ionic bases for the electrocardiographic J wave, T wave, U wave, and long QT intervals as well as improve our understanding of some of the complex factors contributing to the development of cardiac arrhythmias.

Action Potentials↗
PubMed1993

The effects of PEG-interleukin-2 and interleukin-2 on essential hypertension and cellular immune function in the spontaneously hypertensive rat.

The effects of recombinant human interleukin-2 covalently linked to polyethylene glycol (PEG-IL-2) or interleukin-2 (IL-2) on hypertension and in vitro suppressor T cell function in the spontaneously hypertensive rats (SHR) were investigated. Male young prehypertensive (4 weeks old) SHRs and adult (10 weeks old) SHRs with established hypertension were injected with low (5,000 units (u)/kg) or high (50,000-100,000 u/kg) dose of PEG-IL-2 or IL-2 as a single bolus or repeated injections. Systolic blood pressure was measured twice weekly using the tail-cuff technique. Systolic blood pressure in the PEG-IL-2 or IL-2 treated animals, irrespective of age, dose, or route of injection, did not differ significantly from that measured in vehicle-treated controls over a 10 week period. Mean arterial pressure measured by intra-arterial catheter was 159 +/- 7 mm Hg 10 weeks after treatment with repeated injections of 5,000 u/kg of PEG-IL-2 and 158 +/- 9 mm Hg in vehicle-treated controls. All rats injected with IL-2 had IL-2-specific IgG antibody in their sera. None of the PEG-IL-2 treated rats had any detectable anti-IL-2 antibodies in their sera. Thus, PEG-IL-2 showed far less immunogenicity than IL-2. Suppressor T (Ts) cells generated from adult SHR spleen cells failed to suppress pokeweed mitogen (PWM)-driven immunoglobulin G (IgG) synthesis. PEG-IL-2 or IL-2 supplementation both in vitro and in vivo restored the ability of adult SHR to generate Ts cells able to inhibit IgG synthesis. Our data suggest that PEG-IL-2 or IL-2 administration does correct a prominent defective Ts cell activity found in adult SHR, but that correction of this immune abnormality is not attended by an attenuation of hypertension.

Age Factors↗
PubMed1991

Afterdepolarizations and triggered activity develop in a select population of cells (M cells) in canine ventricular myocardium: the effects of acetylstrophanthidin and Bay K 8644.

Early afterdepolarizations (EADs) are membrane oscillations that interrupt or retard the repolarization phase of the cardiac action potential, whereas delayed afterdepolarizations (DADs) are oscillations that arise after full repolarization. When EADs and DADs are sufficiently large to depolarize the cell membrane to its voltage threshold, they give rise to triggered action potentials, which are believed to underlie some forms of extrasystolic activity and tachyarrhythmias. EAD- and DAD-induced triggered activity have been described and well characterized in isolated Purkinje fibers exposed to a wide variety of drugs, but are rarely seen in syncytial preparations of ventricular myocardium. These results are inconsistent with those of in vivo studies or experiments involving enzymatically dissociated myocytes. In the present study, we used the cardiotonic agent acetylstrophanthidin (AcS) and the calcium channel agonist Bay K 8644 to provide evidence in support of the hypothesis that induction of prominent EADs, DADs, and triggered activity occurs in a select population of cells in ventricular myocardium. The data indicate that EADs, DADs, and triggered activity produced by digitalis and Bay K 8644 are limited to or more readily induced in the deep subepicardial cell layers of the canine ventricle (M cells). Afterdepolarization-induced triggered activity was never observed in the epicardial or endocardial layers.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle. The M cell.

Recent studies have shown that canine ventricular epicardium and endocardium differ with respect to electrophysiological characteristics and pharmacological responsiveness and that these differences are in large part due to the presence of a prominent transient outward current Ito and a spike-and-dome morphology of the action potential in epicardium but not endocardium. In attempting to quantitate these differences and assess their gradation across the ventricular wall, we encountered a subpopulation of cells in the deep subepicardial layers with electrophysiological characteristics different from those of either epicardium or endocardium. These cells, which we have termed M cells, display a spike-and-dome morphology typical of epicardium but a maximal rate of rise of the action potential upstroke that is considerably greater than that of either epicardium or endocardium. Using the restitution of the amplitude of phase 1 of the action potential as a marker for the reactivation of Ito, we showed M cells to possess a prominent 4-aminopyridine-sensitive Ito with a reactivation time course characterized by two components with fast and slow time constants. The rate dependence of action potential duration of M cells was considerably more accentuated than that of epicardium or endocardium and more akin to that of Purkinje fibers (not observed histologically in this region). Phase 4 depolarization was never observed in M cells, not even after exposure to catecholamines and/or low [K+]o. In summary, our study presents evidence for the existence of a unique subpopulation of cells in the deep subepicardium of the canine left and right ventricles with electrophysiological features intermediate between those of conducting and myocardial cells. Although their function is unknown, M cells may facilitate conduction in epicardium and are likely to influence or mediate the manifestation of electrocardiographic J waves, T waves, U waves, and long QT intervals and contribute importantly to arrhythmogenesis.

4-Aminopyridine↗
PubMed1991

Sodium channel block produces opposite electrophysiological effects in canine ventricular epicardium and endocardium.

Using microelectrode techniques we compared the effects of tetrodotoxin (TTX, 2-3 microM), DL-propranolol (1-3 micrograms/ml), and flecainide acetate (10-15 microM) on isolated canine ventricular epicardial (epicardium) and endocardial (endocardium) tissues. Propranolol, TTX, and flecainide decreased Vmax and phase 0 amplitude in a use-dependent manner in both tissues. The effects of propranolol were slow to develop and wash out. TTX and propranolol always abbreviated action potential duration in endocardium. Action potential duration was abbreviated by 23.8 +/- 5.6 msec after propranolol (1 microgram/ml, basic cycle length [BCL] = 1,000 msec) and 10.8 +/- 12.9 msec after TTX (2 microM, BCL = 1,000 msec). In epicardium, the reduction of phase 0 and 1 amplitudes led to a slowing of the second action potential upstroke and an increase in the amplitude of phase 2. This accentuation of the notch resulted in a paradoxical prolongation of the epicardial action potential. Action potential duration was prolonged 34.4 +/- 11.3 msec after 4 hours of exposure to propranolol (1 microgram/ml, BCL = 1,000 msec), 11.1 +/- 6.3 msec after 15 minutes of exposure to TTX (2 microM, BCL = 1,000 msec), and 19.9 +/- 8.2 msec after 25-45 minutes of exposure to flecainide (15 microM, BCL = 500 msec). With stronger sodium block, phase 1 terminated at more negative potentials, the second upstroke often failed to appear, and an all-or-none repolarization ensued causing a marked abbreviation of the epicardial action potential. In some epicardial preparations, we observed marked abbreviation at some sites but prolongation at other sites after sodium blockade with flecainide. The dispersion of repolarization was often attended by reentrant activity. The differential response of epicardium and endocardium to sodium blockade was not observed when the preparations were pretreated with 4-aminopyridine or ryanodine, agents known to diminish the transient outward current and epicardial notch. Acceleration-induced prolongation of refractoriness was observed after sodium blockade in epicardium but not in endocardium. Postrepolarization refractoriness also occurred in epicardium but not in endocardium after TTX, propranolol, or flecainide exposure. The data indicate that propranolol, TTX, and flecainide, via their action to block sodium current, may exert opposite effects on action potential duration and refractoriness in cells spanning the ventricular wall. The presence of the transient outward current in epicardium but not in endocardium appears to contribute importantly to these differences.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1990

Differences in the electrophysiological response of canine ventricular subendocardium and subepicardium to acetylcholine and isoproterenol. A direct effect of acetylcholine in ventricular myocardium.

A prolongation of the ventricular effective refractory period in response to cholinergic agonists or vagal stimulation has been demonstrated in a number of in vivo animal models. However, exposure of isolated myocardial tissues obtained from these hearts to as much as 10(-4) M acetylcholine has been shown to produce essentially no change in action potential duration or effective refractory period. The discrepancy between the in vivo and in vitro findings generally has been explained on the basis of accentuated antagonism, whereby parasympathetic agonists exert their influence through antagonism of the effects of beta-adrenergic tone in vivo. The fact that acetylcholine exerts little if any direct effect on the electrical activity of ventricular myocardium, although well accepted, is based exclusively on studies performed using endocardial preparations. Our recent demonstration of major electrophysiological differences between canine ventricular endocardium and epicardium prompted us to examine the effects of acetylcholine and the role of accentuated antagonism in these two tissue types. Using standard microelectrode techniques, we show that acetylcholine (10(-7)-10(-5) M) has little if any effect in canine ventricular endocardium but a pronounced effect to either prolong or markedly abbreviate action potential duration and effective refractory period in epicardium. These effects of acetylcholine on epicardium are attended by an accentuation of the spike and dome morphology of the action potential, are readily reversed with atropine, fail to appear when epicardium is pretreated with the transient outward current blocker 4-aminopyridine, are accentuated in the presence of isoproterenol (10(-7) to 5 x 10(-6) M), and persist in the presence of propranolol. Isoproterenol-induced abbreviation of action potential duration and effective refractory period is also shown to be more pronounced in epicardium than in endocardium; equimolar concentrations of acetylcholine completely antagonize the effects of isoproterenol in endocardium and epicardium. We conclude that acetylcholine exerts important direct effects on the electrical response of canine ventricular myocardium, which are accentuated in the presence of beta-adrenergic agonists. Our findings suggest the differential response of epicardium and endocardium to acetylcholine is due to the presence of a transient outward current-mediated spike and dome morphology in the epicardial action potential. Finally, the data suggest that acetylcholine may exert antiarrhythmic as well as arrhythmogenic effects through its actions to alter conduction and refractoriness.

4-Aminopyridine↗
PubMed1989

Rate dependence of action potential duration and refractoriness in canine ventricular endocardium differs from that of epicardium: role of the transient outward current.

Previous studies have provided evidence for an important contribution of the transient outward current to the electrical activity of canine ventricular epicardium, but not endocardium. The present study examines the characteristics of action potential duration and refractoriness in these two tissue types. The time and rate dependence of changes in action potential duration and refractoriness observed in epicardium were significantly more accentuated than in endocardium. The restitution of action potential duration in epicardium paralleled the restitution of phase 1 amplitude of the action potential in this tissue. The correlation between phase 1 amplitude and action potential duration recorded from a large number of epicardial and endocardial preparations was significant under both steady state and restitution conditions. 4-Aminopyridine, a transient outward current blocker, decreased the time dependence of phase 1 amplitude and concomitantly decreased the time dependence of action potential duration in epicardium. 4-Aminopyridine abbreviated the action potential duration of epicardium at slow stimulation rates but had little effect or prolonged it at fast rates or after premature stimulation. (The availability of a transient outward current is relatively small after premature stimulation.) The data support the hypothesis that the prominent presence of a transient outward current in epicardium, but not endocardium, contributes to the differences in the time and rate dependence of action potential duration and refractoriness in the two tissue types. The results also demonstrate the effect of an outward current to prolong the action potential and the effect of an outward current blocker to abbreviate the action potential.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗
PubMed1989

Reflected reentry, delayed conduction, and electrotonic inhibition in segmentally depressed atrial tissues.

Reflection is a subclass of reentrant cardiac arrhythmias in which reexcitation of the heart occurs as a result of to and fro electrotonically mediated transmission of impulses across a narrow zone of impaired conductivity. Although relatively well characterized in ventricular tissues, the reflection mechanism has not been studied in atrial tissues. In this study we examine the possibility of reflected reentry in segmentally depressed atrial tissues and evaluate conduction characteristics in these preparations. Narrow strips of atrial pectinate muscle or crista terminalis (canine and calf) were placed in a three-chambered bath and the central segment was superfused with an isotonic sucrose solution or an "ischemic" Tyrode's solution. Proximal to distal conduction across the 1.0- to 1.2-mm wide ischemic gap showed step delays as long as 210 ms. Reflected reentry was readily demonstrable when prominent step delays occurred during anterograde conduction of the impulse across the gap. Progressive acceleration of the stimulation rate resulted in progressively greater impairment of anterograde conduction until complete block occurred. The incidence and patterns of reflected reentry were therefore a sensitive function of the stimulation rate. Other features exhibited by these preparations include a slow recovery of excitability following the action potential, postrepolarization refractoriness, and electrotonic inhibition and summation. Our data suggest that the characteristics of conduction and reflection in segmentally depressed atrial tissues are qualitatively similar to those in ventricular tissues. The presence of electrotonic inhibition in atrial may also help to explain the functionally inexcitable zone seen in the vortex of the leading circle model of atrial flutter.

Action Potentials↗
PubMed1989

Quinidine-induced action potential prolongation, early afterdepolarizations, and triggered activity in canine Purkinje fibers. Effects of stimulation rate, potassium, and magnesium.

Early afterdepolarization (EAD)-induced triggered activity is thought to contribute to the cardiac arrhythmogenic effects of several class I antiarrhythmic agents. The combination of quinidine therapy, bradycardia, and hypokalemia is known to predispose to torsade de pointes, which is a form of atypical polymorphous ventricular tachycardia commonly associated with long QT intervals. Recent clinical reports have shown suppression of quinidine-induced torsade de pointes with intravenous administration of magnesium sulfate. To provide further understanding of these relations, we used standard microelectrode techniques to examine the time course of quinidine-induced action potential prolongation, EAD, and triggered activity development and the dependence of these changes on [K+]0, [Mg2+]0, and stimulation frequency in isolated Purkinje fiber preparations exposed to low concentrations of the drug. At slow stimulation rates, the quinidine-induced increase of action potential duration was slow to develop and failed to reach a steady state after 3 hours of exposure to the drug. EAD and EAD-induced triggered activity generally became apparent 70-90 minutes after adding the drug. Quinidine produced triggered activity in 10 of 22 preparations superfused with Tyrode's solution containing normal [K+]0 (3.5-4.0 mM) and in six other preparations when [K+]0 was reduced. In the presence of normal [K+]0, two types of EAD and triggered activity were distinguished. In four of 10 preparations, this activity arose from phase 2 of the action potential; in eight of 10, it was associated with phase 3; and in two experiments, both types were present in the same preparation. The incidence of both forms of triggered responses depended greatly on the rate of stimulation. Triggered activity arising from phase 3 was always manifest at rates considerably slower than those giving rise to phase 2 activity. Both forms of triggered activity were sensitive to changes in the extracellular concentration of potassium and magnesium. Lower-than-normal levels of these electrolytes facilitated the manifestation of triggered activity, whereas elevated levels suppressed or caused a shift in the frequency-dependence of the activity. Phase 2, but not phase 3, EADs were abolished in response to increased [Mg2+]0. The data show a clear congruity between the conditions that predispose to torsade de pointes in the clinic and the conditions under which quinidine may induce triggered activity and marked action potential prolongation in isolated Purkinje fibers.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1988

Transient outward current prominent in canine ventricular epicardium but not endocardium.

Previous studies have denied the presence of a transient outward current (Ito) in ventricular myocardium of dog, sheep, and calf. Using conventional microelectrode techniques, we provide evidence for a significant contribution of Ito to epicardial, but not endocardial, activity of canine ventricular myocardium. The epicardial action potential when compared with that of endocardium shows a smaller phase 0 amplitude, a much more prominent phase 1, and a phase 2 amplitude that is greater than that of phase 0. Epicardial action potentials, unlike those of endocardium, display a "spike and dome" morphology that becomes progressively more accentuated at slower stimulation rates. Using the restitution of phase 1 amplitude as a marker for the process responsible for the spike and dome phenomenon, we were able to delineate two exponential components: 1) a slow component that recovers with a time constant of 350-570 msec and 2) a fast component with a time constant of 41-85 msec. The slow component was largely abolished by 1-5 mM 4-aminopyridine, an Ito blocker. The fast component was diminished by 4-aminopyridine, but it was also inhibited by ryanodine and by Sr2+ replacement of Ca2+, which are interventions known to inhibit the Ca2+-activated component of Ito. Following 4-aminopyridine and Sr2+ or ryanodine treatment, the epicardial responses more closely resembled those of endocardium. In summary, the data demonstrate a marked heterogeneity of active membrane properties in canine ventricular muscle. These observations may aid in understanding the basis for rate-dependent changes in the T wave of the ECG, supernormal conduction in ventricular muscle, the greater sensitivity of epicardium to ischemia, and the rate dependence of some cardiac arrhythmias.

4-Aminopyridine↗