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(Circulation Research. 1999;85:168-173.)
© 1999 American Heart Association, Inc.

Original Contribution

Glucocorticoid Regulation of Cardiac K⁺ Currents and L-Type Ca²⁺ Current in Neonatal Mice

Li Wang, Zhong-Ping Feng, Henry J. Duff

From the Cardiovascular Research Group, Department of Medicine, University of Calgary, Alberta, Canada.

Correspondence to H.J. Duff, MD, FRCPC, Department of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta, Canada T2N 4N1. E-mail hduff{at}ucalgary.ca

	Abstract

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Abstract—Previous studies have reported that dexamethasone (Dex) prolongs cardiac action potential repolarization in mice and rats. However, the cellular mechanisms of this effect have not been addressed. Because action potential duration is influenced by a complex interplay of both inward and outward currents, this study evaluated the role of K⁺ currents and the L-type Ca²⁺ current in response to chronic in vivo Dex treatment. Accordingly, neonatal mice were randomly allocated to treatment with Dex (1 mg/kg per day) or placebo (saline) given subcutaneously for 5 days. At 14 to 15 days of age, the L-type Ca²⁺ current and K⁺ currents were recorded in ventricular myocytes using whole-cell patch-clamp techniques. The density of peak outward K⁺ currents was significantly decreased in the chronic Dex-treated group, but the current measured at the end of a 1-second depolarization pulse was similar in both groups. We further measured the magnitudes of the fast-inactivating (I_to) and the slowly inactivating (I_slow) currents that contribute to the peak outward K⁺ currents. I_to was reduced from 17.5±3.0 pA/pF (control) to 10.6±2.5 pA/pF (Dex) at +50 mV (P<0.05), but I_slow was not significantly different. These data suggest that downregulation of I_to is responsible for the reduced peak outward current. Time courses of the onset and offset of in vivo Dex effects were also assessed. A period of 3 days of treatment was required to observe the Dex effect on peak outward K⁺ currents, whereas a 7-day period after discontinuation of Dex was required to recover the baseline current density. Acute in vitro treatment with Dex (1 µmol/L) had no effect on K⁺ current densities. In addition, chronic Dex treatment significantly increased the density of the L-type Ca²⁺ current (I_Ca-L) from –7.2±0.5 pA/pF of control to –8.9±0.6 pA/pF of Dex at +10 mV, P<0.05. In conclusion, chronic in vivo Dex treatment decreases I_to and increases I_Ca-L in neonatal mouse ventricular myocytes, both of which contribute to the prolongation of cardiac action potential repolarization induced by glucocorticoids.

Key Words: dexamethasone • K⁺ current • L-type Ca²⁺ current • action potential duration • mice

	Introduction

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Previous studies have shown that treatment with adrenal glucocorticoids exerts important effects on cardiac action potential duration (APD) in neonatal rats and mice.^{1 2 3} A balance of inward depolarizing and outward repolarizing currents determines APD in heart. If an imbalance of the inward and outward forces occurs, a change in APD will result. Therefore, an increase in the inward depolarizing L-type Ca²⁺ current or a decrease in the outward repolarizing K⁺ currents may contribute to glucocorticoid-induced action potential prolongation.

Recently, Takimoto et al⁴ have reported that mRNA encoding the cardiac _1C isoform of L-type Ca²⁺ channel is upregulated by chronic in vivo dexamethasone (Dex) treatment. In parallel, Dex also significantly increased the dihydropyridine binding site density in rat ventricle,⁴ which raised the possibility of an increase in L-type Ca²⁺ current density. In addition, Takimoto and Levitan also reported that in vivo glucocorticoid treatment upregulates expression of Kv1.5 mRNA in rat heart.⁵ However, no previous studies have explored the mechanisms of glucocorticoid-induced prolongation of APD at the functional channel level by measuring depolarizing or repolarizing currents. Therefore, the purpose of this study was to examine the effects of glucocorticoids on cardiac K⁺ currents and L-type Ca²⁺ current in mouse ventricular myocytes during postnatal development. Accordingly, pairs of neonatal mice were randomly allocated to chronic in vivo Dex (1 mg/kg) or placebo treatment. At 14 to 15 days of life, K⁺ currents and L-type Ca²⁺ current were recorded from cardiac ventricular myocytes using a whole-cell patch-clamp technique. Herein we report that chronic in vivo Dex treatment decreases the density of the fast-inactivating current (I_to) and increases the density of the L-type Ca²⁺ current (I_Ca-L), both of which contribute in a complementary manner to prolongation of APD induced by glucocorticoids in neonatal mice.

	Materials and Methods

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In Vivo Drug Treatment Protocols
CD-1 mice (Charles River, St. Constant, Québec, Canada) were used in this study. Pairs of neonatal mice at day 7 of age were randomly assigned to receive either subcutaneous placebo (saline) or Dex (1 mg/kg per day) treatment for 5 days. The dose and duration of Dex used in this study are similar to those used previously.³ To assess the time course of the onset of the Dex effect, a variable duration of the treatment ranging from 1 to 3 and 5 days was used. To assess the time course of the offset of the Dex effect, all mice were treated with Dex for 5 days; then, whole-cell patch clamp experiments were performed at variable intervals of 1, 3, 5, and 7 days after discontinuation of Dex. To carry out the experiments using mice of similar age, we adjusted the age at which the injections started for the onset/offset studies. All mice were euthanized at 14 to 15 days of age except for the offset studies, with 5- and 7-day intervals after treatment discontinuation. Those mice were studied at 20 days of age. Note that the density of the peak outward currents was similar between 14- and 20-day control mice.

Whole-Cell Patch-Clamp Recording
Single ventricular myocytes were enzymatically isolated from neonatal mice by using a previously described Langendorff perfusion technique.⁶ Macroscopic K⁺ currents and I_Ca-L were recorded by whole-cell patch-clamp method with an Axopatch 200 amplifier (Axon Instruments).

For K⁺ current recordings, the ventricular myocytes were perfused with HEPES-buffered Tyrode solution containing (in mmol/L) NaCl 140, KCl 4, MgCl₂ 1, CaCl₂ 1, glucose 5.5, and HEPES 10, pH 7.4 adjusted with NaOH. L-type Ca²⁺ current was blocked by CdCl₂ (0.3 mmol/L). Tetrodotoxin (TTX; 20 µmol/L) was used to block I_Na in our preliminary study, showing that I_to density and kinetics were similar in the presence and absence of TTX; thus, TTX was not routinely included in the external solution. The pipette solution was composed of (in mmol/L) potassium aspartate 110, MgCl₂ 4, K₂-ATP 4.2, CaCl₂ 1, NaCl 8, HEPES 5, and EGTA 10, pH 7.2 adjusted with KOH. For L-type Ca²⁺ current recordings, the ventricular myocytes were perfused with a Na⁺- and K⁺-free solution modified from that of Aggarwal and Boyden⁷ containing (in mmol/L) tetraethylammonium chloride 130, CaCl₂ 2, MgCl₂ 1, 4-aminopyridine 2, glucose 10, and HEPES 10, pH 7.4 adjusted with CsOH. The pipette solution was composed of (in mmol/L) CsOH 110, aspartic acid 110, Mg-ATP 3, CaCl₂ 1, Na₂-phosphocreatine 3.6, tetraethylammonium chloride 20, EGTA 10, and HEPES 10, pH 7.2 adjusted with CsOH. To minimize the time-dependent rundown effect, all measurements of I_Ca-L were carried out between 10 and 20 minutes after whole-cell membrane rupture. All recordings were conducted at room temperature (22°C to 23°C), and external solutions were bubbled with 100% O₂.

Electrodes had tip resistances of 2 to 4 M when filled with internal solutions. Cell capacitance was calculated from the uncompensated capacity current transients elicited by a 10-mV hyperpolarizing voltage step from a holding potential of –80 mV. Series resistance compensation was between 40% and 80% during all experiments. Series resistance was checked regularly to ensure no variation with time.

Data analysis was performed using the CLAMPFIT module of pClamp software (Axon Instruments). The figures were plotted using Figure P graphic software (Biosoft). Current densities were determined by dividing current amplitudes by cell capacitance. The electrophysiological characteristics of control and Dex-treated groups were statistically compared using unpaired Student t test. Statistical tests were considered significant at a value of P<0.05. All results are presented as mean±SD.

View larger version (17K): [in this window] [in a new window]   Figure 1. Whole-cell outward K+ currents recorded from ventricular myocytes isolated from control (A) and Dex-treated (B) mice. The waveform of outward K+ currents was evoked by 1-second depolarizing voltage steps from a holding potential of -80 mV to test potentials from –40 to +50 mV in 10-mV increments. The interpulse interval was 20 seconds. The amplitude of Ipeak in the cell isolated from Dex-treated mice (A) was decreased compared with that recorded from control cell (B).

	Results

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Density and Inactivation Kinetics of the Outward K⁺ Currents
Figure 1 displays the whole-cell voltage-clamp recordings of depolarization-activated outward K⁺ currents in ventricular myocytes isolated from control (1A) and chronic Dex-treated (1B) mice. The amplitude of peak outward K⁺ current (I_peak) at all test potentials was substantially lower in the cells isolated from Dex-treated mouse (Figure 1B) than from control mouse (Figure 1A). Because the cell capacitance was smaller in chronic Dex-treated mice (75.7±18.2 pF, n=38) than that in control mice (91.8±14.9 pF, n=40, P<0.01), the current amplitude was normalized to the cell capacitance and then expressed as current density. The I_peak density was significantly reduced in cells isolated from the chronic Dex-treated mice (23.4±3.8 pA/pF) compared with control mice (34.6±7.4 pA/pF, P<0.05). In contrast, the current density measured at the end of 1-second voltage steps was not significantly different in the cells isolated from control (13.1±3.2 pA/pF) and Dex-treated (11.5±2.3 pA/pF) mice.

As reported previously, the decay phases of I_peak in mouse ventricular myocytes consist of 2 inactivating components: the fast-inactivating current, I_to^{6 8} and the slowly inactivating current, I_slow.^{9 10} To assess their contribution to the reduced I_peak in Dex-treated cells, the amplitudes of I_to and I_slow were determined by biexponential fit using the Clampfit program. Figure 2 shows examples of current traces and exponential fittings in ventricular myocytes isolated from control (Figure 2A) and chronic Dex-treated (Figure 2B) mice. Dex treatment did not affect the inactivation kinetics of I_to and I_slow (Figure 2C). However, as shown in Figure 2D, chronic Dex treatment selectively decreased the density of I_to but did not significantly affect the density of I_slow.

View larger version (21K): [in this window] [in a new window]   Figure 2. Inactivation time constants of the outward K+ currents in ventricular myocytes isolated from control and Dex-treated mice. Representative examples of exponential fittings to the decay phases of the outward K+ currents are shown in the cells isolated from control (A) and Dex-treated (B) mice. In both control and Dex-treated mice, the decay phases of the outward K+ currents are not fit to a monoexponential equation (insets) but are well described by a biexponential function. C, Mean data of both fast and slow inactivation time constants in ventricular myocytes isolated from control and Dex-treated mice. Both fast and slow inactivation time constants of the outward K+ currents are similar between the 2 groups. D, Mean densities of Ito and Islow. *Significant difference between Dex-treated and control mice, P<0.05.

In addition, we have directly applied Dex (0.01 to 1 µmol/L) to in vitro neonatal mouse ventricular myocytes for up to 20 minutes. Even at the concentration of 1 µmol/L, Dex failed to alter the K⁺ current densities (n=6) (data not shown).

Steady-State Inactivation of the Outward K⁺ Currents
Figure 3 displays representative current traces elicited by a typical double-pulse protocol for steady-state inactivation in cells isolated from control (Figure 3A) and Dex-treated (Figure 3B) mice. Outward K⁺ currents were evoked during 3-second depolarization to +50 mV. Before each depolarization to +50 mV, the cell was held for 5 seconds at a conditioning potential between –100 and 0 mV. The amplitudes of I_to and I_slow evoked from each conditioning potential were measured in individual cells and normalized to the amplitudes evoked from a conditioning potential of –100 mV. The mean values of half-inactivation potential (V_h) and slope factor (k) for I_to were –46.4±9.5 mV and –4.5±1.5 mV for control (n=6) and –47.2±9.9 mV and –4.4±1.3 mV for Dex treatment, respectively (n=5; NS). The mean values of V_h and k for I_slow were –38.8±6.4 mV and –10.1±2.1 mV for control (n=6) and –39.4±7.2 mV and –10.8±2.3 mV for Dex treatment (n=5; NS). Therefore, shifts in steady-state inactivation could not account for the differences in reduced I_to density in the ventricular myocytes isolated from Dex-treated mice.

View larger version (17K): [in this window] [in a new window]   Figure 3. A and B, Examples of the current traces for steady-state inactivation of outward K+ currents in ventricular myocytes isolated from control (A) and Dex-treated (B) mice. A 2-pulse protocol was used to assess the voltage dependence of steady-state inactivation. The conditioning potential was used to depolarize the ventricular myocytes to different membrane voltages ranging from -100 to 0 mV for 5 seconds. Each conditioning potential was followed by a single test pulse, which depolarized the cell to +50 mV. The voltage dependence of steady-state inactivation of the currents is unaffected by Dex.

Time Courses for the Onset and Offset Effects of Dex on the Outward K⁺ Currents
To assess whether the reduced magnitudes of the peak outward K⁺ current vary as a function of the duration of in vivo Dex treatment, the ventricular myocytes were isolated from neonatal mice after 1, 3, and 5 days of Dex treatment, and I_peak was measured. As shown in Figure 4A, Dex treatment for 1 day was not sufficient to alter the magnitude of the peak current density. Both 3 and 5 days of Dex treatments significantly decreased the density of I_peak.

View larger version (14K): [in this window] [in a new window]   Figure 4. Time-dependent effects of Dex on outward K+ currents in ventricular myocytes. A, Time course of the onset effects on Ipeak. *Significant difference between control and Dex-treated mice, P<0,05. B, Time course of the offset effects on Ipeak. *Significant difference compared with the density of Ipeak recorded from 1 day after termination of Dex treatment.

To assess the reversibility of Dex-induced effects on cardiac K⁺ currents, all mice were treated with Dex for 5 days. Then, the density of I_peak was examined at 1-, 3-, 5-, and 7-day intervals after discontinuation of Dex. The results are summarized in Figure 4B. Partial recovery was observed after termination of the treatment for 5 days, and full recovery occurred at 7 days after termination of the treatment.

Inwardly Rectifying K⁺ Current (I_K1)
We also examined the effect of in vivo Dex treatment on I_K1. The family of K⁺ currents shown in Figure 5 was evoked from a holding potential of –50 mV to test potentials ranging from –110 to +40 mV in 10-mV increments for 1 second. This protocol enables a comparison of the effect of Dex treatment on both depolarization-activated outward K⁺ currents and the inwardly rectifying K⁺ current, I_K1, in the same cell. Note that the magnitude of the peak transient outward current was substantially reduced by chronic Dex treatment (Figure 5B), whereas the magnitude of I_K1 was increased in the same cell. Figure 5C shows the mean current density-voltage relationships of I_K1.

View larger version (19K): [in this window] [in a new window]   Figure 5. Representative examples of family K+ currents recorded from ventricular myocytes isolated from control (A) and Dex-treated (B) mice. The currents were evoked from a holding potential of –50 mV to test potentials ranging from –110 to +40 mV in 10-mV increments for 1 second. Note that the amplitude of IK1 was larger in the ventricular myocyte isolated from Dex-treated mice (B) than that in control (A). However, in the same cell, the amplitude of the peak outward K+ current was smaller in ventricular myocytes isolated from Dex-treated mice. C, Mean current density and voltage relationships of IK1. *Significant difference from control, P<0.05.

Current Density and Voltage Relationship of I_Ca-L
To assess whether chronic in vivo treatment with Dex affects I_Ca-L, whole-cell I_Ca-L was recorded in ventricular myocytes isolated from control and Dex-treated mice. For I_Ca-L measurements, the holding potential was at –50 mV, a membrane potential at which T-type Ca²⁺ current is inactivated.¹¹ Figure 6 shows representative examples of I_Ca-L tracings recorded from control (Figure 6A) and Dex-treated (Figure 6B) ventricular myocytes. The I_Ca-L elicited from –50 mV was completely blocked by a selective L-type Ca²⁺ blocker, nisoldipine, at a concentration of 0.4 µmol/L (data not shown). The mean current density-voltage relations are illustrated in Figure 6C. In both control and Dex-treated ventricular myocytes, I_Ca-L activation-threshold was approximately –25 mV, and the current peaked around +10 mV. Moreover, the average density of I_Ca-L was significantly increased in ventricular myocytes isolated from Dex-treated mice (n=10) as compared with those from control mice (n=12, P<0.05). These data suggest that Dex-induced prolongation of action potential duration likely relates to the combination of an increase in I_Ca-L density and a reduction of I_to density.

View larger version (20K): [in this window] [in a new window]   Figure 6. Typical ICa-L tracings from mouse ventricular myocytes of control (A) and Dex-treated (B) mice were elicited from a holding potential of –50 mV to test potentials ranging from –40 to +60 mV by 5-mV increment steps for 200 ms. Calibration bars are for both sets of current tracings. The peak ICa-L was measured and normalized to the cell capacitance to give current density (pA/pF). C, Averaged current density and voltage relationships. The mean density of the peak ICa-L in ventricular myocytes was significantly increased in Dex-treated mice (P<0.05).

Action Potential Configuration
The ventricular action potential configuration of control and Dex-treated mice was recorded at 37°C using a conventional microelectrode technique under physiological conditions as described previously.¹² Representative examples of cardiac action potentials from control and Dex-treated neonatal mice are shown in Figure 7A and 7B, respectively. As expected, chronic in vivo Dex treatment significantly prolonged APD₅₀ from 14.7±1.4 (control, n=6) to 20.3±6.3 ms (Dex, n=17), P<0.05, and APD₉₀ from 38.7±6.7 (control) to 50.2±11.7 ms (Dex), P<0.05.

View larger version (13K): [in this window] [in a new window]   Figure 7. Representative examples of action potential waveforms recorded from right ventricular myocardium of control (A) and Dex-treated (B) mice using a conventional microelectrode technique. The tissues were paced at 2 Hz and superfused with normal Tyrode solution at 37°C. Note a wider action potential in Dex-treated ventricle than in control.

	Discussion

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In the present study, we have demonstrated that chronic in vivo Dex treatment decreases the density of I_to but does not alter the density of I_slow in neonatal mouse ventricular myocytes. The effect of chronic in vivo Dex treatment on I_to is time dependent and completely reversible. In addition, the density of I_Ca-L is significantly increased in the ventricular myocytes isolated from chronic in vivo Dex-treated neonatal mice. Direct application of Dex to the isolated ventricular myocytes does not affect the channel properties. These data suggest that Dex-induced alteration in current densities occurs likely through the regulation of gene expression.

Comparison to Previous Work
Maternal glucocorticoid levels decline sharply before birth and continue to decline in the neonatal rat until the third postnatal week.¹³ During this developmental period, a substantial shortening of cardiac action potential was observed.^{2 5} To correlate the relation between decreased glucocorticoid level and action potential shortening during postnatal development, Penefsky and McCann² reported that pretreatment of neonatal rats with Dex largely inhibited the developmental shortening of phase 1 of APD. Initial rapid repolarization (phase 1) of APD is largely determined by I_to, which indicates that the level of circulating glucocorticoids may affect I_to channel expression. In this study, we observe that pretreatment of neonatal mice with Dex results in a significant decrease in I_to density without alteration of the biophysical properties. This finding is in keeping with the work of Penefsky and McCann² and is also consistent with our previous report that developmental increase in I_to contributes to developmental shortening of APD in neonatal mice.⁶ Because I_to density is decreased by Dex, a prolonged APD would be expected. Indeed, APD is longer in Dex-treated neonatal mice compared with that in control mice. The significant increase in I_K1 density was observed only at negative potentials and therefore likely does not contribute to the observed APD change.

Takimoto and Levitan⁵ found that glucocorticoids caused an induction of Kv1.5 channel gene expression in ventricles of adrenalectomized adult rat. Recent studies indicate that Kv1.5 channel gene may contribute to I_slow in mouse ventricular myocytes.^{9 10} However, our study shows no significant effect on I_slow in ventricular myocytes isolated from neonatal mice pretreated with Dex. This discrepancy may relate to different ages of the experimental animals and species.

In terms of regulation of Ca²⁺ channel expression by glucocorticoids, the results obtained from the present study are in keeping with the previous biochemical studies. Takimoto et al⁴ have reported that Dex produces an increase in mRNA levels encoding _1C isoform of the L-type Ca²⁺ channel paralleled by an increase in the dihydropyridine binding site density in rat ventricle. In keeping with those findings, we have shown in this study that the density of L-type Ca²⁺ current is significantly increased in the ventricular myocytes isolated from neonatal mice pretreated with Dex.

In conclusion, upregulation of I_Ca-L and downregulation of I_to contribute to the glucocorticoid-induced action potential prolongation in neonatal mice.

	Acknowledgments

 
This study was supported by Medical Research Council of Canada, the Heart and Stroke Foundation of Alberta, and the Andrew Family Professorship for Cardiovascular Research.

Received October 13, 1998; accepted May 3, 1999.

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