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J Appl Physiol 90: 1327-1333, 2001;
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Vol. 90, Issue 4, 1327-1333, April 2001

Endurance training alters outward K+ current characteristics in rat cardiocytes

Korinne N. Jew, M. Charlotte Olsson, Eric A. Mokelke, Bradley M. Palmer, and Russell L. Moore

Department of Kinesiology and Applied Physiology, The University of Colorado Cardiovascular Institute, University of Colorado, Boulder, Colorado 80309-0354


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The effect of endurance run training on outward K+ currents with rapidly inactivating (Ito) and sustained or slowly inactivating (Isus) characteristics was examined in left ventricular (LV) cardiocytes isolated from sedentary (Sed) and treadmill-trained (Tr) female Sprague-Dawley rats. Isolated LV cardiocytes were used in whole cell patch-clamp studies to characterize whole cell Ito and Isus. Peak Ito was greatest in cells isolated from the Tr group. When Ito was corrected for cell capacitance to yield a current density, most, but not all, of the Sed vs. Tr differences in Ito magnitude were eliminated. Regardless of how Ito was expressed (e.g., Ito or Ito density), the time required to achieve a peak value was markedly shortened in the cardiocytes isolated from the Tr group. Training elicited a reduction in Isus density. Action potential characteristics were determined in Sed and Tr cardiocytes in primary culture. Training did not affect resting membrane potential, whereas peak membrane potential was reduced and time to peak membrane potential was prolonged in the Tr group. In addition, time to 50% repolarization was significantly increased in cells from the Tr group. Collectively, these data indicate that Ito and Isus characteristics are altered by training in isolated LV cardiocytes. These alterations in Ito and Isus may be responsible, at least in part, for the training-induced alterations in action potential configuration in cardiocytes in primary culture.

action potential; potassium currents


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE VENTRICULAR ACTION POTENTIAL and a number of the membrane currents associated with it respond adaptively to a variety of physiological and pathophysiological states. In rat ventricle, voltage-activated outward K+ currents are known to be involved in both early and late action potential repolarization. Although there is some recent evidence that up to four distinct voltage-gated K+ currents may exist in rat ventricle (7), repolarizing K+ currents have been historically subdivided into two primary components on the basis of kinetic and pharmacological criteria (4). One component displays rapidly activating and inactivating characteristics, is classically referred to as the transient outward current (Ito), and is thought to be involved in early action potential repolarization. The other component displays slowly inactivating or sustained current characteristics, has been referred to as Isus (17, 19) [or Ilate (7)], and is likely involved in later action potential repolarization. Both of these outward K+ current components (i.e., Ito and Isus) are known to be altered by a variety of experimental and pathophysiological challenges, and these alterations are thought to underlie some of the changes in action potential configuration that are observed under these conditions (10-12, 17-19, 22, 23).

Interestingly, action potential prolongation in rat ventricular myocardium has been reported to occur in several models of endurance training (6, 21), but the ionic basis for this adaptation has not been identified. From the few studies that have addressed this general issue, it appears that endurance training does not significantly affect the intrinsic characteristics of the slow, inward (L-type) Ca2+ current (ICa) and may suppress forward sarcolemmal Na+/Ca2+ exchange activity in intact cardiocytes (13, 15). Both are known to be important in defining the shape of the ventricular action potential (2).

In view of these findings and the general observation that repolarizing K+ currents exhibit considerable plasticity in a variety of experimental and pathophysiological settings (10-12, 17-19, 22, 23), it is reasonable to hypothesize that training-induced adaptations in the ventricular action potential might be associated with training-induced alterations in these currents.

The purpose of this study was to examine the effect of endurance training on Ito and Isus characteristics in single cardiocytes isolated from the rat left ventricle (LV). The data presented herein indicate that endurance training elicits adaptations in single cardiocyte Ito and Isus characteristics that are consistent with some, but not all, of the changes observed in single cardiocyte action potential configuration.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animal Model

Female Sprague-Dawley rats (3-4 mo old) were randomly assigned to a sedentary (Sed) group (n = 9) or a run-trained (Tr) group (n = 10). All animals were housed in a 12:12-h light-dark cycle and given standard rat chow and water ad libitum. Animals in the Tr group underwent at least 20 wk of treadmill running. During the first 6 wk, daily running duration began at 10 min and was prolonged biweekly in 10-min intervals; running grade was 5%, and treadmill speed ranged from 20 to 28 m/min. During the next 6 wk, running grade was increased to 10%, and treadmill speed ranged from 20 to 35 m/min. The final training protocol consisted of treadmill running 5 days/wk up a 10% grade for 1 h/day at 20 m/min for 15 min, 28 m/min for 30 min, and 35 m/min for 15 min. All animals were 9-11 mo of age when killed for cardiocyte isolation, at which time the adrenal glands and spleen were dissected and weighed; the plantaris muscle was dissected, homogenized, and assayed for citrate synthase activity (20). This study was conducted under the guidelines accepted by the American Physiological Society and received prior approval from the Institutional Animal Care and Use Committee at the University of Colorado, Boulder campus.

Cardiocyte Isolation

Cardiocytes were obtained from the LV and septal-free wall by methods previously described in detail (14). All chemicals and reagents were acquired from Sigma Chemical (St. Louis, MO) unless otherwise noted. Isolated cardiocytes were suspended in growth media and seeded onto laminin-coated (10 µg/ml) glass coverslips and incubated at 37°C in a 5% CO2-21% O2 (balance N2) environment. All cardiocyte experiments were performed between 2 and 8 h postdispersion and at ambient temperatures of 24-26°C.

Measurement of Ito

Measurements of Ito were recorded from cardiocytes of five Sed rats (2-5 cells sampled per animal) and six Tr rats (3-5 cells sampled per animal). Glass coverslips were removed from the growth medium and placed on the stage of an inverted microscope (Olympus). The external bathing solution contained (in mM) 130 choline chloride, 10 NaCl, 5.4 KCl, 0.5 CaCl2, 0.5 MgCl2, 0.3 CdCl2, and 0.5 HEPES at pH 7.4. Current recordings were made using fire-polished, low-resistance (1.3-2.5 MOmega ) glass pipettes containing an internal buffer composed of (in mM) 120 potassium aspartate, 20 KCl, 5 Na2ATP, 1 MgCl2, and 5 HEPES, pH 7.2 with KOH. The very low external Na+ concentration minimized the recording of significant inward Na+ and Na+/Ca2+ exchange currents, and the inclusion of CdCl2 in the external buffer was designed to suppress slow, inward Ca2+ and Na+/Ca2+ exchange currents (8). The Ito resulting from voltage steps from -90 to +45 mV was found to be sensitive to 4-aminopyridine; 1 mM 4-aminopyridine was sufficient to completely abolish the transient current without significantly suppressing the remaining sustained current. Whole cell currents were elicited and amplified using the Axopatch 1D amplifier (Axon Instruments, Foster City, CA) in voltage-clamp mode and recorded onto a personal computer using pCLAMP 5.0 software (Axon Instruments). Whole cell current recordings were analyzed for peak current, Isus, i.e., mean current over the last 10 ms of a voltage step, peak minus Isus, i.e., Ito, time to peak Ito, and time to 25%, 50%, 75%, and 90% reduction in Ito. An example of a recorded whole cell current and those characteristics used in this study are presented in Fig. 1.


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  		Fig. 1.   Examples of recorded whole cell currents over voltage steps from -60 to 45 mV and associated characteristics. Outward K+ current (Ito) was defined as the difference between the peak current and the sustained current, (Isus), which was measured as the average current in the last 10 ms of the voltage step. Time to peak Ito (TTP) and times to 25, 50, 75, and 90% return from peak Ito (T25, T50, T75, and T90, respectively) were determined relative to time of voltage step initiation.

Current-voltage relationship. Cardiocytes were voltage clamped to a holding potential of -90 mV, and Ito was recorded during 10 voltage steps of 1-s duration, which were delivered at 0.5 Hz and ranged from -75 to +45 mV in 15-mV increments. Each voltage step was preceded by a transient, rectangular 10-mV hyperpolarizing pulse, and the resulting current data were used to estimate cell capacitance as previously described (13). The current measurements reported here were made 1 min after gaining electrical access to each cardiocyte.

Steady-state inactivation. Steady-state inactivation characteristics of Ito were examined using a two-pulse protocol. The first 500-ms pulse consisted of 11 voltage steps from the -90-mV holding potential to voltages ranging from -80 to +20 mV in 10-mV increments. These initial voltage steps were immediately followed by a second 500-ms step to +60 mV.

Ito recovery. Ito recovery characteristics were examined using a double-pulse protocol that was qualitatively similar to that previously described for studying ICa inactivation (13). Briefly, two 500-ms maximally activating voltage steps (-90 to +60 mV) were separated by intervals of variable duration. Over the course of 10 episodes, the interpulse interval was increased in increments of 15 ms from 15 to 150 ms. Ito recovery was expressed as the magnitude of Ito elicited during the second voltage step relative to that elicited during the first voltage step.

Measurement of Action Potentials

Action potential characteristics of individual LV cardiocytes were assessed as previously described (22). Briefly, cardiocytes were bathed in an external solution containing (in mM) 140 NaCl, 4 KCl, 1 CaCl2, 10 HEPES, and 1 MgCl2, pH 7.4 with NaOH. Action potential recordings were made using fire-polished glass pipettes (0.5-1.5 MOmega ) containing an internal buffer composed of (in mM) 140 KCl, 1 MgCl2, 5 HEPES , 5 Na2ATP, and 0.1 mM EGTA, pH 7.2 with KOH. Action potentials were elicited with 1.25-ms maximally activating current pulses delivered at a frequency of 0.5 Hz and amplified using the Axopatch 1D amplifier (Axon Instruments) in current-clamp mode. Recorded membrane potentials were analyzed for resting potential (Vrest), maximum membrane potential (Vmax), time to Vmax, times to 25%, 50%, and 90% repolarization, and times to 40 and 20 mV above Vrest during repolarization. All times were determined relative to the end of the 1.25-ms current injection.

Data Analysis

Electrophysiological data analysis was performed using custom-made IDL 4.0 software (Research Systems, Boulder, CO). Statistical analyses were performed using SPSS 6.1 software (SPSS, Chicago, IL). Simple between-group (Sed vs. Tr) analyses were conducted using a Student's t-test. Intra- and interanimal variabilities in myocyte electrophysiological data were not significantly different. Between-group comparisons across multiple voltage steps were made using a repeated measures ANOVA. All data are presented as means ± SE. To reduce the possibility of committing a type II interpretive error, i.e., a false negative, significance was reported at both the P < 0.05 and P < 0.10 levels (25).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animal Model

Training did not significantly affect body weight, tibia lengths, adrenal weights, or spleen weight in these animals (Table 1). These results are consistent with previous studies in our laboratory using female Sprague-Dawley rats (13-16). Citrate synthase activities of plantaris muscle homogenates and the mean capacitance of LV cardiocytes were significantly increased by run training. Collectively, these data provide verification that our treadmill-training protocol was effective in producing a trained state without eliciting overt signs of stress in this animal model, as has been described previously (13-16).

                              
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  		Table 1.   Characteristics of rats used in isolated cardiocyte experiments

Ito vs. Voltage Relationship

Run training generally elicited an increase in Ito ("training" main effect: P = 0.09) during voltage steps between -60 and 45 mV (Fig. 2A). Independent t-tests revealed a significant increase in Ito for the Tr group at voltage steps to -30 and -15 mV (P < 0.05) and to 0 and 15 mV (P < 0.10). The training ANOVA main effect was abolished when peak Ito was corrected for cell capacitance, i.e., current density, although there was still significantly higher Ito densities for the Tr group at voltage steps of -30 and -15 mV (P < 0.05; Fig. 2B).


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  		Fig. 2.   Ito vs. voltage relationship. Cardiocytes were voltage-clamped with a holding potential of -90 mV. A: Ito was found to be greatest in the trained (Tr) group and was specifically enhanced during voltage steps to -30, -15, 0, and 15 mV. Sed, sedentary group. B: Ito density tended to be greater in the Tr cells, particularly at voltage steps to -30 and -15 mV. n = 27 Sed and 25 Tr cells isolated from 7 and 9 hearts, respectively. *P < 0.05 and dagger P < 0.10.

Temporal Characteristics of Ito

Time to peak Ito was generally shorter in the Tr group than in the Sed group (ANOVA training main effect: P = 0.019, Fig. 3). This training-induced reduction in the time to peak Ito was most evident at voltage steps to -30 and -15 mV. Times to 25%, 50%, 75%, and 90% return from peak Ito to baseline did not significantly differ between Tr and Sed groups.


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  		Fig. 3.   Temporal characteristics of Ito vs. voltage relationship. TTP was generally shorter in the Tr group than in the Sed group (ANOVA "training" main effect, P < 0.05). TTP was specifically shorter at voltage steps to -30 and -15 mV (ANOVA simple effects, dagger P < 0.10). n = 27 Sed and 25 Tr cells isolated from 7 and 9 hearts, respectively.

Steady-State Inactivation of Ito

The inactivation of Ito was characterized by a Boltzmann distribution, which was fitted to the Ito in the second pulse normalized to that in the first pulse using a nonlinear, least-squares fit routine. The parameter V0.5 represented the voltage at which one-half of the Ito was inactivated, and k described the slope factor, i.e., the voltage sensitivity of Ito inactivation around V0.5 (9, 22). Values for V0.5 and k were not different between groups and imply that the steady-state voltage inactivation properties of channels that are responsible for Ito were not affected by run training (Table 2).

                              
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  		Table 2.   Steady-state inactivation and recovery characteristics of Ito

Recovery of Ito

The temporal recovery of Ito was characterized by the exponential time constant, tau , which provided the best least-squares fit of a single exponential function to the interpulse interval dependence of Ito. The tau  was not found to differ between the Sed and Tr groups (Table 2).

Isus vs. Voltage Relationship

Training elicited a significant reduction in Isus density that was particularly evident at voltage steps between -60 and +30 mV (P < 0.05) (Fig. 4).


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  		Fig. 4.   Isus density vs. voltage relationship. Cardiocyte Isus density was significantly reduced in Tr myocytes compared with Sed myocytes (Sed vs. Tr was P < 0.05 at the voltage steps indicated and P < 0.10 at all other steps). Sample sizes are as indicated in Fig. 2.

Action Potential

Characteristics of the cardiocyte action potential were significantly affected by run training (Fig. 5 and Table 3). Although Vrest was not affected by run training, Vmax was significantly reduced in the Tr group. Time to Vmax was also prolonged in the Tr group.


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  		Fig. 5.   Representative examples of cardiocyte action potentials recorded from Sed and Tr rats. In general, action potentials in the Sed group demonstrated significantly greater overshoot and a shorter time to peak membrane potential. Although times to percent repolarization were longer in the Tr group, times to absolute values of membrane potential above resting membrane potential were comparable between groups, as indicated by the similar records after 20 ms.


                              
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  		Table 3.   Effects of run training on characteristics of cardiocyte action potentials

Although some temporal characteristics of repolarization were found to be greater in the Tr group, the duration of the action potential was generally similar between Sed and Tr groups. As depicted in Table 2, times to 25 and 50% repolarization were longer in the Tr group. However, because Vmax was reduced in the Tr group, these times to repolarization may be inappropriate for quantifying the duration of the action potential. The times to 40 and 20 mV above Vrest during repolarization were not found to be different between the Sed and Tr groups. These latter results, in addition to the similar times to 90% repolarization (Fig. 5 and Table 3), imply that overall action potential duration was not markedly affected by run training.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The results of this study indicate that run training elicits 1) an increase in the rate at which peak Ito magnitude is attained, 2) a small but significant alteration in peak Ito density, and 3) a reduction in Isus density in response to controlled membrane voltage steps. Alterations in Ito characteristics were not associated with significant training-induced alterations in Ito steady-state inactivation characteristics or in fractional Ito recovery properties following prior current activation. At the single cardiocyte level, the types of training-induced alterations that were observed in Ito and Isus characteristics would be expected to exert influence on early and late action potential repolarization. Because there is no evidence that the intrinsic characteristics of the slow inward ICa is affected by training (13), the early occurrence of peak Ito and the reduction of Isus density in Tr cardiocytes would be predicted to affect the amplitude and shape of the early and later repolarizing phases of the ventricular action potential, respectively.

Examination of single cardiocyte action potential characteristics revealed that training elicited an overall suppression in action potential amplitude during all phases. It seems unlikely that Ito alterations had a significant effect on the reduction in the amplitude of phase 0 (i.e., Vmax) of the action potential in Tr myocytes. This is because the fast inward Na+ current responsible for phase 0 of the action potential is transiently activated and inactivated in only several milliseconds, whereas peak Ito is achieved ~15-30 ms after depolarization of the sarcolemma. The simplest hypothetical explanation for the Tr-induced reduction in the amplitude of phase 0 of the action potential is that there was a decrease in the magnitude of Na+ current.

Because Ito is thought to be a key determinant of early action potential repolarization, it seems logical that the earlier onset of Ito in Tr myocytes would be expected to exert earlier repolarizing influences and to affect the shape of phase 2 (and 3) of the action potential. However, because peak action potential amplitude (Vmax) was smaller in isolated Tr myocytes, one could also predict that the extent of Ito activation would be significantly smaller in Tr myocytes. This latter effect would offset the former effect, perhaps leading to less of an early repolarizing influence. This type of change would be consistent with our observation that training affected the shape of the early half of the action potential, as was indicated by the prolongation in time required to achieve 25 and 50% repolarization, whereas no changes in overall action potential duration were detected (Table 2). This type of action potential prolongation is also consistent with our observation that Isus density was attenuated by training. These temporal observations are qualitatively similar to the results of Tibbits et al. (21) in which, in recordings from the endocardium of intact ventricular myocardial preparations, training appeared to elicit a prolongation in only the very early plateau phase of the action potential.

Our results differ from those of Tibbits et al. (21) in that we observed a Tr-induced reduction in peak action potential amplitude, whereas this was not observed in the earlier study. This difference markedly alters the interpretive significance of early action potential prolongation observed in the trained state. In the previous study (21), early action potential prolongation in Tr hearts was reflected as more positive membrane potentials in the early action potential plateau phase. This was interpreted to be indicative of a greater ICa and Ca2+ influx during excitation-contraction coupling in Tr hearts. In the current study, despite our metrics of Tr-induced early action potential prolongation, the membrane potentials achieved by Tr myocytes during most of the action potential were lower than those observed in the Sed cardiocytes. This would suggest that, relative to Sed cardiocytes, ICa and Ca2+ influx were reduced in Tr cardiocytes. Such a scenario might provide an explanation for the recent work indicating that training may elicit a reduction in the intracellular Ca2+ load in individual, paced cardiocytes in primary cultures (15).

In this study and the only other study (21) to examine the effect of endurance training on action potential characteristics in mature adult animals, the models of training that were used were quite similar (i.e., female running rat). However, the preparations that were used and conditions under which action potential measurements were made were very different [single cell (herein) vs. intact heart (21)]. These methodological dissimilarities may explain some of the differences that were observed across both studies. In the present study, we attempted to measure action potential characteristics at the single myocyte level under conditions similar to those used to detect training-induced Ito differences. An advantage of studying these related phenomena at the single cell level is that single cells represent the highest level of cellular organization under which specific membrane currents (Ito, ICa, and so forth) can be isolated and studied in a highly controlled environment. At present, this is the only means by which the effects of training on intrinsic membrane current characteristics can be unambiguously examined. A potential interpretive disadvantage, however, is that ventricular myocardium does not exist and does not operate as a collection of individual and independent cardiocytes but rather as a highly organized syncytium of mechanically and electrically coupled cells. A clear compromise of the "single cell" approach is that there is great potential for loss of regulatory integration that undoubtedly exists at the level of the intact organ. Indeed, the functional and theoretical ramifications of electrically uncoupling cardiocytes on action potential characteristics have recently been addressed in some detail by Zaniboni et al. (26). The results of the current study should be viewed in this context.

Although the results of this study provide evidence that Ito and Isus respond adaptively to endurance exercise training, they also give rise to a variety of other interesting questions. As mentioned earlier, there is now evidence that, in rat ventricle, the transient and sustained outward currents are actually composites of up to four other identifiable currents that, using the nomenclature of Himmel et al. (7), have been designated as Ito (a rapidly activating and inactivating current), IK (a rapidly activating, slowly inactivating delayed-rectifier-like current), IKx (a novel, slowly inactivating current), and Iss (a rapidly activating, noninactivating current). The relative contribution of these currents to Ito and Isus as defined by us and others (17, 19) is thought to be quite variable and dependent on experimental recording conditions (7). Under the recording conditions of our studies (voltage steps from -90 mV), the magnitude of the current we designated as Ito should have been dominated by a classically defined transient outward current since IK should have been largely inactivated and Iss would have been accounted for by our Ipeak - Isus definition of Ito (i.e., Fig. 1). Interestingly, however, we cannot exclude the possibility that the Tr-induced changes in the temporal occurrence of peak Ito were reflective of alterations in the activation times of a current or currents other than Ito. Himmel et al. also propose that Ilate (our Isus) is actually a composite of IK, IKx, and Iss. Because IK should have been largely unavailable for activation at a holding potential of -90 mV, then we are left to speculate that the Tr-induced reduction in Isus that we observed was reflective of reductions in IKx and/or Iss. This is clearly an area in need of further investigation.

Finally, considerable regional variabilities in Ito current densities (and inactivation/reactivation characteristics) and in the protein expression of the K+ channels thought to carry Ito-like currents have been demonstrated across the rat ventricle (1, 3, 5, 24). Such a regional distribution in the sustained K+ currents has not been demonstrated. In the present study, we examined cardiocytes pooled from the LV free wall and septum of the heart. As a consequence of this feature of our experimental design, it is not possible to ascertain if the Tr-induced differences we observed in Ito characteristics were representative of adaptations that occurred uniformly across the epicardial, endocardial, and septal regions of the LV or if they were representative of regionally specific adaptations. The issue of the regional specificity of the Ito adaptations is also one in need of resolution.

In conclusion, training elicits a reduction in Isus density, an increase in the rate at which peak Ito is attained, and a subtle but significant increase in Ito density in single rat LV cardiocytes. Training also appeared to affect the peak amplitude and shape of the early repolarizing phase of action potentials recorded from single myocytes in primary culture. Some but not all of these changes may have been associated with the types of Ito and Isus adaptations that were observed in this study. The results of this study provide the foundation for future work to determine which of the more specific current components that contribute to the composite Ito and Isus are affected by training and to determine whether these voltage-activated, repolarizing K+ current adaptations are regionally variable in ventricular myocardium.


    ACKNOWLEDGEMENTS

This work was supported in part by grants from the National Heart, Lung, and Blood Institute (HL-40306 to R. L. Moore and B. M. Palmer) and the American Heart Association, Colorado/Wyoming Affiliate (CWGS-40-97 to R. L. Moore) and a Graduate Student Scholarship for Women from the American College of Sports Medicine and a Graduate Student Fellowship from the Womens' Forum of Colorado Foundation (to K. N. Jew).


    FOOTNOTES

Present address of B. M. Palmer: Dept. of Molecular Physiology and Biophysics, Univ. of Vermont College of Medicine, Burlington, VT 05405.

Address for reprint requests and other correspondence: K. N. Jew, Dept. of Kinesiology & Applied Physiology, Campus Box 354, Univ. of Colorado, Boulder, CO 80309-0354 (E-mail: kjew{at}spot.colorado.edu).

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.

Received 5 October 2000; accepted in final form 30 October 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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J APPL PHYSIOL 90(4):1327-1333
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