© 1996 American Heart Association, Inc.
Articles |
A Cellular Mechanism Contributing to Postvagal Tachycardia Studied in Isolated Pacemaker Cells From Cat Right Atrium
the Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Ill.
Correspondence to Stephen L. Lipsius, PhD, Department of Physiology, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153.
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Abstract |
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Vagal nerve-induced inhibition of the heartbeat is followed by a postvagal increase in heart rate above control levels, postvagal tachycardia. In the present study, we used a perforated-patch/whole-cell recording method to determine the role of L-type Ca2+ current (ICa,L) and the hyperpolarization-activated inward current (If) in the positive chronotropic response elicited by withdrawal of acetylcholine (ACh). Experiments were performed on sinoatrial node (SAN) and latent atrial pacemaker (LAP) cells isolated from cat right atrium. Withdrawal of a 2-minute exposure to 1 µmol/L ACh elicited a rebound stimulation of ICa,L in both SAN (33±4%) and LAP (50±6%) cells above control. Similarly, withdrawal of ACh (1 µmol/L) elicited a rebound stimulation of If in both SAN (21±4%) and LAP (20±6%) cells. During the rebound stimulation of ICa,L, peak amplitude was increased throughout the voltage range, and the voltage dependence of activation was shifted to more negative voltages. Action potential recordings from both SAN and LAP cells showed that following ACh-induced inhibition, withdrawal of ACh elicited a concomitant rebound increase in action potential amplitude (+21±2% and +21±3%, respectively) and decrease in pacemaker cycle length (30±5% and 44±5%, respectively) compared with control. H-89 (2 µmol/L), an inhibitor of cAMP-dependent protein kinase A, abolished the rebound increase of ICa,L, If, action potential amplitude, and decrease in pacemaker cycle length elicited by withdrawal of ACh. In the presence of 2 mmol/L cesium, a blocker of If, the rebound decrease in pacemaker cycle length elicited by withdrawal of ACh was unchanged. We conclude that in SAN and LAP cells, withdrawal of ACh elicits a positive chronotropic response primarily through a cAMP-mediated rebound stimulation of ICa,L. These findings are the first demonstration of an intrinsic cellular mechanism that may contribute directly to the nonadrenergic component of postvagal tachycardia.
Key Words: perforated patch • cAMP • whole cell • Ca2+ current • pacemaker current
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Introduction |
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In vivo, vagal nerve-induced bradycardia is followed by a positive chronotropic response to levels above control, ie, PVT.1 This phenomenon has been demonstrated in several animal species, including dogs,2 cats,3 and humans.4 PVT has both adrenergic and nonadrenergic components. Multiple factors may contribute to both components. In relation to the adrenergic component, sympathetic fibers run concurrently within the vagosympathetic nerve trunk.5 Because NE degrades more slowly than ACh, termination of vagosympathetic nerve activity can result in a residual NE-induced stimulation of the pacemaker rate.2 Moreover, ACh may elicit the release of catecholamines from chromaffin cells in the region of the SAN.6 However, the fact that PVT persists after depletion of catecholamines in sympathetic nerves7 8 or after ß-adrenergic receptor block3 4 indicates the presence of a nonadrenergic component of PVT. In this regard, it has been reported that vagally induced tachycardia is more prominent at higher frequencies of nerve stimulation.9 These findings led to studies suggesting that corelease of neuropeptides from vagal nerve terminals,10 11 such as vasoactive intestinal polypeptide, may contribute a nonadrenergic component of PVT.
Recent work in our laboratory indicates that in cat atrial myocytes withdrawal of ACh elicits a rebound stimulation of ICa,L that is mediated via stimulation of the cAMP-signaling pathway.12 Because ICa,L is a primary determinant of atrial pacemaker activity, an ACh-induced rebound stimulation of ICa,L may contribute significantly to a nonadrenergic component of PVT. Similarly, because If is modulated by cAMP,13 14 it too may contribute to an ACh-induced rebound stimulation of atrial pacemaker activity. In the present study, therefore, we used a perforated-patch/whole-cell recording method to determine whether withdrawal of ACh elicits a rebound stimulation of ICa,L and If in atrial pacemaker cells and whether this mechanism contributes to a positive chronotropic response elicited by withdrawal of ACh.
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Materials and Methods |
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Details of the isolation and recording methods have been published previously.15 16 Briefly, adult cats of either sex were anesthetized with sodium pentobarbital (70 mg/kg IP). After excision, hearts were perfused via a Langendorff apparatus with 0.06% collagenase (Worthington Biochemical, type II). Following collagenase perfusion, the right atrium was isolated. The SAN region and the region containing LAPs16 were cut into small pieces and agitated in fresh collagenase and 0.01% protease. Cells were washed through a nylon mesh in 100 µmol/L Ca2+-HEPES Tyrode's solution and then slowly exposed to normal Ca2+ levels.
Cells used for study were transferred to a small (0.3-mL) tissue bath on the stage of an inverted microscope (Nikon Diaphot) and superfused with a modified Tyrode's solution containing (mmol/L) NaCl 137, KCl 5.4, MgCl2 1.0, CaCl2 2.5, HEPES 5, and glucose 11 and titrated with NaOH to a pH of 7.4. Solutions were perfused by gravity at 
5 mL/min, and experiments were performed at 35±1°C. Cells selected for study exhibited morphological and functional features typical of atrial pacemaker cells, ie, small diameters (<10 µm), elongated, tapered ends, a single central nucleus, and beating rhythmically.15 16 Only cells that exhibited If in response to hyperpolarizing clamp steps were used in the present study. Voltage and ionic currents were recorded using a nystatin-perforated patch17 whole-cell recording method.18 This method minimizes dialysis of intracellular constituents with the internal pipette solution and rundown of pacemaker activity.16 Nystatin was dissolved in dimethyl sulfoxide at a concentration of 50 mg/mL and then added to the internal pipette solution to yield a final nystatin concentration of 150 µg/mL. The internal pipette solution contained (mmol/L) potassium glutamate 100, KCl 40, MgCl2 1.0, Na2-ATP 4, EGTA 0.5, and HEPES 5 and was titrated with KOH to a pH of 7.2. When recording ICa,L, Cs+ replaced K+ in the internal pipette solution, and 20 CsCl was added to the external solutions to block ACh-activated K+ current. When recording If, external solutions contained 1 mmol/L Ba2+ to block ACh-activated K+ currents. Cells that exhibited ACh-activated K+ currents were not studied. When filled with internal solution, pipettes had resistances of 2 to 3 M
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A single suction pipette was used to record voltage (bridge mode) or ionic currents (discontinuous voltage-clamp mode) using an Axoclamp 2A amplifier (Axon Instruments, Inc). In the voltage-clamp mode, the sample rate was 10 to 12 kHz. A second scope was used to monitor the duty cycle to ensure complete settling of the voltage transient between samples. Computer software (PClamp, Axon Instruments, Inc) was used to deliver voltage protocols and to acquire and analyze data. Signals also were digitally recorded on VCR tape. ICa,L was activated by depolarizing voltage-clamp steps from a holding potential of -40 mV (to inactivate fast Na+ channels) to 0 mV for 200 milliseconds at 0.5 Hz. The voltage dependence of ICa,L activation was determined by delivering depolarizing voltage-clamp pulses in 10-mV increments every 2 seconds. If was activated by hyperpolarizing clamp steps from a holding potential of -50 mV. Current densities (pA/pF) were determined by normalizing currents to total cell capacitance.16 Mean cell capacitance for SAN cells was 27±4 pF (n=9) and for LAP cells was 22±1 pF (n=21). Total action potential amplitude was measured from the maximum diastolic potential to the peak of action potential upstroke. Pacemaker cycle length was measured as the average of 10 consecutive cycles. In some experiments, a biotachometer (Gould) was used to monitor changes in pacemaker cycle length. Drugs used in this study included ACh chloride, ISO, atropine, propranolol (Sigma Chemical Co), and H-89 (Seikagaku America, Inc). Statistical significance of paired and unpaired data was determined by Student's t test at values of P<.05. Data are expressed as mean±SEM.
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Results |
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Fig 1
shows original traces of ICa,L recorded from an SAN pacemaker cell (panel A) and consecutive measurements of peak ICa,L amplitude obtained throughout the experiment (panel B). ICa,L was recorded before, during, and after a 2-minute exposure to 1 µmol/L ACh. The letters a through d in panel B correspond to the selected currents shown in panel A. Under control conditions, SAN pacemaker cells exhibited a basal peak ICa,L current density (8.4±0.9 pA/pF, n=9) that was not different from that in LAP cells (8.3±0.9 pA/pF, n=21). Interestingly, these values are about twofold larger than those exhibited by cat atrial myocytes (4.6±0.4 pA/pF, n=16). Exposure to ACh elicited a typical decrease in basal ICa,L amplitude (b). As shown in the graph, within 30 seconds of withdrawing ACh, peak ICa,L exhibited a marked rebound increase above the control value (c). ICa,L amplitude recovered to baseline levels within 5 minutes (d). The rebound increase in ICa,L was evident throughout the voltage range tested (see Fig 3). In a total of 9 SAN cells studied, ACh decreased ICa,L by 27±5% (at 0 mV), and withdrawal of ACh elicited a rebound increase of ICa,L by 33±4% above control (P<.05). Similar results were obtained in 21 LAP cells studied; ACh decreased ICa,L by 24±3%, and withdrawal of ACh elicited a rebound increase of 50±6% above the control value (P<.01). The time course of recovery of ICa,L to baseline in LAP cells was similar to that in SAN cells. Both the inhibitory and rebound stimulatory effects of ACh were prevented by 1 µmol/L atropine and unchanged by 1 µmol/L propranolol. These findings indicate that in atrial pacemaker cells withdrawal of ACh elicits a rebound stimulation of ICa,L similar to that reported in cat atrial myocytes.12
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), during (
), and after (
) the rebound stimulation of ICa,L elicited by the withdrawal of ACh. During rebound stimulation, peak ICa,L amplitude increased throughout the voltage range, and maximum peak ICa,L shifted negative by
ACh exerted qualitatively similar effects on If. Fig 1
, panel C shows original If currents recorded from an SAN pacemaker cell, and panel D shows consecutive measurements of the changes in time-dependent If induced by a 2-minute exposure to 1 µmol/L ACh. Under control conditions, basal time-dependent If current densities measured at -120 mV were not significantly different between SAN (-5.3±0.4 pA/pF, n=7) and LAP (-4.2±0.6 pA/pF, n=8) cells. To block ACh-activated K+ currents, pacemaker cells were exposed to 1 mmol/L Ba2+. Interestingly, Ba2+ significantly decreased the time-dependent inward current, and the block was more effective at less negative voltages. In 7 SAN cells, Ba2+ decreased inward current by 54±8% at -80 mV and 25±4% at -120 mV. Presumably, the Ba2+-insensitive time-dependent inward current is If. Exposure to 1 µmol/L ACh for 2 minutes decreased (b) and withdrawal of ACh rebound increased If elicited at both -80 and -120 mV (c). Recovery of If to baseline required 3 minutes (d). In a total of 7 SAN cells studied, ACh decreased If by 19±1% (at -120 mV) and elicited a rebound increase of 21±4% above control (P<.05). Similar results were obtained in a total of 8 LAP cells studied; ACh decreased If by 21±4%, and rebound increased If by 20±6% above control (P<.05). The time course of If recovery was similar in LAP and SAN pacemaker cells. All effects of ACh were prevented by 1 µmol/L atropine and unchanged by 1 µmol/L propranolol. Clearly, the ACh-induced rebound stimulation of If was significantly smaller than that of ICa,L.
Our previous findings in atrial myocytes indicated that the rebound stimulation of ICa,L elicited by withdrawal of ACh is due to a rebound stimulation of cAMP.12 It seemed likely, therefore, that the same mechanism was responsible for the rebound stimulation of ICa,L and If in atrial pacemaker cells. As shown in Fig 2, this idea was examined by testing ACh in the absence (panels A and C) and presence (panels B and D) of 2 µmol/L H-89, a potent antagonist of cAMP-dependent protein kinase A.19 Panels A and C show typical responses of ICa,L and If, respectively, to a 2-minute exposure and then withdrawal of 1 µmol/L ACh. Exposure to ACh inhibited and withdrawal of ACh stimulated each current. H-89 alone elicited a small decrease in basal ICa,L (panel B), whereas If (panel D) was unchanged. Interestingly, in the presence of H-89, 1 µmol/L ACh still decreased both ICa,L and If. This was a consistent finding in both SAN and LAP cells. H-89, however, abolished the rebound stimulation of ICa,L and If typically elicited by the withdrawal of ACh. Similar results were obtained in a total of 4 SAN pacemaker cells and 4 LAP cells. The present results indicate that in atrial pacemaker cells, the rebound stimulatory effects of withdrawing ACh are mediated via cAMP, as reported for atrial myocytes.12 Although not the focus of the present study, the present findings also suggest that in cat atrial pacemaker cells, ACh-induced inhibition of ICa,L and If may not be mediated primarily via the inhibition of cAMP. This latter conclusion will require further study.
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The ability of H-89 to block the rebound stimulation of ICa,L is similar to that obtained in atrial myocytes,12 where H-89 or Rp-cAMPs, a more selective inhibitor of protein kinase A,20 abolished the rebound response. To further establish that H-89 is acting specifically through inhibition of cAMP-dependent protein kinase A, we tested the ability of H-89 to block the stimulatory effects of ISO on ICa,L. In 4 SAN pacemaker cells, 0.2 µmol/L ISO increased peak ICa,L amplitude throughout the voltage range and elicited a 10-mV negative shift in maximum peak ICa,L (not shown). ISO increased ICa,L by 85% (at +10 mV), comparable to the ACh-induced rebound increase in ICa,L at this voltage. In the presence of 2 µmol/L H-89, reexposure to 0.2 µmol/L ISO failed to elicit any significant increase in ICa,L.
If cAMP is mediating the rebound stimulation of ICa,L, then the voltage dependence of ICa,L activation should be shifted to more negative voltages,21 as described above for ISO. This was determined by delivering depolarizing voltage pulses before, during, and after the post-ACh rebound period. The graph in Fig 3 shows mean data obtained from 6 SAN pacemaker cells. Under control conditions, ICa,L activation exhibited typical features, with the maximum peak ICa,L at +20 mV (-10.4±1.5 pA/pF). When the same voltage protocol was repeated 30 seconds after withdrawal of ACh, peak ICa,L was increased throughout the voltage range, and maximum peak ICa,L was shifted negatively to +10 mV (-18.6±1.7 pA). After 5 minutes, the I-V relationship returned to control values. A similar 10-mV negative shift in ICa,L activation was obtained during the rebound response in LAP cells (n=3). These findings are similar to those reported in atrial myocytes12 and provide further support for cAMP as the primary mediator responsible for the rebound increase in ICa,L elicited by withdrawal of ACh.
Because ICa,L and If are thought to contribute to both SAN22 and LAP function,23 we investigated whether a rebound stimulation of these currents may contribute to a positive chronotropic response elicited by withdrawal of ACh. Fig 4 shows spontaneous SAN pacemaker action potentials recorded in the absence (panel A) and presence of 2 µmol/L H-89 (panel B). Under control conditions, spontaneous pacemaker rate was 50 bpm. Exposure to ACh (1 µmol/L) for 2 minutes (solid bar) suppressed pacemaker activity, although a few spontaneous beats appeared during ACh exposure. Withdrawal of ACh initiated a slow depolarization and a rapid initial return of pacemaker activity. However, within 20 seconds of withdrawing ACh, a second component appeared that exhibited a concomitant increase in action potential amplitude and pacemaker rate above control levels. Pacemaker rate reached a maximum of 128 bpm and then slowly returned to control levels within 3 minutes. In panel B, the same protocol was repeated on another SAN pacemaker cell in the presence of 2 µmol/L H-89. This particular cell exhibited a basal pacemaker rate of 85 bpm. Once again, following ACh-induced inhibition of pacemaker activity, the withdrawal of ACh initiated a slow depolarization and a return of pacemaker activity. In the presence of H-89, however, the rebound increase in action potential amplitude and pacemaker rate was abolished. In a total of 7 SAN pacemaker cells studied, withdrawal from a 2-minute exposure to 1 µmol/L ACh decreased pacemaker cycle length from 893±62 to 616±51 milliseconds (30±5%) and increased action potential amplitude by 21±2% compared with control. Similar results were obtained in a total of 7 LAP cells; withdrawal of ACh decreased pacemaker cycle length from 1293±67 to 721±87 milliseconds (44±5%) and increased action potential amplitude by 21±3%. These findings also show that basal SAN pacemaker cycle length is significantly shorter than that of LAPs, as reported in multicellular pacemaker preparations.24 H-89 abolished the rebound increase in action potential amplitude and decrease in pacemaker cycle length elicited by withdrawal of ACh in all SAN (n=4) and LAP (n=5) cells studied.
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A consistent finding of the present experiments is that withdrawal of ACh elicits a larger rebound stimulation of ICa,L than of If. Therefore, it seemed likely that ICa,L contributes relatively more than If to the positive chronotropic response elicited by withdrawal of ACh. To examine this point, we tested the effects of ACh in the presence of 2 mmol/L Cs+. Cs+ blocks If in SAN pacemakers13 and LAP cells.16 In the present study, we performed four additional experiments and confirmed that external 2 mmol/L Cs+ completely blocked If at voltages compatible with the maximum diastolic potential in both types of pacemaker cells (not shown). Action potential recordings from a total of 4 SAN pacemaker cells showed that Cs+ had no effect on the rebound decrease in pacemaker cycle length elicited by withdrawal of ACh (27±5% [control] versus 25±4% [Cs+]). Similar results were obtained in a total of 3 LAP cells (35±3% [control] versus 33±5% [Cs+]). These results suggest that under the present conditions, rebound stimulation of If does not contribute significantly to the positive chronotropic response elicited by the withdrawal of ACh.
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Discussion |
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The main findings of the present study are that withdrawal of ACh elicits a rebound stimulation of ICa,L, If, and pacemaker rate in both SAN pacemaker and LAP cells. These effects of ACh are mediated via muscarinic receptors and a rebound stimulation of cAMP. To the best of our knowledge, this is the first demonstration of a "PVT" response at the level of a single pacemaker cell. In addition, these findings provide evidence of an intrinsic cellular mechanism that may contribute directly to the nonadrenergic component of PVT.
Several mechanisms have been proposed to explain both the adrenergic and nonadrenergic components of PVT.1 The importance of the present findings is that a positive chronotropic response elicited by withdrawal of ACh has been demonstrated in isolated single pacemaker cells. Clearly, these cells are completely denervated and devoid of any adjacent chromaffin cells containing catecholamines. This precludes the possibility that the underlying mechanism is due to the neural release of NE or neuropeptides or to ACh-induced release of catecholamine stores. The present results indicate that the effects of ACh withdrawal are mediated by a rebound stimulation of cAMP-regulated ionic currents that govern atrial pacemaker activity. Thus, the rebound stimulations of ICa,L, If, and pacemaker rate each followed similar time courses of onset and decay. In addition, the rebound stimulation of ICa,L is associated with a negative shift in the voltage dependence of activation, similar to that elicited by ISO and reported for ß-adrenergic regulation of ICa,L.21 Moreover, inhibition of the effects of cAMP by H-89 abolished all stimulatory effects of ACh withdrawal, ie, rebound stimulation of ICa,L, If, action potential amplitude, and pacemaker rate. Our more extensive studies of ACh-induced regulation of ICa,L in atrial myocytes indicate that the rebound stimulation of ICa,L elicited by the withdrawal of ACh is due to recovery of endogenous cAMP at a time when phosphodiesterase activity is still inhibited by the prior exposure to ACh.12 Withdrawal of ACh elicits a similar rebound stimulation of ICa,L in guinea pig cardiac Purkinje fibers.25 The rebound response in Purkinje fibers, however, occurred only in the continuous presence of ß-adrenergic agonist.25 Because ß-adrenergic stimulation enhances cAMP levels, these experiments support the idea that cAMP underlies the stimulatory rebound response to ACh withdrawal. Moreover, direct measurements of cAMP in chick heart cells have demonstrated that withdrawal of ACh elicits a rebound stimulation in cAMP concentration.26 Taken together, the present results indicate that cAMP-mediated increases in ICa,L and to a lesser extent If are responsible for the positive chronotropic response elicited by withdrawal of ACh.
The present findings indicate that the rebound stimulation of ICa,L is significantly greater than that of If and that If contributes little to the post-ACh-induced increase in rate. It was not possible to directly determine the relative contribution of ICa,L because pharmacological block of ICa,L completely suppresses pacemaker action potentials. However, the idea that ICa,L plays a larger role than If is supported by the relative lack of sensitivity of If to endogenous cAMP compared with that of ICa,L. Thus, exposure of cat SAN pacemaker cells to 50 µmol/L isobutylmethylxanthine, a nonselective phosphodiesterase inhibitor, elicited an 87% increase in ICa,L compared with only a 15% increase in If (n=2; authors' unpublished data, 1996). Moreover, as shown in the present study, inhibition of the effects of cAMP by H-89 decreased basal ICa,L but had no effect on basal If. In addition, the functional importance of ICa,L is evident in that action potential amplitude and pacemaker rate rebound increased concurrently. We propose, therefore, that the rebound stimulation of ICa,L elicited by withdrawal of ACh is a primary mechanism contributing to the nonadrenergic component of PVT. Although If contributed little under the present conditions, it may play more of a role under conditions in which the cAMP-signaling pathway is stimulated by background ß-adrenergic tone.
In the present study, LAP cells exhibited a greater percent rebound increase in pacemaker rate than did SAN pacemaker cells. This is due primarily to the fact that basal LAP rate is significantly lower than basal SAN pacemaker rate. Nevertheless, these findings suggest that LAPs may be more sensitive than SAN pacemakers to the stimulatory effects of withdrawing ACh. This could be related to differences in their sensitivities to ACh, cAMP, and/or the ionic current mechanisms responsible for each type of pacemaker activity. In fact, the present results show that the rebound stimulation of ICa,L was greater in LAP than in SAN pacemaker cells. In addition, LAP activity appears to be more dependent than SAN activity on ICa,L to trigger SR Ca2+ release and thereby stimulate Na+-Ca2+ exchange current during diastole.27 Therefore, a rebound stimulation of ICa,L may exert more of a stimulatory effect on latent than primary pacemaker activity. As a result, termination of vagal stimulation may initiate pacemaker shifts to and/or premature atrial depolarizations at sites outside of the SAN region. In addition, our previous work has shown that low concentrations of ß-adrenergic stimulation accentuate the rebound stimulation of ICa,L elicited by ACh withdrawal.12 In this way, background ß-adrenergic stimulation exerted by circulating catecholamines may accentuate the rebound stimulation of atrial pacemaker activity elicited by the withdrawal of ACh. This adrenergic/postcholinergic interaction may be responsible, at least in part, for an adrenergic component of PVT. Through a similar mechanism, ß-adrenergic tone may enhance the development of atrial premature beats initiated by the withdrawal of vagal nerve stimulation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL-27652 and a Cardiology Endowment Fund grant, Loyola University Medical Center. We thank C. Rechenmacher for her expert technical assistance with these experiments.
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Footnotes |
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Previously published in part in abstract form (Biophys J. 1995;68:12).
Received December 4, 1995; accepted April 2, 1996.
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References |
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Y. G. Wang, A. M Samarel, and S. L Lipsius Laminin acts via {beta}1 integrin signalling to alter cholinergic regulation of L-type Ca2+ current in cat atrial myocytes J. Physiol., July 1, 2000; 526(1): 57 - 68. [Abstract] [Full Text] [PDF]
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J. Huser, L. A Blatter, and S. L Lipsius Intracellular Ca2+ release contributes to automaticity in cat atrial pacemaker cells J. Physiol., April 15, 2000; 524(2): 415 - 422. [Abstract] [Full Text] [PDF]
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 Y. G. Wang, C. E. Rechenmacher, and S. L. Lipsius Nitric Oxide Signaling Mediates Stimulation of L-Type Ca2+ Current Elicited by Withdrawal of Acetylcholine in Cat Atrial Myocytes J. Gen. Physiol., January 1, 1998; 111(1): 113 - 125. [Abstract] [Full Text] [PDF]
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D. W. Wallick, A. Kuguoglu, T. Yang, S. L. Stuesse, and M. N. Levy Effects of ionic channel antagonists barium, cesium, and UL-FS-49 on vagal slowing of atrial rate in dogs Am J Physiol Heart Circ Physiol, November 1, 1997; 273(5): H2155 - H2160. [Abstract] [Full Text] [PDF]
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 Y.G. Wang, J. Huser, L.A. Blatter, and S.L. Lipsius Withdrawal of Acetylcholine Elicits Ca2+-Induced Delayed Afterdepolarizations in Cat Atrial Myocytes Circulation, August 19, 1997; 96(4): 1275 - 1281. [Abstract] [Full Text]
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