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Department of Pharmacology, Center of Molecular Therapeutics, Columbia University, New York, New York 10032
Submitted 29 January 2004 ; accepted in final form 11 April 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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-adrenergic responsiveness of ICa,L exists between EBZ and remote cells of the 14-day hearts, but this regional heterogeneity is gone in the healed infarcted heart. In IZ14d, the transient outward K+ current (Ito) begins to reemerge and is accompanied by an upregulated tetraethylammonium-sensitive outward current. By 2-mo postocclusion, Ito and sustained outward K+ current have completed the reverse remodeling process. During the healing process post-MI, canine epicardial cells downregulate the fast Ito but compensate by upregulating a K+ current that in normal cells is minimally functional. For recovering ICa,L of the 14-day and 2-mo EBZ cells, voltage-dependent processes appear to be reset, such that ICa,L "window" current occurs at hyperpolarized potentials. Thus dynamic changes in both Ca2+ and K+ currents contribute to the altered AP observed in 14-day fibers and may account for return of APs of 2 mo EBZ fibers.
myocardial infarction
-adrenergic agonist, isoproterenol (Iso), and cAMP (2, 25). Action potentials (APs) recorded from 5-day EBZ fibers show no or reduced phase 1 consistent with the loss in the voltage-dependent transient outward current (Ito) (20). Altered APs of the EBZ cells from the 5-day infarcted heart continue to be altered by day 14 postocclusion (6, 26). However, by 2 mo, EBZ cell APs appear "normal," yet conduction of the wavefronts remains abnormal (26). This suggests that a very active process exists that restores ion channel function to these surviving epicardial cells. We hypothesize that the changes in transmembrane APs are due to a changing distribution of ion channels in density or function. Thus the goal of this study was to determine the changes in Ca2+ and K+ currents that occur in cells isolated from the 14-day (IZ14d) and 2-mo (IZ2m) EBZ area and compare them with changes in ion channel function occurring in cells from the same hearts but remote (Rem) from the EBZ.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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This investigation conforms to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Pub. No. 85-23, 1996).
Healthy male mongrel dogs (12–15 kg, 2–3 yr old) were used in these studies. Under isoflurane anesthesia (30 mg/kg), MI was produced by a two-step total occlusion of the left coronary artery using the Harris procedure (15). On 5 days (N = 5 dogs), 14 days (N = 24 dogs), and 2 mo (N = 15 dogs) after occlusion, the infarcted hearts were used for the myocyte study. Noninfarcted hearts were used for controls. Sham-operated animals were animals that had an operation but no occlusion was done. Sham animals were used for study 14 days (N = 5) and 2 mo (N = 4) post operation.
Myocyte Preparation
Single Ca2+-tolerant cells were dispersed from the epicardium sections with the use of a modification of our previously described method (20). The tissue was rinsed twice in a Ca2+-free solution that contained (in mM) 115 NaCl, 5 KCl, 35 sucrose, 10 dextrose, 10 HEPES, and 4 taurine, pH 6.95, to remove blood. The solution was then triturated in 20 ml of enzyme containing solution (0.38 mg/ml collagenase Type II from Worthington Biochemical; 0.05 mg/ml protease from Sigma; 36–37°C) for 30 min, after which the solution was decanted and discarded. The second trituration without the protease was discarded after 30 min. The next 6–7 triturations were each done for 15 min. Each time the solution was centrifuged for 3 min to collect the supernatant and dispersed cells. The resuspension solution was changed every 30 min for solutions containing increasing concentrations of Ca2+. With this procedure, the viable cell yield was 
30–40%. We used only rod-shaped cells with staircase ends, clear cross-striations, and surface membranes free from blebs for this study. Several groups of cells were studied. One group was cells dispersed from control noninfarcted left ventricular epicardium (NZs). Other groups comprised cells dispersed from the EBZ of the 5-day, 14-day, and 2-mo infarcted heart (IZ5d, IZ14d, and IZ2m, respectively), cells dispersed from left ventricular epicardial sections from a region remote from the infarct (Rem) in the 14-day and 2-mo healed hearts (Rem14d and Rem2m, respectively). Epicardial cells from EBZ area of sham-operated animals formed two groups corresponding to the 14-day and 2-mo time points (Sham14d and Sham2m, respectively).
Electrophysiological Studies
For study, an aliquot of cells was transferred onto a poly-lysine-coated glass coverslip placed at the bottom of a 0.5-ml tissue chamber, which had been mounted on the stage of an inverted microscope (Nikon Diaphot; Tokyo, Japan). Myocytes were continuously superfused (2–3 ml/min) with normal Tyrode solution containing (in mM) 137 NaCl, 24 NaHCO3, 1.8 NaH2PO4, 0.5 MgCl2, 2.0 CaCl2, 4.0 KCl, and 5.5 dextrose, pH 7.4. The solution was bubbled with 5% CO2-95% O2.
To measure Ca2+ currents, pipette resistances ranged between 1 and 2 M
when filled with an internal solution composed of (in mmol/l) 125 CsOH, 125 aspartic acid, 20 tetraethylammonium chloride (TEA), 10 HEPES, 5 Mg-ATP, 10 EGTA, and 3.6 phosphocreatine (pH 7.3 with CsOH). After the formation of the gigaohm seal, the stray capacitance was electronically nulled, the cell membrane under the pipette tip was ruptured, and, by a brief increase in suction, the whole cell recording configuration was then formed. A period of 10 min was then allowed for intracellular dialysis to begin before being switched to the nominal sodium-free recording solution composed of (in mmol/l) 5.0 CaCl2, 0.5 MgCl2, 140 TEA, 10 HEPES, 10 dextrose, and 2 4-aminopyridine (pH 7.3 with CsOH, 35.0 ± 0.5°C).
ICa,L magnitude was normalized by each cell's membrane capacitance (pF) and expressed as current density (pA/pF). Voltages were not corrected for the liquid junction potential between the bath and pipette solutions. When myocytes are dialyzed during whole cell recordings, there is the decrease of peak ICa,L with time. We (1) have previously established that rundown is similar in cells of the two groups. Thus, for these studies, we started data acquisition at similar times after membrane rupture and establishment of whole cell configuration (see figures).
Peak ICa,L at various test voltages (Vt) was measured as the difference between the maximal inward peak and the current level at the end of 250-ms voltage-clamp step. The time course of ICa,L decay was characterized by fitting the current change between the inward peak and the current level 250 ms after depolarization (Clampfit, pCLAMP, Axon Instruments) using a biexponential function. Steady-state inactivation variables of ICa,L were determined using a double-pulse protocol. For each cell, the peak current elicited at each test pulse was expressed as a fraction of the current obtained with the most negative conditioning prepulse potential (–70 mV, 1,000-ms duration) and a Boltzmann equation was used to fit data and to obtain the half-maximum inactivation voltage (V0.5) and slope factor (k) for each cell. Average values were used to determine the differences between cells from the different groups.
To measure K+ currents, patch pipette resistances equaled 1–2 M when filled with the internal solution composed of (in mM) 140 KCl, 1 MgCl2, 10 EGTA, 5 MgATP, 5 creatine phosphate, 0.2 GTP, and 10 HEPES, pH 7.2, with KOH. Cells were superfused with a Na+-free solution composed of (in mM) 144 N-methyl-D-glucamine-Cl, 5.4 KCl, 1 MgCl2, 2.5 CaCl2, 0.5 CdCl2, and 10 HEPES, pH 7.4, 30–31°C. Na+ currents were suppressed via use of a Na+-free solution. ICa,L was blocked with 0.5 mM Cd2+. Membrane currents associated with Na+/Ca2+ exchange were eliminated by the absence of external Na+. Currents were elicited by 210-ms voltage step to Vts of –50 and +60 mV from a holding potential of –60 mV at 0.1 Hz after a 10-ms prepulse to –90 mV to maximally activate Ito. Ito amplitude was determined as the difference between the peak current and that at the end of the pulse or as stated. The sustained outward K+ current (Isus) was taken as the amplitude of the current at the end of test pulse relative to zero-current level. Ito decay was fit with a double exponential function to estimate time constants of current decay. Steady-state inactivation relationships were determined using the following protocol: a 500-ms prepulse to various conditioning potentials between –90 and +20 mV, followed by a 210-ms test pulse to 60 mV. Because inactivation of the delayed rectifier K+ current contaminates Ito inactivation at the most negative voltage (4), only data obtained from potentials positive to –55 mV were used to fit with Boltzmann equation to get V0.5 and slope factor (k) of Ito for each cell. The time course of recovery from inactivation was evaluated with a paired-pulse protocol. Two identical 210-ms pulses with a holding potential of –80 to +40 mV were delivered with interpulse coupling intervals (IPI) that increased from 5 to 5,000 ms. The degree of recovery was determined by normalizing Ito at each IPI by the Ito at IPI 5,000 ms. The time course of recovery was estimated by fitting the data points to a biexponential function with the use of a simplex algorithm.
Drugs
Isoproterenol (Iso)-containing solutions were made on the day of the experiment from stock solution (1 mg/ml). TEA (Sigma) was dissolved in double-distilled H2O for stock solution. Flecainide (Sigma) was dissolved in DMSO at 100 mM and diluted in the external recording solution. TTX (Sigma) was dissolved in distilled H2O for stock solution and used on the day of the experiment.
Statistics
Data are presented as means ± SE. All data were tested using ANOVA for multiple comparisons. If significant changes occurred, group means were compared with the use of Bonferroni's method. P < 0.05 was significant.
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RESULTS |
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Like data for IZ5d (1), cells from IZ14d and IZ2m were significantly increased in cell size (by 46% and 29%, respectively) versus NZ and sham cells (Table 1). Cells from the remote regions (Rem14d and Rem2m) were not different from their respective IZ counterparts but were larger than NZ cells. In this dataset, as well as others, sham cells were similar to NZ cells. Therefore, here and in the remaining text, a reference is made only to differences from NZ values.
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-adrenergic responsiveness in cells from the healed infarcted hearts. Figure 3A shows an example of Ca2+ currents in the absence and presence of Iso in IZ14d and IZ2m. Note that there is a reduced fold effect of Iso in IZ14d cells versus that in Rem14d cells (Fig. 3B). Importantly, Iso has a large significant effect on ICa,L of IZ2m cells. In fact, the responses of Iso in Rem2m and IZ2m cells do not differ (Fig. 3B and Tables 5 and 6). Thus the difference in the response of ICa,L to Iso seen between the two regions of the 14-day infarcted heart (EBZ and remote areas) is gone by 2 mo after occlusion.
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For these studies, we focused on Ito and Isus induced by steps in voltage in IZ14d and IZ2m because in IZ5d we noted that there are diminished or no transient K+ currents (20). We compared IZ14d and IZ2m values with values obtained from cells from regions of same left ventricles but remote from the EBZ (Rem14d and Rem2m) and sham cells.
Figure 4, A and B, shows original current tracings for cells from the different groups. In Fig. 4, C and D, Ito and Isus average densities are shown for cells in all groups. Note that Ito density in IZ14d cells recovered to 8.97 ± 0.82 pA/pF (at +40 mV) compared with cells of IZ5d, where little or no Ito was observed (20). However, Ito in IZ14d remained significantly reduced compared with Rem14d (20 ± 2.0 pA/pF). There was no difference between sham, Rem, and NZ values. By 2 mo after occlusion, Ito in IZ2m returned toward NZ/Sham values and was no different compared with Rem2m (Fig. 4C). Isus did not differ in the cells of the different groups (Fig. 4D).
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If there is a change in the components of channel isoforms contributing to Ito and Isus in IZ14d and IZ2m, then we would predict a change in sensitivity to drugs that are selective for specific channel isoforms. Thus we determined the effects of TEA (5 mM) on the currents of IZ14d, IZ2m, and NZs. In this subset of cells, we found a small TEA-sensitive Ito in NZs, IZ14d, and IZ2M (Fig. 6A). However, in IZ14d with small, partially recovered Ito (Fig. 4), we found a significant increase in a TEA-sensitive Isus component (0.3 pA/pF at +40 mV) (Fig. 6B). Furthermore, when testing for TEA-sensitive currents in IZ5d, we determined there was also a considerable TEA-sensitive Isus in IZ5d. However, by 2 mo, TEA-sensitive currents in IZ2m are equivalent to NZs (0.04 pA/pF). Thus the recovered Ito of IZ14d appears to be accompanied by sevenfold increase in a TEA-sensitive sustained current.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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-adrenergic responsiveness of ICa,L exists between EBZ and remote cells of the 14-day hearts, it is gone in the healed infarcted heart (2 mo). Finally, in IZ14d cells, Ito begins to reemerge but it is accompanied by an upregulated TEA-sensitive outward current. Comparison With Other Studies on Ion Channel Function in Long-Term MI Models
Ca2+ current changes. Cells from the EBZ of the 5-day infarcted heart have reduced Ca2+ current density as well as reduced responsiveness to Iso as reported earlier (1, 2). These remodeled Ca2+ currents were accompanied by an acceleration in peak current decay and no change in availability. However, when cells are dispersed from different regions of the reentrant circuit of the 5-day EBZ, there are regional differences in ICa,L and its kinetics. Importantly, in cells from the center path of the reentrant circuit, ICa,L availability is shifted negatively and in the cells from the outer pathway, the time course of recovery of ICa,L from inactivation is slowed (10). The results of the current study suggest that ICa,L densities remain reduced in the cells from 14-day and 2-mo infarcted heart and the kinetic changes previously identified in the 5-day heart begin, but do not recover fully, to NZ values. An important point here is the finding that the Ca2+ currents in the EBZ and Rem regions of the healed heart show a slowed recovery from inactivation perhaps secondary to generalized hypertrophic signals. For example, this kinetic change would be consistent with an increase in the basal level of phosphorylation of the channel. However, the precise mechanism is beyond the scope of this study. This slowed recovery could lead to augmented frequency-dependent effects on ICa,L amplitude.
Myocytes adjacent to an 8-wk infarct in the rabbit heart showed a significant decrease in peak ICa,L without a change in the current-voltage relationship or gating parameters (19). In cats with a healed (2–4 mo) MI and CHF, there is marked disparity in refractoriness in subendocardial border adjacent to infarcted areas and remote areas, especially during sympathetic stimulation (23), and ICa,L was found to be reduced in both the hypertrophied remote and the MI area (endocardial) cells. Inactivation curves were shifted in a hyperpolarizing direction in both cell types but no differences in time course of recovery and decay were reported. Reduced -adrenergic responsiveness of ICa,L occurred in both remote and MI area cells in this study. Typically, the areas remote from the infarct scar show a tendency toward an increase in Ca2+ current amplitudes (23, 24); however, current densities (pA/pF) were reduced as a result of the increased cell capacitance of remote cells suggesting that channel protein expression did not exactly follow the increased plasmalemma of these hypertrophied cells. A longer-term study (3) in rats post-MI (4–6 mo) reported reduced peak Ca2+ current densities with no specific kinetic changes except for a slowing in peak current decay. Note that the cells studied in that report were from various regions of the infarcted ventricle and not necessarily from an EBZ or remote epicardial area.
Studies using cells dispersed from human hearts post-MI have been scarce. In a recent study (8), most human hearts were post-MI and cells were reported to have no change in basal ICa,L versus cells from normal hearts. Cells used in these studies were most probably from tissues remote from the healed scar of the previous infarct. The time postocclusion was not given in this report. Interestingly, ICa,L activation curves were shifted negatively in these diseased human cells much like our data for IZ14d and IZ2m cells. Unfortunately, other kinetic parameters such as steady-state inactivation relations and the time course of recovery from inactivation were not studied. Cells from post-MI human hearts also show a hypoadrenergic responsiveness of ICa,L to Iso similar to our data and other studies using animal models. However, in our study, we show that the regional heterogeneity in this hypoadrenergic response exists in the 14-day hearts and is gone in the healed (2 mo) heart.
ICa,T. In our previous work (1, 7) in cells from the MI canine heart, we reported ICa,T changes in both subendocardial cells from the 48-h heart and cells from the EBZ of the 5-day heart. Thus it is notable that there is an increase in T-type current density in IZ14d cells and not in IZ2m cells. In fact, we found that T-type currents existed in nearly all IZ14d studied. In rat healed (3–4 wk) MI cells, the T-type current was recorded in 35% of post-MI left ventricular cells, but channel expression had increased by 158% (16). However, it is important to note that ICa,T was not reported in the remodeled cells of the post-MI human heart (8). This may be because ICa,T manifestation is linked only at certain times to the ongoing process of cellular remodeling. Its function may be dedicated to a specific cell function (i.e., gene expression) and/or its reexpression in pathophysiological conditions (16, 21) related to levels of angiotensin II (11) and/or endothelin-1 (12).
Depolarization-activated K+ currents. The return of a voltage-dependent Ito in IZ14d is striking and obviously has occurred after day 5 postocclusion because we found no or little Ito in IZ5d (20). The important aspects of the newly emerged Ito in these EBZ cells are its small current density, its positive midpoint of inactivation, and slow recovery from inactivation. All these features are reminiscent of endocardial myocytes of the noninfarcted canine heart or epicardial cells in the presence of angiotensin (28). Furthermore, the pharmacology of Ito/Isus of IZ14d suggests that a portion of the "new" depolarization activated current is less sensitive to flecainide and more sensitive to TEA (see below).
In the rat post-MI model, two long-term studies have been reported. Kaprielian et al. (18) reported that, whereas action potential duration is prolonged in 2-mo post-MI cells, Ito is reduced more in the right ventricle than in septal cells and density changes were not linked to differences in gating parameters. No data were reported from EBZ or epicardial cells in that study. We report here that in the 2-mo heart, Ito in IZs and Rem do not differ from each other or sham/normal values. Thus, even in the presence of an increase in cell size (Table 1), Ito in canine epicardial cells 2-mo post-MI are reasonably normal. In another study (post-MI 4–6 mo, rat), Ito was reduced by 50% in all cell regions studied but gating parameters did not differ (3). Epicardial cells overlying the infarct were not sampled.
Human cell studies post-MI have not been done yet. In human heart failure, where some cases of heart failure were secondary to an MI, Ito is downregulated in left ventricular myocytes (17). However, it is still difficult to evaluate regional changes in Ito in human hearts. In no previous study of ventricular cells post MI has an augmented TEA-sensitive current been reported.
In summary, it appears that in the process of ionic remodeling of canine epicardial cells, early after coronary occlusion (5 days), Ito disappears and a sustained TEA-sensitive current emerges. By day 14, Ito reemerges in combination with the augmented TEA-sensitive current. By 2 mo postocclusion, Ito/Isus currents have completed a "reverse remodeling" process.
Implications of Pharmacology
As in other reports (9, 14), NZs and IZ2m show a 40% block of Ito with flecainide, consistent with a Kv4 isoform contributing to canine Ito (9). In IZ14d, we report here that the effect of flecainide is blunted in that only 27% of peak current was blocked. Thus it may be because there is less of a contribution of Kv4s to Ito in IZ14d.
In addition, and different from a previous report (14), we observed TEA-sensitive transients in NZs, IZ14d, and IZ2m. Furthermore, and differing from the observed effects in NZs, we saw an 18% inhibition of Isus with TEA in both IZ14d and IZ5d. Large TEA-sensitive currents were not seen in Rem or IZ2m cells. It is unlikely that these TEA-sensitive currents are due to Kv1.4 currents because the latter is not TEA sensitive. Rather, the emergence of augmented TEA-sensitive currents in these remodeled cells, where epicardial Ito has been downregulated, resembles the regional upregulation of TEA-sensitive Kv2.1 currents in ventricular cells of KvDN mice where fast Ito is suppressed and a slow Ito is induced (5, 13, 29). Interestingly, phorbol ester-induced hypertrophy in a cell monolayer system is associated with a downregulation of Kv4 subunits (and Ito) and an enhancement of Kv2.1 subunits (and TEA-sensitive Isus) (27). The changes in K+ current function in post-MI cells may be related to a robust PKC stimulation but only in cells of the EBZ of the 5- and 14-day hearts. Thus, during the healing process post-MI, canine epicardial cells downregulate the fast Ito, but compensate by upregulating a K+ current that in normal cells is minimally functional. In IZ14d, this augmented K+ current in the absence of a robust Ca2+ current would contribute to the shortened APs of these cells (6, 26).
Our results are surprising. First, despite the return of a normal-appearing AP in 2-mo EBZ fibers (26), Ca2+ currents remain abnormal, whereas Ito/Isus has regained full NZ like function. Perhaps these subtle differences could contribute to the restored AP plateau of 2-mo IZs. Cellular modeling of these changes is underway to test such. Second, the reverse remodeling process of the Ito/Isus currents is dynamic with changes in 5-day EBZ cells differing from changes in 14-day cells differing from changes in 2-mo cells and the lost and/or markedly inhibited Ito currents in the 5- and 14-day cells are accompanied by augmented TEA-sensitive currents.
Limitations
The changes in the fast/slow Na+ currents in EBZ cells post-MI are not included in this study. Changes in these currents could contribute to the abnormal impulse propagation in the EBZ of the healed infarcted heart as well as the AP changes of 2-mo EBZ fibers. Furthermore, we have not identified changes in Ca2+ and K+ currents in all regions of the remodeled heart but rather have focused on the changes in the substrate (the EBZ) where reentrant tachycardias have been mapped.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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subunit. Circ Res 83: 560–567, 1998.-adrenergic receptor complex in the epicardial border zone of the 5-day infarcted canine heart. Circulation 91: 2824–2833, 1995.This article has been cited by other articles:
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  E. Vigmond, F. Vadakkumpadan, V. Gurev, H. Arevalo, M. Deo, G. Plank, and N. Trayanova Towards predictive modelling of the electrophysiology of the heart Exp Physiol, May 1, 2009; 94(5): 563 - 577. [Abstract] [Full Text] [PDF]
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 T. J. Hund, P. J. Wright, W. Dun, J. S. Snyder, P. A. Boyden, and P. J. Mohler Regulation of the ankyrin-B-based targeting pathway following myocardial infarction Cardiovasc Res, March 1, 2009; 81(4): 742 - 749. [Abstract] [Full Text] [PDF]
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 A. Sridhar, Y. Nishijima, D. Terentyev, R. Terentyeva, R. Uelmen, M. Kukielka, I. M. Bonilla, G. A. Robertson, S. Gyorke, G. E. Billman, et al. Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2008; 295(5): R1463 - R1472. [Abstract] [Full Text] [PDF]
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 F. R. Heinzel, V. Bito, L. Biesmans, M. Wu, E. Detre, F. von Wegner, P. Claus, S. Dymarkowski, F. Maes, J. Bogaert, et al. Remodeling of T-Tubules and Reduced Synchrony of Ca2+ Release in Myocytes From Chronically Ischemic Myocardium Circ. Res., February 15, 2008; 102(3): 338 - 346. [Abstract] [Full Text] [PDF]
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 S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]
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 G. Antoons, P. G. A. Volders, T. Stankovicova, V. Bito, M. Stengl, M. A. Vos, and K. R. Sipido Window Ca2+ current and its modulation by Ca2+ release in hypertrophied cardiac myocytes from dogs with chronic atrioventricular block J. Physiol., February 15, 2007; 579(1): 147 - 160. [Abstract] [Full Text] [PDF]
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 T. Namiki, R. W. Joyner, and M. B. Wagner Developmental changes in time course of recovery from inactivation in L-type calcium currents of rabbit ventricular myocytes Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H295 - H303. [Abstract] [Full Text] [PDF]
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W. R. Mills, N. Mal, F. Forudi, Z. B. Popovic, M. S. Penn, and K. R. Laurita Optical mapping of late myocardial infarction in rats Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1298 - H1306. [Abstract] [Full Text] [PDF]
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P < 0.05 vs. IZ2m.
) of decay of Ito at various Vt potentials (Vts) in NZ (n = 66, N = 42), IZ14d (n = 40, N = 24), and IZ2m (n = 20, N = 15). Average 