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(Circulation Research. 1996;79:79-85.)
© 1996 American Heart Association, Inc.

Articles

Developmental Changes in the Delayed Rectifier K⁺ Channels in Mouse Heart

Li Wang, Zhong-Ping Feng, Colleen S. Kondo, Robert S. Sheldon, Henry J. Duff

the Department of Medicine, University of Calgary (Canada).

Correspondence to H.J. Duff, MD, FRCPC, Department of Medicine, University of Calgary, 3330 Hospital Dr, NW, Calgary, Alberta, Canada, T2N 4N1.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Expression of cardiac transient outward current and inwardly rectifying K⁺ current is age dependent. However, little is known about age-related changes in cardiac delayed rectifier K⁺ current (I_K, with rapidly and slowly activating components, I_Kr and I_Ks, respectively). Accordingly, the purpose of the present study was to assess developmental changes in I_K channels in fetal, neonatal, and adult mouse ventricles. Three techniques were used: conventional microelectrode to measure the action potential, voltage clamp to record macroscopic currents of I_K, and radioligand assay to examine [³H]dofetilide binding sites. The extent of prolongation of action potential duration at 95% repolarization (APD₉₅) by a selective I_Kr blocker, dofetilide (1 µmol/L), dramatically decreased from fetal (137%±18%) to day-1 (75%±29%) and day-3 (20%±15%) neonatal mouse ventricular tissues (P<.01). Dofetilide did not prolong APD₉₅ in adult myocardium. I_Kr is the sole component of I_K in day-18 fetal mouse ventricular myocytes. However, both I_Kr and I_Ks were observed in day-1 neonatal ventricular myocytes. With further development, I_Ks became the dominant component of I_K in day-3 neonates. In adult mouse ventricular myocytes, neither I_Kr nor I_Ks was observed. Correspondingly, a high-affinity binding site for [³H]dofetilide was present in fetal mouse ventricles but was absent in adult ventricles. The complementary data from microelectrode, voltage-clamp, and [³H]dofetilide binding studies demonstrate that expression of the I_K channel is developmentally regulated in the mouse heart.

Key Words: delayed rectifier current/channel • cardiac action potential • mouse heart • development

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Expression of I_to and I_K1 changes during development, resulting in an alteration of action potential characteristics in the heart.^{1 2 3 4 5} However, there is little information about developmental changes in I_K. I_K is one of the major repolarizing K⁺ currents in the hearts of many species⁶ and is also the target for many class III antiarrhythmic drugs in humans.⁷ We have recently reported that I_Kr is the dominant repolarizing K⁺ current in fetal mouse ventricular myocytes.⁸ Benndorf and Nilius⁹ have reported that I_to is the dominant repolarizing K⁺ current in adult mouse ventricular myocytes. These data suggest that the developmental changes in I_K occur in the mouse heart. To further define these changes, I_K was assessed by the voltage-clamp technique in single ventricular myocytes isolated from fetal (day 18 of gestation), neonatal (days 1 and 3), and adult mice. To assess the functional significance of developmental changes in I_K, action potential configuration and the extent of prolongation of action potential duration by selective I_K channel blockers were measured at the same developmental stages. To further examine whether developmental changes in I_Kr were due to an alteration in the density of the channels, the B_max and K_d of the [³H]dofetilide binding sites were also assessed at the same developmental stages.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Conventional Microelectrode Method
A conventional microelectrode method was used to record the action potential configuration in right ventricular endocardium from day-18 fetal, day-1 and day-3 neonatal, and adult mice (CD-1 mice). The recording procedure has been previously described in detail.¹⁰ Briefly, right ventricular tissues were rapidly isolated and pinned to the bottom of a Sylgard-coated Lucite muscle chamber with the endocardium facing up. The preparations were superfused at 37±0.2°C with oxygenated HEPES-buffered Tyrode's solution containing (mmol/L) NaCl 128, KCl 5, CaCl₂ 1.1, MgCl₂ 1, sodium acetate 2.8, glucose 10, and HEPES 10, pH 7.4 adjusted with NaOH. The electrodes, filled with 3 mol/L KCl with tip resistances of 10 to 20 M, were used to record transmembrane potentials. An IBM AT computer with a custom-made software routine (Bascom Consultants) was used to measure the resting membrane potential, APD₅₀ and APD₉₅, and the maximal upstroke velocity of phase 0 of the action potential (V_max). Action potential configurations were recorded, stored, and processed using CELLSOFT (University of Calgary, Calgary, Alberta, Canada).

Whole-Cell Voltage-Clamp Technique
Ventricular Myocytes From Fetal and Neonatal Mice
Single ventricular myocytes from fetal and neonatal mice were isolated using the procedure for isolating neonatal rat ventricular myocytes described by Chiamvimonvat et al.¹¹ The cells were plated at a density of 1.0 to 2.0x10⁵ cells per milliliter in tissue culture dishes containing glass coverslips and maintained at 37°C in a 5% CO₂ incubator until used (within 48 hours). Freshly isolated fetal and neonatal mouse ventricular myocytes were spherical in appearance without visible striations. After short-term cell culture, the cells flattened, spread, and displayed spontaneous contractile activity.

Ventricular Myocytes From Adult Mice
Single ventricular myocytes from adult male mice were isolated using a modified Langendorff procedure described by Benndorf et al.¹² The modifications in the cell isolation procedure included use of a different collagenase (0.125 mg/mL, Yakult) and use of KB solution as our final washing solution containing (mmol/L) taurine 20, L-glutamic acid 70, KCl 25, KH₂PO₄ 10, MgCl₂ 3, EGTA 0.5, HEPES 10, and glucose 10, pH 7.4 adjusted with KOH. The adult mouse ventricular myocytes were Ca²⁺ tolerant and had a typical rod-shaped appearance and clear cross striations.

Whole-Cell Voltage-Clamp Recordings
The recordings were performed at room temperature (21°C to 22°C), and the cells were superfused with HEPES-buffered Tyrode's solution containing (mmol/L) NaCl 140, KCl 4, MgCl₂ 1, CaCl₂ 1, glucose 5.5, and HEPES 10, pH 7.4 adjusted with NaOH. The electrodes had resistances of 3.5 to 5 M for fetal and neonatal cells and 1 to 2 M for adult cells when filled with an internal solution containing (mmol/L) potassium aspartate 110, MgCl₂ 6.4, K₂ATP 4.2, CaCl₂ 2.7, NaCl 8, HEPES 5, and EGTA 5, pH 7.2 adjusted with KOH. A liquid junction potential of 10 mV (pipette negative) was corrected electrically. In addition, since the aim of the present study was to assess developmental changes in I_K, the Na⁺ current was inactivated by holding the membrane potential at -40 mV, and the L-type Ca²⁺ current was blocked by nisoldipine (0.4 µmol/L), a selective Ca²⁺ channel blocker.¹³

An Axopatch 200 amplifier (Axon Instruments) was used in all voltage-clamp measurements. The amplifier was interfaced with a 386/33-MHz IBM compatible computer by a 12- kHz Labmaster board (Scientific Solution Inc). Data acquisition and analysis were carried out using pCLAMP software (Axon Instruments). The kinetics of activation and deactivation of I_K were analyzed using an exponential fitting program provided in CLAMPFIT, unless otherwise mentioned.

[³H]Dofetilide Equilibrium Binding
A crude membrane homogenate of the mouse ventricles was used in the [³H]dofetilide binding assay. Hearts from fetal, neonatal, and adult mice were rapidly excised and placed in nominally Ca²⁺-free MEM (GIBCO). Ventricles were isolated and then immediately homogenized with a Brinkmann Polytron homogenizer for 20 seconds in ice-cold Ca²⁺-free incubation solution containing (mmol/L) NaCl 135, KCl 5, MgCl₂ 1, HEPES 10, glucose 10, and EGTA 1, pH 7.4 adjusted with NaOH. The homogenate was then filtered through a 200-µm silk-screen mesh. The protein concentrations were determined by the Lowry assay, with BSA used as a standard.

This ventricular crude membrane homogenate (400 µg protein per assay) was incubated for 30 minutes at 37°C with [³H]dofetilide (10 nmol/L) in the absence or presence of a range of concentrations of unlabeled dofetilide (300 pmol/L to 10 µmol/L). Reactions were terminated by adding 3 mL Tris buffer solution to the assay. Tris buffer solution contained (mmol/L) Tris-HCl 25, NaCl 130, KCl 5.5, MgSO₄ 0.8, and glucose 10, along with 50 µmol/L CaCl₂ and 0.01% BSA, pH 7.4 adjusted with Tris base. Then the reaction solution was filtered through presoaked Whatman GF/C glass filters with Tris buffer supplemented with 1% BSA, followed by two rinses with 3 mL Tris buffer using a 24-well Brandel cell harvester (model M-24R). The filters were dried and counted in Beckman Ready Safe scintillation fluid with 60% efficiency. The retained radioactivity represents [³H]dofetilide bound to the crude membrane protein. Total binding was determined in the absence of unlabeled dofetilide, and nonspecific binding was determined in the presence of an excess of unlabeled dofetilide (10 µmol/L). Specific [³H]dofetilide binding was determined by subtracting the nonspecific binding from total binding. The binding affinity (K_d) and density (B_max) of [³H]dofetilide, as a specific ligand, to its binding sites on crude membrane were determined by Scatchard analysis using the nonlinear least-squares curve-fitting program LIGAND (Elsevier Biosoft).

Statistics
Statistical significance among groups was determined using one-way ANOVA. To define the difference between the subgroups compared within ANOVA, Dunnett's multiple range test was used. In addition, to evaluate the difference between paired observations, Student's t test was used. A value of P<.05 was considered significantly different. Data are presented as mean±SD.

Chemicals
[³H]Dofetilide and unlabeled dofetilide (N-[4-2-{2-[4-(methanesulfonamide)phenoxy]-N-methylethylamino}ethyl phenyl]) were kindly provided by Pfizer Research Central. Dofetilide was dissolved in acidified distilled water (pH 4.0, adjusted with HCl) to prepare the stock solution at a concentration of 10 mmol/L.¹⁴ The stock solution was stored at 4°C and diluted to the final concentration during experiments. Nisoldipine (a gift from Bayer, Leverkusen, Germany) was prepared as a 2 mmol/L stock solution in 100% ethanol. All salts were purchased from Sigma Chemical Co.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Age-Related Changes in the Action Potential Configuration in Mouse Ventricles
Representative action potentials recorded from fetal, day-1 and day-3 neonatal, and adult mouse ventricular endocardium are illustrated in Fig 1. The action potential configuration was profoundly altered during development in mouse heart. As shown in Fig 1, the action potential in the fetus has a distinct plateau with a long duration. The action potential duration dramatically decreased within 1 day after birth and then further shortened by the third day of neonatal life. The action potential configuration became spikelike in the adult. These data suggest that the developmental decrease in the action potential duration may be associated with an age-related change in K⁺ currents. Action potentials with large and rapid phase-1 repolarization followed by a prolonged plateau (130 to 150 milliseconds) at more negative potentials (-40 mV) were observed in 3 of 60 records from 12 adult mice. Since these distinct and uncommon action potentials may have been recorded from a distinct cell type, such as Purkinje fibers, this type of action potential was not included in data analysis in the present study. Only the stable action potential recordings from each age group were included in Table 1 for statistical analysis (n=9 for adult mice).

View larger version (20K): [in this window] [in a new window]   Figure 1. Representative action potentials obtained from fetal, day-1 and day-3 neonatal, and adult mouse hearts. The action potentials were recorded from right ventricular endocardium at a pacing cycle length of 500 milliseconds under control conditions at 37°C. The action potential duration profoundly decreases during development, indicating that the underlying K+ currents may vary with age in mouse hearts. For mean data, see Table 1.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Action Potentials in Mouse Ventricular Endocardium During Development

To assess whether I_K plays a functional role in action potential repolarization and whether the functional role of I_K in repolarization is age dependent, the extent of prolongation of the action potential duration by selective I_K channel blockers in ventricular endocardium from fetal, neonatal, and adult mice was investigated. Since I_K consists of two components, I_Kr and I_Ks,^{15 16 17} the effects of a selective I_Kr blocker, dofetilide,^{14 18} and a selective I_Ks blocker, indapamide,¹⁹ on the action potential duration were assessed. The age-dependent effects of dofetilide (1 µmol/L) on the action potential duration in mouse ventricles are shown in Fig 2. Dofetilide dramatically prolonged the action potential duration in fetal mouse ventricular endocardium (APD₉₅, 137%±18%; n=7). The extent of prolongation of the action potential duration by dofetilide profoundly decreased in day-1 neonates (APD₉₅, 75%±29%; n=5) and further decreased by the third neonatal day (APD₉₅, 20%±15%; n=5). In adult mouse ventricular endocardium, dofetilide did not prolong the action potential duration. Dofetilide at the concentration used in the present study had no effect on the resting membrane potential and V_max. These results indicate that the functional role of I_Kr in action potential repolarization in mouse ventricles changes during development.

View larger version (24K): [in this window] [in a new window]   Figure 2. Representative action potentials recorded in fetal, day-1 and day-3 neonatal, and adult mouse ventricles before () and after perfusion with dofetilide (1 µmol/L) (). Dofetilide produced a substantial prolongation of the action potential duration in fetal mouse hearts, less effect in neonatal hearts, and no effect in the adult hearts.

To examine whether I_Ks is also involved in action potential repolarization in mouse heart, indapamide (100 µmol/L) was applied to the myocardial preparations from each of the age groups. This concentration of indapamide did not prolong the action potential duration in mouse ventricles in any age group after 20 minutes of superfusion, suggesting that I_Ks may not be an important repolarizing K⁺ current in mouse ventricles.

Age-Related Changes in I_K in Mouse Ventricular Myocytes
I_Kr and I_Ks differ in their activation kinetics, rectification properties, and pharmacological sensitivity.¹⁵ The data from microelectrode studies indicate that I_Ks does not appear to be an important contributor to repolarization in the mouse heart at any developmental stage under our experimental conditions. In contrast, I_Kr plays an important role in action potential repolarization in fetal mouse ventricles. The functional role of I_Kr progressively declined during postnatal development and disappeared in adults. Accordingly, to assess whether both I_Kr and I_Ks exist in the mouse heart and whether I_Kr and I_Ks are developmentally regulated, we evaluated the properties of I_K in ventricular myocytes isolated from fetal, neonatal, and adult mice. As shown in Fig 3, the properties of I_K recorded from fetal and day-3 neonatal mouse ventricular myocytes are different. In fetal mouse ventricular myocytes, I_K activated rapidly. The amplitudes of the time-dependent I_K-out and deactivating I_K-tail progressively increased from -30 to -10 mV (Figs 3A an 3B). With further depolarization, the amplitude of I_K-out declined, but the I_K-tail remained relatively constant (Figs 3A and 3B). Therefore, the resultant current-voltage relationship displays a negative slope conductance at voltages positive to 0 mV (Fig 3B). The properties of rapid activation and this negative slope conductance indicate that this current is I_Kr. In contrast, in day-3 neonatal mouse ventricular myocytes, the current activated slowly and did not reach a steady state even during a 5000-millisecond depolarization pulse (Fig 3C). The amplitude of I_K-out increased continuously with membrane depolarization. As a result, the current-voltage relationship of I_K-out shows a positive slope conductance throughout the voltage range examined (Fig 3D). The properties of slow activation and outward rectification suggest that this current is largely I_Ks.

View larger version (25K): [in this window] [in a new window]   Figure 3. The properties of IK in fetal and day-3 neonatal mouse ventricular myocytes. The holding potential was -40 mV in both preparations. However, the duration of the depolarization pulses in the day-3 neonatal cell was 10-fold longer than in the fetal cell (5000 vs 500 milliseconds). Panels A and B show that the properties of IK in fetal mouse ventricular myocytes are consistent with IKr in other species (n=6), whereas panels C and D display that the properties of IK in day-3 neonatal mouse ventricular myocytes are dominant IKs (n=5).

The properties of I_K in day-1 neonatal ventricular myocytes varied from cell to cell. As shown in Fig 4, some cells from day-1 neonates expressed dominant I_Kr, which was characterized by rapid activation and inward rectification (Fig 4A). Other cells from day-1 neonates expressed dominant I_Ks, which was characterized by slow activation and outward rectification (Fig 4B). However, the density of I_Ks in day-1 neonates was significantly smaller than that recorded in day-3 neonatal mouse ventricular myocytes (Fig 5).

View larger version (18K): [in this window] [in a new window]   Figure 4. The variation of IK in day-1 neonatal ventricular myocytes. Both IKr and IKs are present in day-1 neonates. Panel A shows an example of a cell that expressed dominant IKr, and panel B shows an example of a cell that expressed dominant IKs. The currents were evoked from a holding potential (-40 mV) to test potential (+30 mV) for 500 milliseconds (A) and 5 seconds (B).

View larger version (21K): [in this window] [in a new window]   Figure 5. Comparison of the density of IKs in day-1 and day-3 neonatal mouse ventricular myocytes (Neo-1 day and Neo-3 day, respectively). The density of IKs significantly increased from Neo-1 day to Neo-3 day (n=4). *Significantly different from Neo-1 day (P<.05).

In contrast to these findings in fetal and neonatal mouse ventricular myocytes, neither I_Kr- nor I_Ks-type current was observed in adult mouse ventricular myocytes when the same depolarization protocol was applied.

It has been shown that dofetilide at 1 µmol/L completely abolishes the I_Kr currents but has no effect on I_Ks.¹⁸ Fig 6 compares the effects of dofetilide (1 µmol/L) on I_K in fetal (Fig 6A) and day-3 neonatal mouse ventricular myocytes (Fig 6B) and on the I_to-type current in adult mouse ventricular myocytes (Fig 6C). In fetal mouse ventricular myocytes, I_K-tail was completely abolished by dofetilide, suggesting that only I_Kr contributes to this tail current (Fig 6A). In day-3 neonatal ventricular myocytes, dofetilide partially blocked I_K-tail, suggesting that although I_Ks is dominant in day-3 neonates, I_Kr is still present at this stage. In adult mouse ventricular myocytes, the current evoked by the same protocol displayed rapid activation and relatively slow inactivation. These characteristics fundamentally differ from the properties of I_Kr or I_Ks. Dofetilide had no effects on the current in adult mouse ventricular myocytes.

View larger version (12K): [in this window] [in a new window]   Figure 6. Effects of dofetilide on IK in mouse ventricular myocytes at different developmental stages. The currents were evoked by depolarizing the cells to +10 mV for 5 seconds and then returning to a holding potential of -40 mV. Dofetilide (1 µmol/L) completely abolished IK-tail in fetal mouse ventricular myocytes (A) but only partially blocked IK-tail in day-3 neonatal cells (B). Panel C shows that dofetilide had no effect on the current recorded in adult mouse ventricular myocytes.

Age-Related Changes in [³H]Dofetilide Binding Sites
It has been reported that [³H]dofetilide is a specific radioligand for I_Kr channels in guinea pig ventricular myocytes.^{20 21} Therefore, a [³H]dofetilide binding assay was used to study developmental expression of I_Kr channels in mouse ventricles. Under our experimental conditions, the specific binding of [³H]dofetilide was 50% to 63% in the crude ventricular membrane homogenate from fetal and day-1 and day-3 neonatal mice. The specific binding of [³H]dofetilide was not detected in adult mouse ventricular homogenate.

A representative [³H]dofetilide binding isotherm with its Scatchard plot from fetal mouse ventricles is shown in Fig 7. Both displacement curve and Scatchard analysis of these data are best fit to a single binding site model with a high binding affinity. The mean data of K_d and B_max of [³H]dofetilide binding in mouse ventricular homogenate from different age groups are summarized in Table 2. The average B_max and K_d of [³H]dofetilide binding in fetal tissues were 26±9 fmol/mg protein and 13±4 nmol/L (n=4), respectively. The B_max value was not significantly changed during early postnatal development compared with fetal development. However, the K_d value of [³H]dofetilide binding in day-3 neonatal mouse ventricles was significantly increased to 37±19 nmol/L (P<.05, n=8), suggesting that the affinity of the [³H]dofetilide binding sites in mouse ventricles decreased in day-3 neonates. Although the B_max was not changed, the declined affinity suggests that the properties of the [³H]dofetilide binding protein may be altered at 3 days after birth. In adult, no specific [³H]dofetilide binding was detected. The presence of a high-affinity [³H]dofetilide binding site in the fetus and its absence in the adult parallel our electrophysiological findings of developmental changes in I_Kr.

View larger version (18K): [in this window] [in a new window]   Figure 7. A representative example of [3H]dofetilide binding isotherm with its Scatchard plot (inset) from fetal mouse ventricular homogenate. The data were best fit to a single binding site model. For the mean Kd and Bmax values, see Table 2.

View this table: [in this window] [in a new window]   Table 2. Comparison of Kd and Bmax in Crude Mouse Ventricular Membrane Homogenates During Development

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The present study demonstrates that expression of I_Kr and I_Ks in the mouse heart is developmentally regulated. I_Kr is the dominant repolarizing K⁺ current in fetal mouse ventricles, but its expression is altered during early postnatal development and disappears in the adult mouse. Expression of I_Ks in the mouse heart is transient. I_Ks is absent in day-18 fetal ventricular myocytes, coexists with I_Kr in the early neonatal stages, and disappears in adult mouse ventricles. In parallel, the conventional microelectrode studies show that dofetilide produces a profound prolongation of action potential duration in the fetus and significantly less prolongation of action potential duration in the neonate but has no effect on action potential duration in the adult. Finally, in keeping with these electrophysiological findings, alteration of [³H]dofetilide binding in mouse ventricles also occurs during development. A high-affinity [³H]dofetilide binding site is present in fetal mouse ventricles and is absent in adult ventricles.

Two Components of I_K in Mammalian Heart
Two components of I_K (I_Kr and I_Ks) in cardiac myocytes have been well documented by the patch-clamp technique on the basis of their different activation kinetics, rectification properties, and pharmacological sensitivity.¹⁵ Recently, two candidate genes that may encode I_Kr and I_Ks channel proteins have also been identified.^{22 23 24 25} It has been shown that the human ether-a-go-go–related gene, HERG, encodes a delayed rectifier K⁺ channel with biophysical characteristics nearly identical to I_Kr²² and that minK current shares many biophysical properties with I_Ks in native cardiac myocytes.^{23 24 25}

I_K has also been identified in neonatal mouse ventricular myocytes.^{26 27} Nuss and Marban²⁷ reported that I_K in a mixed population of day-1 and day-3 neonatal mouse ventricular myocytes consists of both I_Kr and I_Ks, but largely I_Ks. However, we have recently shown that I_Kr is the sole component of I_K in day-18 fetal mouse ventricular myocytes.⁸

Developmental Changes in I_K
To our knowledge, developmental changes in cardiac I_K have not been systematically examined from late fetal to adult mouse. Abrahamsson et al²⁸ have shown that almokalant (an I_K channel blocker) significantly prolonged action potential duration in fetal rat hearts but did not prolong action potential duration in adult rat hearts.²⁸ However, I_Kr and I_Ks were not distinguished in their study, and no sequential time course was examined. Recently, Davies et al²⁹ have reported the in utero developmental changes in K⁺ currents in mice. In that study, I_Ks was not present in the early phases of fetal development in mouse hearts but was observed at day 20 of fetal development. The study of Davies et al complements our study in that Davies focused on intrauterine development, whereas the present study systematically examined the age-dependent changes in I_K in mouse ventricles from late fetus to adult. We demonstrate that expression of both I_Kr and I_Ks in mouse ventricles is developmentally regulated. However, the expression pattern of these two currents is different during development. I_Kr is downregulated, and I_Ks is only transiently expressed in mouse ventricle during development. The presence of specific [³H]dofetilide binding sites with a high affinity in fetal mouse ventricles is well correlated with the observation of dominant I_Kr in fetal mouse ventricular myocytes. In adult mouse ventricles, the absence of the specific [³H]dofetilide binding sites also parallels the results of the electrophysiological recordings at the same age group. On the other hand, the pattern of change in I_Ks in mouse heart found in the present study is consistent with the results of Felipe et al,³⁰ who reported that expression of minK mRNA in mouse hearts abruptly increased at day 19 of gestation and peaked at day 7 in neonates. Thereafter, the minK mRNAs dramatically declined and reached an almost undetectable level in adult mouse hearts.

Although I_Ks was present in neonatal mouse hearts, I_Ks channel blocker did not significantly prolong the action potential duration in the neonates. Since APD₅₀ and APD₉₅ in the ventricles of day-3 neonates were only 18±6 and 51±9 milliseconds at 37°C, such a short duration of the action potentials is expected to activate little I_Ks. This may explain the lack of effect of indapamide on action potential prolongation in the neonatal mouse heart.

The biology of I_K channel expression in the early postnatal period is complicated in the mouse heart. The B_max of [³H]dofetilide binding in the neonates was not significantly changed, whereas the K_d of [³H]dofetilide binding was significantly increased in day-3 neonates. Although the mechanism of this age-dependent increase in K_d is not established, the altered K_d implies structural or allosteric changes in the [³H]dofetilide binding sites. The molecular mechanisms of developmental changes in the K_d of [³H]dofetilide binding in mouse ventricles during the early postnatal period remain to be elucidated.

	Selected Abbreviations and Acronyms

 

APD50, APD95 = action potential duration at 50% and 95% repolarization IK = delayed rectifier K+ current IK-out = outward IK current IK-tail = IK tail current IK1 = inwardly rectifying K+ current IKr = rapidly activating component of IK IKs = slowly activating component of IK Ito = transient outward K+ current

	Acknowledgments

 
This study was supported by the Alberta Heritage Foundation for Medical Research (Edmonton, Alberta, Canada), the Medical Research Council of Canada (Ottawa, Ontario, Canada), the Heart and Stroke Foundation of Canada (Ottawa, Ontario, Canada), and Pfizer Central Research (Sandwich, UK).

Received June 12, 1995; accepted April 5, 1996.

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