© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
The slow component of the delayed rectifier potassium current in undiseased human ventricular myocytes
aDepartment of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical University, Dóm tér 12, P.O. Box 427, H-6720 Szeged, Hungary
bDepartment of Cardiac Surgery, Albert Szent-Györgyi Medical University, Szeged, Hungary
cDepartment of Surgery, Albert Szent-Györgyi Medical University, Szeged, Hungary
dResearch Unit for Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary
* Corresponding author. Tel.: +36-62-545-681; fax: +36-62-544-565 papp{at}phcol.szote.u-szeged.hu
Received 28 January 2000; accepted 21 November 2000
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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Objective: The purpose of this study was to investigate the properties of the slow component of the delayed rectifier potassium current (IKs) in myocytes isolated from undiseased human left ventricles. Methods: The whole-cell configuration of the patch-clamp technique was applied in 58 left ventricular myocytes from 15 hearts at 37°C. Nisoldipine (1 µM) was used to block inward calcium current (ICa) and E-4031 (1–5 µM) was applied to inhibit the rapid component of the delayed rectifier potassium current (IKr). Results: In 31 myocytes, an E-4031 insensitive, but L-735,821 and chromanol 293B sensitive, tail current was identified which was attributed to the slow component of IK (IKs). Activation of IKs was slow (
= 903±101 ms at 50 mV, n = 14), but deactivation of the current was relatively rapid ( = 122.4±11.7 ms at –40 mV, n = 19). The activation of IKs was voltage independent but its deactivation showed clear voltage dependence. The deactivation was faster at negative voltages (about 100 ms at –50 mV) and slower at depolarized potentials (about 300 ms at 0 mV). In six cells, the reversal potential was –81.6±2.8 mV on an average which is close to the K+ equilibrium potential suggesting K+ as the main charge carrier. Conclusion: In undiseased human ventricular myocytes, IKs exhibits slow activation and fast deactivation kinetics. Therefore, in humans IKs differs from that reported in guinea pig, and it best resembles IKs described in dog and rabbit ventricular myocytes.
KEYWORDS Cell culture/isolation; K-channel; Membrane currents; Myocytes; Ventricular arrhythmias
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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The delayed rectifier potassium current (IK) is an important repolarizing current in the ventricle [1,2] that has been identified in various mammalian cardiac preparations [3–6]. In most species, IK can be separated into rapid (IKr) and slow (IKs) components that differ from one other in terms of their sensitivity to drugs, rectification characteristics and kinetic properties [7–9]. Since the properties and relative magnitude of IKr and IKs show species and tissue dependent variation the question arises as to how the findings obtained in experimental animals may be extrapolated to humans. In spite of the well known difficulties in obtaining human cardiac tissue for research purposes, there have been several reports of IK in human ventricular muscle. The IKr current was first described in man by Veldkamp et al. [10] and by Li et al. [11] and it was further characterized by Iost et al. [12].
The available data regarding IKs in human ventricular muscle are less certain than the available information on IKr as was thoroughly discussed in a recent editorial by Veldkamp [13]. In right ventricular myocytes obtained from explanted hearts, Li et al. [11] described an E-4031 insensitive and indapamide-sensitive current, which was attributed to IKs. These measurements were, however, performed in the presence of CdCl2 and BaCl2 making the interpretation of the results difficult. A previous report from our laboratory noted that it was not possible to identify IKs current in myocytes obtained from undiseased human left ventricle [12]. Although this latter study verified the presence of properties of IKr, it raised further questions about the existence of IKs in undiseased human ventricular muscle [12].
However, in recent experiments using different experimental conditions (changing the content of pipette and extracellular solutions) we were able to record an E-4031-insensitive, L-735,821- and chromanol 293B-sensitive current in undiseased human ventricular myocytes. In the present study we describe the properties of this current, which we attribute to IKs.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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2.1 Patients
Cells were prepared from 15 undiseased donor hearts. The hearts were obtained from general organ donor patients (male=7, female=8; mean age=44.3±4.3 years) undergoing pulmonary and aortic valve transplantation surgery. Before explantation of the hearts, the patients did not receive any medication except for dobutamine, furosemide and plasma expanders. The experimental protocol complied with the Declaration of World Medical Association proclaimed in Helsinki and was approved by the Ethical Review Board of the Albert Szent-Györgyi Medical University (No. 51-57/1997 OEj).
2.2 Cell isolation
Ventricular myocytes were isolated from the human hearts by an enzymatic dissociation procedure as described previously [12]. After explantation and removal of the valves, hearts were transported to the laboratory in cold (4°C) cardioplegic solution. A portion of the left ventricular wall was excised together with its arterial branch and was mounted on a modified 60-cm high Langendorff perfusion apparatus, where it was perfused through a branch of the left anterior descending coronary artery with solutions in the following sequence: isolation solution supplemented with 1 mM CaCl2 (10 min), isolation solution (10 min), isolation solution to which collagenase (type I, 0.66 mg/ml, Sigma Chemical, St. Louis, MO, USA), elastase (type III, 0.045 mg/ml, Sigma) and bovine serum albumin (fraction V, fatty acid free, 2 mg/ml, Sigma) had been added (15 min). After the first step of enzymatic digestion, the solution was supplemented with protease (type XIV, 0.12 mg/ml, Sigma) for a further 30–45 min. Portions of the left ventricular wall that were clearly digested by the enzymes were cut into small pieces and were placed either into Kraft–Brühe (KB) solution, or into isolation solution supplemented with taurine (50 mM) and CaCl2 (1.25 mM) for 15 min. The tissue chunks were then gently agitated in a small beaker to obtain single cells. During the entire isolation procedure, the solutions were oxygenated (100% O2) and temperature was maintained at 37°C. The cells were allowed to settle to the bottom of the beaker for 10 min, and then half of the supernatant was replaced by new solution. These procedures were repeated three times. The cells in KB solution were stored at 4°C, and the cells stored in isolation solution (1.25 mM CaCl2) were maintained on 12–14°C. The characteristics of IKs current recorded from cells stored in KB solution did not differ from those stored in isolation solution. At least 1 h was allowed before the start of the experiments.
2.3 Solutions used for cell isolation:
The composition of the solutions was as follows (in mM): (a) cardioplegic solution: NaCl 110, KCl 16, MgCl2 16, CaCl2 1.2, NaHCO3 10; (b) isolation solution (Ca2+-free): NaCl 135, KCl 4.7, KH2PO4 1.2, MgSO4 1.2, HEPES 10, Na pyruvate 5, taurine 20, NaHCO3 4.4, glucose 10 (pH 7.2 adjusted with NaOH); (c) KB solution: KOH 90, L-glutamic acid 70, taurine 15, KCl 30, KH2PO4 10, MgCl2 0.5, HEPES 10, glucose 11, EGTA 0.5 (pH 7.3 adjusted with KOH);
2.4 Experimental techniques and solutions
One drop of cell suspension was placed in a transparent recording chamber mounted on the stage of an inverted microscope (TMS Nikon Co, Tokyo, Japan) and the individual myocytes were allowed to settle to the bottom of the recording chamber for at least 5 min before superfusion. Only rod-shaped cells, which showed clear striations, were used. Although the yield varied greatly between isolations (from 5 to 70%), the ease with which seals were formed, the stability of the seals and the quality of the measurements did not correlate with yield. Cell capacitance (182±15 pF, n = 19) was measured by applying 10 mV hyperpolarizing pulse from –10 mV. The holding potential was –90 mV. The capacity was measured by integration of the capacitive transient divided by the amplitude of the voltage step (10 mV). HEPES-buffered Tyrode's solution was used as normal superfusate. This solution contained (mM): NaCl 144, NaH2PO4 0.33, KCl 4.0, CaCl2 1.8, MgCl2 0.53, glucose 5.5, and HEPES 5.0 at pH of 7.4. Superfusion was maintained by gravity flow. E-4031 (obtained as a gift from the Institute for Drug Research, Budapest, Hungary) was prepared freshly daily as a 5-mM aqueous stock solution. Final bath concentrations of 1–5 µM E-4031 were chosen for experiments on the basis of studies showing that these concentrations completely blocked IKr in guinea pig myocytes [7]. Chromanol 293 B (obtained as a gift from the Hoechst AG, Frankfurt, Germany) was also prepared freshly daily in 50% ethanol as a 5-mM stock solution. L-735,821 (obtained as a gift from Merck-Sharpe & Dohme, NY, USA) was prepared in 100% DMSO as a 1-mM stock solution and was used at 100 nM in order to completely block IKs as reported in dog [14]. Micropipettes were fabricated from borosilicate glass capillaries (Clark, Reading, UK) using a microprocessor controlled horizontal puller (Sutter Instruments Co., Novato CA, USA) and had a resistance of 1.5–2.5 MOhm when filled with a solution containing (in mM) KOH 100, KCl 20, K2HPO4 10, MgCl2 5, K2EGTA 5, HEPES 10, Na2ATP 5, KADP 0.5, Na pyruvate 5, glutamate 5, creatine 5, glucose 5. The pH of the solution was adjusted to 7.2 with aspartic acid. The external solution contained 1 µM nisoldipine (kind gift form Bayer Hungary Ltd, Budapest) in order to completely block the inward Ca2+ current (ICa). To increase the amplitude of IKs most of the experiments were carried out in the presence of 1 µM forskolin. The inward sodium current (INa) was inactivated by applying a holding potential of –40 mV, which largely inactivated the transient outward current (Ito) as well. The membrane currents were recorded with Axopatch-1D and Axopatch-200B patch-clamp amplifiers (Axon Instruments, Foster City CA, USA) using the whole-cell configuration of the patch-clamp technique. After establishing high (1–10 GOhm) resistance seals by gentle suction, the cell membrane beneath the tip of the electrode was disrupted by further suction or by applying 1.5 V electrical pulses for 1–5 ms. The series resistance was typically 4–8 MOhm before compensation (usually 50–80% depending on the voltage protocols). Those experiments in which the series resistance was high, or substantially increased during the measurements, were discarded from the analysis. The membrane currents were digitized using a 333-kHz analog-to-digital converter (Digidata 1200, Axon Instruments, Foster City CA, USA) under software control (pClamp 6.0 and 7.0, Axon Instruments). The results were analyzed using software programs purchased from Axon (pClamp 6.0 and 7.0, Axon Instruments) and were low-pass filtered at 1 kHz. The experiments were carried out at 37°C. Numerical data are expressed as mean±S.E.M.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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Results were obtained from 31 cells from 15 hearts (average 2.1 cells/heart, range 1–4). We specifically chose to use only cells with high-quality seals and low, stable series resistance (Rs), opting for a smaller number of excellent recordings from each preparation rather than more recordings of variable quality. In additional 27 cells we could either not observe IKs or the IKs amplitudes were so small that it was difficult to distinguish the current from the noise.
Fig. 1A shows tail currents elicited by test pulses to 50 mV with gradually increasing duration (from 10 to 5000 ms). In this particular experiment the pulse frequency was 0.05 Hz. This was necessary because the deactivation of IKr in human myocyte is very slow [12]. However, in the rest of the study where IKr was abolished by E-4031, we applied a pulse frequency of 0.1 Hz which allowed for the E-4031 insensitive tail current to be fully deactivated. The current was activated with a double exponential time course (fast=22.4 ms, slow=2388 ms) suggesting that it represented both IKr and IKs currents. Complete block of IKr by 5 µM E-4031 markedly reduced the amplitude of the tail currents and changed its activation to a single exponential ( = 1763 ms) with a slow time course (Fig. 1B). Additional superfusion of the cell with 30 µM chromanol 293B, a blocker of IKs, entirely abolished this residual tail current suggesting that this current indeed represented IKs (Fig. 1C). All of the other experiments on IKs, therefore, were performed in the presence of 1 or 5 µM E-4031 to completely block IKr, thereby facilitating the separation of IKs from IKr.
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Since IKs is relatively small, and other currents (transient outward, non-specific cation, chloride and Na+/Ca2+ exchanger currents) could be also activated during depolarizing pulses and during the time course of experiments, the tail current after the end of the test pulse was measured to assess IKs.
An instantaneous, background-like, outward current was often developed in long lasting (45–90 min) measurements (see Figs. 1 and 2
). This may represent a current activated because of the dialysis between the pipette and the intracellular milieu.
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Fig. 2A and B show representative current traces in the presence of 1 µM E-4031 under control conditions and after application of 100 nM L-735,821, respectively. The inset in Fig. 2A indicates that the IKs tail current deactivated rapidly (
= 122.4±11.7 ms, from 50 mV, n = 19) and was completely eliminated by L-735,821, another more specific blocker of IKs (see Fig. 2B). Fig. 2C indicates average data obtained in 12–14 cells showing the IKs tail current normalized to the cell capacitance in respect to gradually increasing voltages. Currents were studied at a holding potential (HP) of –40 mV. The cells were depolarized with 5000 ms long test pulses between –10 and +50 mV and then clamped back to –40 mV. Tail current amplitude was measured as the difference between the peak and the steady state current level at the end of the pulse after returning back to –40 mV HP. Fig. 3 shows the activation kinetics of IKs tail current. To determine the activation kinetics of IKs we used the envelope of tails test protocol. From holding potential of –40 mV test pulses to 50 mV were applied with increasing duration ranging from 100 to 5000 ms and the amplitude of the tail currents was measured. Fig. 3 contains the result of a representative experiment, indicating that activation of the tail current was rather slow (903±101 ms at 50 mV, n = 14). In some cells, the voltage dependence of activation of IKs was also studied. The activation kinetics of the IKs tail current measured at –40 mV was apparently not voltage dependent in the test voltage range of 10–60 mV (Fig. 4A and B).
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The voltage dependence of the deactivation kinetics of IKs current was determined by the following protocol: IKs current was activated by 5-s long test pulse to 50 mV from a holding potential of –40 mV. Then the cells were clamped back to different voltages ranging from –50 to 0 mV. Fig. 4C indicates that the deactivation of IKs tail current was clearly voltage dependent, i.e. being faster at negative voltages (about 100 ms at –50 mV) and slower at depolarized potentials (about 300 ms at 0 mV).
The reversal potential of IKs was measured by clamping the cells back to voltages between –100 and 0 mV after a 5000-ms long depolarizing pulse to 50 mV from a holding potential of –40 mV. The results of a representative experiment are shown in Fig. 5. The tail current in these measurements was determined as L-735,821 sensitive current (subtracting the current traces before and after application of 100 nM L-735,821). In six cells, the reversal potential was –81.6±2.8 mV on an average which is close to the K+ equilibrium potential suggesting K+ as the main charge carrier.
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Li et al. [11] reported a relatively large (about 200 pA) IKs tail current in myocytes obtained from the right ventricle in failing human hearts. In this latter study the extracellular solution contained Cd2+ and Ba2+ to block ICa and IK1. These divalent ions, however, markedly alter the kinetics of IK [12,15] and in particular Ba2+ blocks IK1 in a voltage-dependent manner [16]. Therefore, in some cells we also measured ‘IKs’ in the presence of 0.5 mM BaCl2. As Fig. 6 shows, in the presence of the selective blocker of IKr (1 µM E-4031) and IKs (100 nM L-735,821), as expected, no tail current was recorded at –40 mV after a step potential to +30 mV for various durations. Cells were then exposed to 0.5 mM BaCl2 that elicited a slowly developing tail current that resembled IKs, as it was also found in two other cells. However, since both IKs and IKr were completely blocked by 100 nM L-735,821 and 1 µM E-4031 this current could not be due to the activation of IK.
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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The main finding of the present study is that IKs exists in undiseased human ventricular myocytes and, as in the dog ventricle, exhibits slow activation and relatively rapid deactivation kinetics.
Earlier reports regarding the existence of IKs in human ventricular myocytes were controversial. In some studies using diseased human ventricles no evidence was found for IKs [10,17–19]. In our previous study we could identify IKr but not IKs in undiseased human ventricular cells [12]. In the present study, we made use of a different pipette solution to that used earlier [12], and it is not yet clear which component of this solution is important for recording IKs. It is also worth noting that the amplitude of the IKs tail current reported here is relatively small even in the continuous presence of 1 µM forskolin. In addition, in 27 out of 58 cells IKs was either absent or was too small to be distinguished from the noise. In an earlier report it was suggested that IKs might be particularly sensitive to the isolation technique and as such it was difficult to measure it in human preparations [11].
One may speculate that this new pipette solution contained more free K+ than that used in our previous experiments, and also contained HPO42– and ADP, which could enhance intracellular ATP synthesis. In addition, the osmolarity of the new pipette solution was higher than that used previously. This may explain the development of an instantaneous outward current during the time course of our experiments due to the activation of the swelling induced chloride channels. In this study however no attempt was made to clarify the nature of this current.
As mentioned above, in a fairly large number of cells in this study and in the cells in our previous study [12] no discernible IKs was recorded. It can not be ruled out either that, in addition to the unavoidable slight variation in the cell isolation technique, and the change in pipette solution, the cells might have originated from different layers of the ventricular wall, thereby reflecting regional heterogeneity of the cells rather than merely a technical reason.
As already mentioned, in an earlier study in human ventricular myocytes [11] a relatively large E-4031 insensitive and indapamide sensitive tail current was observed in the presence of Cd2+ and Ba2+. This is the only study so far in which IKs was reported in human ventricular cells. With Ba2+ in the extracellular solution, however, we could record an IKs like tail current in the presence of IKs and IKr blockers. Hirano et al. [16] showed that the Ba2+ induced IK1 block disappeared at positive step potentials, and slowly developed again after returning to negative voltages and may have appeared as a tail current. We therefore speculate that this tail current could be the result of voltage-dependent interactions of Ba2+ with IK1 channels. In the study of Li et al. [11], high concentration of indapamide (1 mM) was used to block IKs and separate it from IKr. However, indapamide at high concentrations blocks both IKs and IK1 currents [20] and as such it could depress both the IKs tail current and the IK1 current evoked by BaCl2, thereby making interpretation of this study of IKs uncertain.
Cloned human KvLQT1+MinK channels expressed in COS cells [21] shared some similar properties (activation range, and kinetics) with the current described in this paper. However, the deactivation of the cloned channel seems considerably slower than that of the native current presented in our study. Further data to be obtained under more similar experimental conditions are necessary to understand the reason for the difference between the native and cloned human IKs currents.
The properties of IKs measured in the present study most closely resembled those described in dog [8,14] and rabbit [22] ventricular myocytes, i.e. having slow activation and fast deactivation kinetics. The amplitude of IKs in human seems to be smaller than that reported in dog and rabbit. Whether this is the consequence of the less well-developed cell isolation technique applied in human or reflects different channel densities, remains to be clarified in further studies.
4.1 Possible limitation of the study
This study may have some limitations. The relatively infrequent and irregular access to human heart makes difficult to obtain large number of cells and sometimes to get sufficiently long lasting seals. This is a limitation, which is almost impossible to avoid. It was also previously reported that IKs is rather sensitive to the isolation technique [11]. Therefore, it can not be ruled out that during the isolation procedure we damaged some of the transmembrane ionic channels particularly IKs. In spite of these obvious limitations, however, we think that the successive measurements presented in this study provide important evidence about the existence of IKs and help to elucidate some of its basic properties in undiseased human ventricular cells.
4.2 Potential significance
Our results provide further evidence of the existence of IKs in the human ventricle. This finding is relevant to previous molecular biology experiments in which expression of the gene encoding this channel was identified [23,24], and mutations were identified that may lead to a disease called long LQT1 syndrome [25]. The exact role of IKs controlling normal repolarization seems to be uncertain since the current activates slowly and at relatively positive potential compared to the duration and the voltage range of the plateau phase of the action potential. Also, selective blockers of IKs did not lengthen substantially the normal action potential in the dog papillary muscle, unless other repolarizing currents were affected [14]. Further studies are now needed to elucidate the role of IKs in the repolarization in the normal human ventricle.
Time for primary review 24 days.
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Acknowledgments |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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This work was supported by grants from the Hungarian National Research Foundation (OTKA T-020604, T-032558), Hungarian Ministry of Health (ETT T-06 125/POT97, 536/2000, T-06 037/1998, 532/2000), Hungarian Ministry of Education (FKFP 1025/1997), the Hungarian Academy of Sciences and by a János Bolyai Research Scholarship (for VL). The authors would like to thank Dr Uwe Gerlach (Hoechst AG, Germany) and Dr Joseph J. Salata (Merck-Sharpe & Dohme, NY, USA) who kindly provided chromanol 293 B and L-735,821. The authors are grateful to Professor G. Dockray for revising the English of the manuscript.
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