Regional Differences in Transient Outward Current Density and Inhomogeneities of Repolarization in Rabbit Right Atrium
Background Recent experimental and clinical studies on atrial flutter have demonstrated that the crista terminalis (CT) plays an important role in the genesis of atrial reentry. To elucidate the underlying mechanism of its role, we characterized the electrophysiological repolarization properties of CT cells by comparing them with those of the pectinate muscles (PM).
Methods and Results After action potential properties of both regions were compared by conventional microelectrode technique in multicellular atrial tissues, the whole-cell clamp experiments were applied in atrial cells isolated from both regions. Action potential duration (APD) was more prolonged in CT than in PM in multicellular preparations (APD90 77±5 ms versus 52±8 ms at 1 Hz, P<.01), though the other properties did not differ significantly. Similarly, in isolated atrial cells, APD was more prolonged in CT cells than in PM cells (APD90 63±7 ms versus 41±6 ms at 0.1 Hz, P<.01). Isolated single cells were larger in CT than in PM. The whole-cell clamp recordings showed no definite distinctions in the density of the voltage-dependent L-type Ca2+ current and the inwardly rectifying K+ current between these cells but revealed a significant reduction of the density of the 4-aminopyridine–sensitive transient outward current (Ito) in CT cells compared with that in PM cells (6.3±0.7 pA/pF versus 10.3±0.8 pA/pF at +20 mV, P<.05). However, no differences in the kinetics or the voltage dependence of Ito were observed between the cells. The time course of recovery from inactivation of Ito was also similar in both types of cells.
Conclusions These results suggest that the preferential reduction in the density of Ito in the CT cells could contribute to prolong their APD, which may be related to the genesis of atrial reentry.
Recent progress in catheter ablation technique has made it possible to ablate reentrant arrhythmias.1 2 3 Because the target for catheter ablation has been focused on the slow conduction area in the reentrant circuit, the electrophysiological and anatomic basis for slow conduction is mandatory for successful elimination of the arrhythmias. Many experimental and clinical studies on atrial flutter have recently demonstrated that the anatomic architecture in the right atrium plays an important role in the genesis of atrial reentry.4 5 6 7 8 9 10 The CT in the right atrium, which is both a unique anatomic structure of the right atrium and physiologically a preferential conduction pathway from the sinus node to the right atrium,11 provides an area for conduction block and delay, leading to initiation, maintenance, and termination of atrial flutter.4 5 6 7 8 9 10 11 12 13
Conduction disturbances at initiation of reentrant arrhythmias are believed to result from alterations in cell electrophysiological properties and/or anisotropic conduction caused by alterations in cell-to-cell couplings.14 Whether the former or the latter alone can cause atrial reentry is not yet certain. Therefore, it is necessary to clarify electrophysiological characteristics of the CT from both viewpoints. In the present study, we focused on repolarization characteristics of the CT, known to be the area for unidirectional block at initiation of atrial flutter.6 7 8 12 13 To have an insight into the mechanism of the important role of the CT in the genesis of atrial flutter, we compared cellular electrophysiological properties between the CT and PM, using conventional glass microelectrode technique in multicellular atrial tissues and also whole-cell voltage-clamp technique in isolated atrial cells.
New Zealand White young rabbits weighing 1.0 to 1.2 kg (≈3 months of age) were used in the present study.
The rabbits were anesthetized with secobarbital 50 to 75 mg IV. The hearts were rapidly removed and perfused for 10 minutes with modified Tyrode solution aerated with 95% O2+5% CO2. Thereafter, the right atrial free wall was excised and pinned to the Sylgard-covered bottom of a 10 mL chamber with endocardial side facing upward. The preparation was then superfused with modified Tyrode solution at a rate of 15 mL/min. The superfusate temperature was maintained at 37°C. One hour was allowed for tissue equilibration before the experiments. APs were recorded from both the CT and PM in the mid right atrium by use of a conventional glass microelectrode technique. A glass microelectrode filled with 3 mol/L KCl and with tip resistance of 5 to 20 MΩ was connected to a high-impedance microelectrode amplifier (MEZ-7200, Nihon Kohden).
Single Cell Preparation
Single atrial cells were enzymatically isolated as reported previously.15 16 Rabbits were anesthetized and the dissected heart was mounted on a Langendorff apparatus and perfused for 7 to 8 minutes with nominally Ca2+-free Tyrode solution containing 120 to 160 μg/mL collagenase (Yakult Ltd) at a perfusion pressure of 80 cm H2O. Thereafter, the enzyme-containing solution was flushed out with storage solution. The right atrium was excised, and the endocardial tissues of the CT and PM regions were separated from other regions visually with a razor. Endocardial side was chosen to correlate data in single cells with data in multicellular preparations, because epicardial cells are known to have different electrophysiological properties from endocardial cells.17 Single cells in each region were obtained by gentle shaking, kept in the storage solution at 4°C for at least 1 hour before use, and dispersed in a recording chamber filled with normal Tyrode solution. Only rod-shaped and quiescent single cells were selected for the experiments. All experiments were performed at 33 to 35°C.
Electrophysiology With Single Cells
APs and ion currents were studied in the whole-cell configuration as described by Hamill et al and Kurachi et al18 19 20 with a patch-clamp amplifier (EPC 7, List) that was interfaced with a personal computer. The signals were filtered at a bandwidth of DC-1 kHz and stored on a videotape by a PCM converter system (RP-880, NF Electronic Circuit Design). Electrodes fabricated from 1.0 mm ID capillary tubes had a resistance of 0.5 to 2 MΩ when filled with internal pipette solution. Pipette current was adjusted to zero just before it was placed on the cell. The input membrane resistance and capacitance of the cell were measured by applying either a small hyperpolarizing current in the current-clamp condition or a −10-mV step pulse in the voltage-clamp condition. The potential response in the former was fitted to a simple exponential curve, whereas in the latter, capacitive transfer and steady state current level were measured. The values of resistance and capacitance obtained from these different methods were very similar.
The modified Tyrode solution used in the multicellular experiments consisted of (mM) NaCl 121, KCl 5.0, NaHCO3 24, MgCl2 1.0, Na2HPO4 1.0, glucose 5.0, CaCl2 1.8, pH 7.4 after equilibration with 95% O2+5% CO2. The normal Tyrode solution used in single-cell experiments consisted of (mmol/L) NaCl 136.5, KCl 5.4, HEPES 5.5, Na2HPO4 0.33, glucose 5.5, CaCl2 1.8, MgCl2 0.53, pH 7.4 adjusted with NaOH. The storage solution contained (mmol/L) glutamic acid 70, KCl 25, KH2PO4 10, taurine 10, oxalic acid 10, glucose 11, EGTA 0.5, HEPES 10, pH 7.4 adjusted with KOH. The internal pipette solution contained (mmol/L) KCl 130, ATPK2 5, HEPES 5, MgCl2 1, EGTA 3, pH 7.2 adjusted with KOH.
Data Acquisition and Analysis
Membrane potentials and current signals replayed from videotapes were converted either onto a recorder or to the analog-digital board for digitization. The digitized data were analyzed with dss4 software programs (Canopus) in multicellular data and with the p-clamp program (Axon Instruments) in single-cell data. To record Ito, 0.3 mmol/L CdCl2 and TTX 10 μmol/L were added to the Tyrode solution in all the experiments. The amplitude of Ito was measured as the difference between the peak of Ito and the value of the current at 200 ms. In some experiments, the 4-AP–sensitive current was measured by subtracting the current in the presence of 2 mmol/L 4-AP from that in its absence (Fig 1⇓). As indicated in Fig 1⇓, 4-AP did not significantly change the current at 200 ms at any command voltage pulses and the 4-AP–sensitive current as shown in Fig 1B⇓ subsided to almost zero at 200 ms. From these observations, it is reasonable that we could determine Ito as the difference between the peak current and the value of the current at 200 ms. The difference between the peak amplitude of ICa in control and that after application of 0.3 mmol/L CdCl2 was considered to be a measure of the amplitude of the voltage-dependent ICa. The amplitude of Ito, ICa, and IK1 was normalized to the cell membrane capacitance. The voltage-dependent inactivation of Ito was studied with the use of double-pulse protocol. The conditioning voltage pulses (500 ms in duration) to various membrane potentials between −80 and +20 mV were applied from a holding potential of −80 mV. At 10 ms after the end of each conditioning pulse, a test pulse to +20 mV (500 ms in duration) was applied to evoke Ito. The ratio of the amplitude of Ito with or without the conditioning pulse was plotted for the membrane potential of each conditioning pulse. The interval between the sets of double pulses was 30 seconds. The time course of recovery of Ito from inactivation (reactivation) was also studied by a double-pulse protocol. The first pulse (PI, 500 ms in duration) was applied from a holding potential of −80 mV. Then, with a varying interpulse interval, the second pulse (PII, 500 ms in duration) was again applied. The reactivation time course was quantified by calculating the percent of decrease in Ito amplitude during the second pulse (percent of inactivation) and plotting this value on a semilogarithmic scale against the interpulse interval. The data were simply fitted by an exponential. Data are expressed as mean±SD. Student’s t test was used for comparison between mean values. Statistical significance was set at a value of P<.05.
In multicellular preparations of atrial free wall, APs from the CT were found to be consistently prolonged in duration from those from the PM (Table 1⇓, Fig 2A⇓), as described in a previous report with canine right atrium.14 Other AP characteristics, including resting membrane potential, maximal upstroke velocity of APs, and AP amplitude, did not differ between the two regions. APD at a stimulation rate of 1 Hz was longer at both early and late repolarization phases in the CT [APD50: 38±7 ms (n=10) versus 18±4 ms (n=10), P<.01; APD90: 77±5 ms (n=10) versus 52±8 ms (n=10), P<.01]. Similar results were obtained from single cells isolated separately. A typical AP configuration recorded at a stimulation rate of 0.1 Hz was illustrated in a cell isolated from the PM (Fig 2B⇓a, left) and CT (Fig 2B⇓b, left). APD50 was 15±6 ms (n=13) versus 35±7 ms (n=13) in PM cells and CT cells, respectively. APD90 of the CT cells was also more prolonged in duration than that of the PM cells [41±6 ms (n=13) and 63±7 ms (n=13), P<.01]. Thus, AP recorded from the CT cells showed a relatively long plateau phase, while that from the PM had a triangle morphology, resulting in prolongation of APD of the CT cells. To investigate the ionic mechanisms underlying the difference of AP shapes between these cell types, the effects of 4-AP were examined in a cell isolated from the PM (Fig 2B⇓a) and the CT (Fig 2B⇓b). As indicated in Fig 2B⇓, 4-AP 2 mmol/L markedly increased the plateau phase and prolonged the APD in both types of cells. 4-AP prolonged the APD in PM cells in particular, and the AP configuration of the PM cells approached that of the CT cells. These observations suggest that the different AP configuration in these types of cells may be attributable mainly to the 4-AP–sensitive current (Ito).
The single cells from the CT were significantly larger in size from those of the PM (Table 2⇓), while the ratio of length and width were similar between the two types of cells. The capacitance of single cells and input resistance were measured under voltage-clamp condition. As indicated in Table 2⇓, the CT cells showed a significant increase in cell capacitance compared with the PM [134±22 pF (n=20) versus 42±13 pF (n=20), P<.01]. Also, the CT had a lower input resistance. The characteristics of cell morphology in the CT cells were compatible with the previous report.21
L-type Calcium Current
To compare the ICa in the two cell types, we determined current-voltage relations in the CT and PM using voltage steps for 500 ms from the holding potential of −40 mV (Fig 3A⇓).15 To minimize contamination of Ito, 3 mmol/L 4-AP was added to the bathing solution.15 21 Ca2+-sensitive Ito that was not blocked did not distort the peak of ICa.22 As indicated in Fig 3B⇓, the current-voltage relations represented by the current density were almost superimposable in the CT cells (n=10) and PM cells (n=10). Thus, the current density of ICa measured from the zero current did not significantly differ between the two cells. Also, the amplitude of ICa was obtained by the difference between the peak amplitude of ICa in control and after application of Cd2+ 0.3 mmol/L, and the density of ICa was determined by dividing the current amplitude by each cell capacitance as indicated in Fig 4⇓. The density of peak ICa was not significantly altered in the CT and PM cells [6.6±1.2 pA/pF (n=10) versus 7.4±1.0 pA/pF (n=10), P=NS].
Steady State Properties
The steady state membrane properties were determined with discontinuous voltage steps for 500 ms from the holding potential of −40 mV (Fig 3A⇑). Currents measured at the end of pulses were consistently larger in the CT cells than in the PM cells. The voltage of the current being zero did not differ between the cells, which is compatible with the findings that the resting membrane potential in the two cells was similar as shown in Table 1⇑. Steady state current density did not show any difference between the two types of cells at each voltage <+40 mV (Fig 3B⇑). Because no time-dependent currents were observed at voltages <−50 mV, the result suggested no difference in the IK1 density between the cells. Though the slight increase in steady state current at voltages >+30 mV in the CT was considered to be due to contamination of delayed rectifier K+ current, we did not recognize it as a major determinant of the APD because it was induced only by the pulses of high voltage and long duration.
Transient Outward Current
Rabbit atrial cells have a remarkable Ito that affects APs in a way similar to that in human atrial cells.15 21 23 We compared the Ito density between the two types of cells using voltage steps for 500 ms from the holding potential of −80 mV as shown in Fig 5A⇓. To minimize overlapping of ICa and INa, 0.3 mmol/L Cd2+ and 10 μmol/L TTX were added to the bath solution. Ito has been known to consist of two components.24 25 26 Because the transient outward components were totally blocked by 5 mmol/L 4-AP in our experimental conditions with 0.3 mmol/L Cd2+ in the bathing solution and 5 mmol/L EGTA in the pipette as in the previous reports,22 23 24 25 26 27 we considered this component as a Ca2+-insensitive and 4-AP–sensitive current. The fact that Cd2+ changes the kinetics and voltage dependence of Ito modified the present results28 but did not interfere in the purpose of the present study. A representative recording and current-voltage relations are shown in Fig 5⇓. The CT cells showed a smaller initial peak Ito compared with that from the PM at any command voltages >0 mV. Therefore, Ito density estimated from the difference between the initial outward peak and the current at 200 ms of the pulses was more decreased in the CT cells (n=10) than in the PM cells (n=10) at command voltages >−10 mV (Fig 4C⇑). The current-voltage relations of Ito showed linear relation in both types of cells, and the voltage dependence of Ito activation did not differ. The measured densities of IK1, ICa, and Ito are summarized in Fig 4⇑. The density of IK1, ICa, and Ito was estimated from the current at −120 mV, the peak ICa, and the Ito at +20 mV, respectively. The voltage-clamp experiments in single cells revealed that there was a statistically significant difference (P<.05) of Ito density in single cells from the CT and the PM. The density of Ito was 6.3±0.7 pA/pF and 10.3±0.8 pA/pF in the cells isolated from the CT and PM, respectively. Next, we determined the kinetics and voltage dependence of Ito in both cells.
Kinetics and Voltage Dependence of Ito
Ito activation time course and its inactivation time course could be evaluated with TTP and the τ of current decay (Fig 6A⇓). TTP was measured as time from the depolarizing step to the peak Ito. We calculated τ by fitting the decay of Ito with double exponential functions. TTP and τ showed no differences between the two cell types and were similar to those reported previously,23 though TTP was much longer than that without Cd2+.28
The voltage dependence of inactivation of Ito was determined by two-step voltage pulses: the first was a conditioning pulse to voltages from −80 to 20 mV for 500 ms from the holding potential of −80 mV, and the second was a test pulse to 20 mV with a delay of 10 ms after the first pulse. The interval between each test pulse was 30 seconds. The peak amplitude of Ito at each test pulse was normalized to the maximal amplitude of Ito. The normalized Ito was plotted against the conditioning voltages (Fig 6B⇑). The normalized values were fitted to a Boltzmann distribution equation. The steady state voltage dependence of Ito inactivation was similar between the two cell types. The CT cells showed the mean voltage at half inactivation of −40.8±4.5 mV and the slope factor of 7.7±0.6 mV (n=5), while the PM ones showed −40.3±3.9 mV and 7.4±0.8 mV (n=5), respectively. The voltage of half inactivation was lower than that in the previous report21 for the rabbit CT probably because of the difference in concentration of Cd2+ used.
The time course of recovery of Ito from inactivation (reactivation) was also investigated by a double-pulse protocol. Two command pulses from a holding potential of −80 mV were applied with a varying interpulse interval. Fig 7A⇓ shows a typical example of a cell isolated from the PM. Ito was absent with an interpulse interval of 10 ms and increased gradually as interval was prolonged in both types of cells (Fig 7B⇓). In Fig 7C⇓, the reactivation time course was quantified by calculating the percent of decrease in Ito amplitude during the second pulse (percent of inactivation) and plotting this value on a semilogarithmic scale against the pulse interval. The reactivation time course could be approximately described by a single exponential function in both cell types. The reactivation time constant was 738±120 ms (n=6) in CT cells and 728±110 ms (n=6) in PM cells (P=NS).
The major findings of the present study were (1) APD was significantly more prolonged in the CT than in the PM in both multicellular preparations and isolated single cells. (2) Cells in the CT were larger in size than those in the PM. (3) Whole-cell voltage-clamp recordings revealed a significant decrease in the density of Ito in the CT cells compared with that in the PM cells, though the kinetics and voltage dependence of Ito were not different between the two types of cells.
Differences in Ito
Using conventional microelectrode technique, Spach et al14 reported that inhomogeneities of repolarization exist in the canine right atrium. Also, the present study clearly illustrated that inhomogeneities of repolarization exist between the CT and PM in the rabbit right atrium. Moreover, the data of single cells using the whole-cell clamp technique suggested that the prolongation of the APD in the CT could be ascribed to intrinsic properties of single cells but not to electrotonic interactions of some specialized fibers. AP recorded from the CT showed a relatively long plateau phase, while that from the PM had a triangle morphology. While application of 4-AP (Fig 2⇑) or the increase of stimulation rate from 1 Hz to 3 Hz (data not shown) increased the plateau phase and prolonged the AP in both types of cells, the APD in the PM cells was more prolonged than in the CT cells and the AP configuration in the former approached that in the latter. These observations strongly suggest that the difference in the APD between the CT and PM is mainly attributable to some differences in Ito in these cells. In the present study, using the whole-cell clamp technique, we have characterized Ito in these two types of cells. The measured density of Ito was decreased in the CT cells and not in the PM cells, although the voltage dependence of activation and steady state inactivation, and kinetics of activation, inactivation, and reactivation did not differ between the two types of cells. Therefore, the difference in the APD was possibly ascribed to a preferential reduction of Ito channel density in the CT cells, not to modified properties of the single channel. Similar results regarding the modification of Ito channel expression have been reported in other specimens. In both canine atrium and ventricle, epicardial cells have more density of Ito channel than endocardial ones.23 36 37 38 Ventricular cells from acromegalic rats are larger in size and have less density of Ito channel than normal cells.39 These reports also have ascribed the change in the APD to a change in the density of Ito channel, not to any changes in the intrinsic channel properties.
Our results demonstrate a difference in the density of Ito in different regions of the rabbit right atrium (CT and PM). The density of Ito was 6.3±0.7 pA/pF in the CT cells and 10.3±0.8 pA/pF at +20 mV (33 to 35°C) in the PM cells. In rabbit ventricular cells, Fedida and Giles38 reported that the density of Ito in epicardial, endocardial, and papillary muscle cells was 7.66 pA/pF, 6.45 pA/pF, and 3.69 pA/pF, respectively, at +20 mV at 35°C. Thus, the current density of Ito in the CT cells is somewhat similar to that reported in rabbit ventricular cells isolated from endothelium or papillary muscle. The density of Ito in the PM cells was much higher than that reported in rabbit ventricular cells,38 which supports the observations of Giles and Imaizumi15 that the density of Ito is lower in ventricular than in atrial cells from the rabbit.
Role of Anatomic Architecture in the Right Atrium
A possible physiological role and cause of the decreased density of Ito in the CT should be discussed. In normal conditions, the CT is the earliest activation site next to the sinus node in the right atrium.11 30 If the atrial cells had almost the same APD irrespective of their locations, this different activation time would lead to different repolarization time, ie, early activation and repolarization in the CT and late activation and repolarization in the PM. However, prolongation of APs in the CT would shorten or cancel the time lag of repolarization time between the CT and PM caused by the different activation, resulting in the simultaneous repolarization of the whole atrium. This would lead to effective contraction of the atrium and at the same time to prevention of reentrant arrhythmias. However, in some pathological conditions that may damage rapid conduction through the CT as demonstrated in human atrial flutter31 and a canine or rabbit model,17 32 these regional inhomogeneities in repolarization may exert an arrhythmogenic effect by providing an area of conduction block from the PM to the CT. Without the early activation of the CT, its prolonged repolarization time, which would be caused by its prolonged APD and its late activation, would fascilitate the conduction block around the CT. This consideration is consistent with the fact that unidirectional block at initiation of atrial reentry always occurred around the CT in canine experimental atrial flutter including the sterile pericarditis model5 6 and our crista ligation model.4 7 Apart from the initiation of atrial reentry, however, the role of Ito should be limited in its maintenance, because Ito channel is almost inactivated rate dependently at a high frequency such as atrial flutter.
In regard to the cause, there are some circumstantial differences between the CT and PM. First, the CT has an embryological origin different from that of the PM.40 CT originates in the right valve of the sinus venosus, while the PM originates in the right atrium. Second, the location of the CT that is fixed by the superior and inferior venae cavae at both ends might make it more difficult to weaken the wall stresses on it than those on the PM. The present results and the previous works might raise a hypothesis that the expression of Ito channel in a cell might be modified dynamically by the circumstances where it lives, by stretch, or by other regional factors including embryological origin. However, this is within the realm of speculation and remains to be determined by future studies.
The present study has several limitations. First, cells that had spontaneous pacemaker activity, which was observed in approximately 10% of the cells, were excluded in the present study. This was more frequently observed in the cells isolated from the CT,21 and their roles remain unknown. Secondly, Ca2+-sensitive 4-AP–insensitive Ito (Ito2), which is known to be Cl− current in rabbit hearts,23 28 was not determined in the present study. Its density was difficult to measure because it is affected by the rundown of ICa.28 No differences in ICa density and relatively small amounts of Ito2 in the previous reports23 28 would make the role of Ito2 minimal in the differences in APD but not negligible, particularly at a high frequency rate. Though limited for these reasons, we believe that the present results provide understanding of the mechanisms underlying the regional inhomogeneities of repolarization in the right atrium, which may be related to the genesis of atrial reentry.
Selected Abbreviations and Acronyms
|ICa||=||inward L-type Ca2+ current|
|IK1||=||inwardly rectifying K+ current|
|Ito||=||transient outward current|
|TTP||=||time to peak current|
This work was partly supported by grants to N. Nakajima from the Ministry of Education, Science and Culture of Japan.
- Received January 20, 1994.
- Revision received May 17, 1995.
- Accepted July 5, 1995.
- Copyright © 1995 by American Heart Association
Feld GK, Fleck RP, Chen PS, Boyce K, Bahnson TD, Stein JB, Calisi CM, Ibarra M. Radiofrequency catheter ablation for the treatment of human type 1 atrial flutter: identification of a critical zone in the reentrant circuit by endocardial mapping techniques. Circulation. 1992;86:1233-1240.
O’Nunain S, Linker NJ, Sneddon JF, Debbas NMG, Camm AJ, Ward DE. Catheter ablation by low energy DC shocks for successful management of atrial flutter. Br Heart J. 1992;67:67-71.
Shimizu A, Nozaki A, Rudy Y, Waldo AL. Multiplexing studies of effects of rapid pacing on the area of slow conduction during atrial flutter in canine pericarditis model. Circulation. 1991;83:983-994.
Inoue H, Yamashita T, Usui M, Nozaki A, Sugimoto T. Antiarrhythmic drugs preferentially produce conduction block at the area of slow conduction in the re-entrant circuit of canine atrial flutter: comparative study of disopyramide, flecainide, and E-4031. Cardiovasc Res. 1991;25:223-229.
Yamashita T, Inoue H, Nozaki A, Kuo T, Usui M, Sugimoto T. Role of anisotropy in determining the selective action of antiarrhythmics in atrial flutter in the dog. Cardiovasc Res. 1992;26:244-249.
Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria: a mechanism for both preventing and initiating reentry. Circ Res. 1989;65:1612-1631.
Wang Z, Fermini B, Nattel S. Repolarization difference between guinea pig atrial endocardium and epicardium: evidence for a role of Ito. Am J Physiol. 1991;260:H1501-H1506.
Nakajima T, Kurachi Y, Ito H, Takikawa R, Sugimoto T. Anti-cholinergic effects of quinidine, disopyramide, and procainamide in isolated atrial myocytes: mediation by different molecular mechanisms. Circ Res. 1989;64:297-303.
Zygmunt AC, Gibbons WR. Properties of the calcium-activated chloride current in heart. J Gen Physiol. 1992;99:391-414.
Shibata EF, Drury T, Refsum H, Aldrete V, Giles W. Contribution of a transient outward current to repolarization in human atrium. Am J Physiol. 1989;257:H1773-H1781.
Tseng G, Hoffman BF. Two components of transient outward current in canine ventricular myocytes. Circ Res. 1989;64:633-647.
Escande D, Coulombe A, Faivre JF, Deroubaix E, Coraboeuf E. Two types of transient outward currents in adult human atrial cells. Am J Physiol. 1987;252:H142-H148.
Zygmunt AC, Gibbons WR. Calcium-activated chloride current in rabbit ventricular myocyte. Circ Res. 1991;68:424-437.
Agus ZS, Dukes ID, Morad M. Divalent cations modulate the transient outward current in rat ventricular myocytes. Am J Physiol. 1991;261:C310-318.
Schoels W, Gough WB, Restivo M, El-Sherif N. Circus movement atrial flutter in the canine sterile pericarditis model: activation patterns during initiation, termination, and sustained reentry in vivo. Circ Res. 1990;67:35-50.
Hiraoka M, Sano T. Role of sinoatrial ring bundle in internodal conduction. Am J Physiol. 1976;231:319-325.
Leier CV, Meacham JA, Schaal SF. Prolonged atrial conduction time: a major predisposing factor for the development of atrial flutter. Circulation. 1978;57:213-216.
Allessie MA, Bonke FIM, Schopman FJG. Circus movement in rabbit atrial muscle as a mechanism of tachycardia, II: the role of nonuniform recovery of excitability in the occurrence of unidirectional block, as studied with multiple microelectrodes. Circ Res. 1976;39:168-177.
Spach MS, Miller WT, Dolber PC, Kootsey M, Sommer JR, Mosher CE. The functional role of structural complexities in the propagation of depolarization in the atrium of the dog: cardiac conduction disturbances due to discontinuities of effective axial resistivity. Circ Res. 1982;50:175-191.
Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle: a model of reentry based on anisotropic discontinuous propagation. Circ Res. 1988;62:811-832.
Litovsky SH, Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. Circ Res. 1988;62:116-126.
Furukawa T, Myerburg RJ, Furukawa N, Bassett AL, Kimura S. Differences in transient outward currents of feline endocardial and epicardial myocytes. Circ Res. 1990;67:1287-1291.
Xu XP, Best PM. Decreased transient outward K+ current in ventricular myocytes from acromegalic rats. Am J Physiol. 1991;260:H935-H942.
Yater WM. Variations and anomalies of the venous valves of the right atrium of the human heart. Arch Path. 1929;7:418-441.