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Role of ATP-sensitive K⁺ channels in electrophysiological alterations during myocardial ischemia: a study using Kir6.2-null mice

¹Department of Pharmacology and ²Department of Cellular and Molecular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan

Submitted 13 July 2004 ; accepted in final form 25 August 2004

	ABSTRACT

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The role of cardiac ATP-sensitive K⁺ (K_ATP) channels in ischemia-induced electrophysiological alterations has not been thoroughly established. Using mice with homozygous knockout (KO) of Kir6.2 (a pore-forming subunit of cardiac K_ATP channel) gene, we investigated the potential contribution of K_ATP channels to electrophysiological alterations and extracellular K⁺ accumulation during myocardial ischemia. Coronary-perfused mouse left ventricular muscles were stimulated at 5 Hz and subjected to no-flow ischemia. Transmembrane potential and extracellular K⁺ concentration ([K⁺]_o) were measured by using conventional and K⁺-selective microelectrodes, respectively. In wild-type (WT) hearts, action potential duration (APD) at 90% repolarization (APD₉₀) was significantly decreased by 70.1 ± 5.2% after 10 min of ischemia (n = 6, P < 0.05). Such ischemia-induced shortening of APD₉₀ did not occur in Kir6.2-deficient (Kir6.2 KO) hearts. Resting membrane potential in WT and Kir6.2 KO hearts similarly decreased by 16.8 ± 5.6 (n = 7, P < 0.05) and 15.0 ± 1.7 (n = 6, P < 0.05) mV, respectively. The [K⁺]_o in WT hearts increased within the first 5 min of ischemia by 6.9 ± 2.5 mM (n = 6, P < 0.05) and then reached a plateau. However, the extracellular K⁺ accumulation similarly occurred in Kir6.2 KO hearts and the degree of [K⁺]_o increase was comparable to that in WT hearts (by 7.0 ± 1.7 mM, n = 6, P < 0.05). In Kir6.2 KO hearts, time-dependent slowing of conduction was more pronounced compared with WT hearts. In conclusion, the present study using Kir6.2 KO hearts provides evidence that the activation of K_ATP channels contributes to the shortening of APD, whereas it is not the primary cause of extracellular K⁺ accumulation during early myocardial ischemia.

ATP-sensitive potassium channel; electrophysiology

The molecular structure of the cardiac K_ATP channel has been defined as an octametric complex of four pore-forming Kir6.2 and four SUR2A sulfonylurea receptors (20). Using mice with homozygous knockout of Kir6.2 gene (Kir6.2 KO) (14), previous studies in our laboratory (23, 24) showed that neither K_ATP channel openers nor metabolic inhibition abbreviates action potentials in Kir6.2 KO mouse ventricular myocytes. Therefore, Kir6.2 KO mice have no functional sarcolemmal K_ATP channels in cardiac cells and are potentially useful to examine whether K⁺ efflux through K_ATP channels is mainly involved in extracellular K⁺ accumulation in ischemic hearts. In this study, we used coronary-perfused Kir6.2 KO mouse hearts and investigated the electrophysiological alterations and extracellular K⁺ accumulation during the early phase of myocardial ischemia.

	MATERIALS AND METHODS

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Kir6.2-deficient mice. A mouse line deficient in K_ATP channels was generated by targeted disruption of the gene coding for Kir6.2, as described previously (14). C57BL/6 mice were used as controls because the KO animals had been backcrossed to a C57BL/6 strain for five generations. All procedures complied with the Guide for the Care and Use of Laboratory Animals (NIH Pub. No. 85–23, 1996 revision) and were approved by the Institutional Animal Care and Use Committee of Chiba University.

Coronary-perfused ventricular preparations. Mice were anesthetized with urethane (1.5 g/kg ip) and anticoagulated with heparin (100 U/kg iv). The hearts were then dissected out and mounted on a Langendorff apparatus. The right and left atria, right ventricular free wall, and septum were removed. The preparation was then mounted in a recording chamber and coronary perfused at a constant flow (2 ml/min) with Tyrode solution containing (in mM) 125 NaCl, 4 KCl, 1.8 NaH₂PO₄, 0.5 MgCl₂, 2.7 CaCl₂, 5.5 glucose, and 25 NaHCO₃ and gassed with 95% O₂-5% CO₂. The surface of the preparation was superfused with substrate-free hypoxic Tyrode solution (5 ml/min) to minimize direct O₂ diffusion from the surface of the preparation into the myocardium interior. The hypoxic Tyrode solution had the same composition as given above, except that it contained no glucose and was gassed with 95% N₂-5% CO₂. The temperature of these solutions was maintained at 36 ± 0.5°C. The coronary flow was completely stopped by closing the electromagnetic valve placed close to the aorta, producing no-flow ischemia of the entire preparation.

Action potential recordings. The basal portion of the preparation was stimulated at 5 Hz throughout the experiment with the use of a pair of platinum electrodes (2-ms rectangular pulses at 2x threshold intensity). Action potentials were recorded from a cell that was located deep (>5 cell layers) in the subepicardial surface by use of a 3 M KCl-filled microelectrode (tip resistance 10–20 M). A direct current preamplifier (MEZ-7200; Nihon Kohden, Tokyo, Japan) was used to record transmembrane potential.

Measurement of [K⁺]_o. [K⁺]_o was monitored continuously with K⁺-selective microelectrodes, as previously described (17). The tips of glass microelectrodes were filled with dimethyldichlorosilane and then baked at 200°C for 1 h. After naturally cooling at room temperature, the K⁺ exchanger (IE190; World Precision Instruments, Sarasota, FL) was introduced to the tip of the electrode and the shaft was backfilled with 500 mM KCl. The K⁺-selective microelectrode was coupled via an Ag-AgCl junction to a high-input impedance amplifier (FD223; World Precision Instruments). Only the K⁺-selective electrodes that exhibited responses >55 mV per 10-fold change in [K⁺]_o (57.3 ± 1.0 mV, n = 16) were accepted for use. Electrodes were calibrated in vitro before and after experiments with Tyrode solution containing different K⁺ concentrations. The results are reported in concentrations rather than activity units.

Measurements of effective refractory period and conduction time. Effective refractory periods (ERPs) were determined by the standard extrastimulus technique. Action potentials were evoked by electrical field stimulation at 5 Hz (2-ms rectangular pulses at 2x threshold intensity). Extrastimuli (S2) were interposed at varying intervals during periods of continuous basic stimuli (S1). ERP was defined as the longest S1-S2 interval that failed to generate an active response. Conduction time was designated as the interval from the stimulus artifact to the action potential upstroke.

Chemicals. Glibenclamide (Sigma, St. Louis, MO) was dissolved as a 10 mM stock solution in dimethyl sulfoxide. Dimethyldichlorosilane was purchased from Wako (Osaka, Japan).

Data acquisition and statistical analysis. Records were simultaneously displayed on an oscilloscope, digitized with an analog-to-digital converter (Mac Lab/2e; ADInstruments, Castle Hill, Australia), and stored on disk in a personal computer (PowerMac 7300/180; Macintosh) with a MacLab data acquisition system (AD Instruments). All data are presented as means ± SE. The number of experiments is shown as n. Intergroup comparisons were made by ANOVA followed by Fisher's post hoc test for multiple groups. A value of P < 0.05 was regarded as significant.

	RESULTS

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Alterations in action potentials. Representative recordings of action potentials before and after 2 and 10 min of ischemia are shown in Fig. 1. No-flow ischemia shortened APD and produced depolarization of resting membrane potential (RMP) in wild-type (WT) hearts (Fig. 1A). The APD in Kir6.2 KO hearts was prolonged at 2 min of ischemia, and the abbreviation of APD was not observed after 10 min of ischemia. The ischemia-induced shortening of APD was attenuated in glibenclamide (1 µM)-treated (WT+Glb) hearts. On the other hand, the depolarization of RMP was observed in both Kir6.2 KO and WT+Glb hearts (Fig. 1, B and C). Figures 2 and 3 summarize the time courses of changes in APD₉₀ and RMP during no-flow ischemia, respectively. There were no significant differences in the basal action potential parameters between WT and Kir6.2 KO hearts. During no-flow ischemia, APD₉₀ decreased significantly from 67.4 ± 2.7 to 19.4 ± 3.5 ms (n = 6, P < 0.05) after 10 min of ischemia in WT hearts. The APD₉₀ shortening during ischemia was significantly attenuated by glibenclamide, and the APD₉₀ change after 10 min of ischemia was not statistically significant in WT+Glb hearts [from 61.8 ± 1.7 to 51.3 ± 7.1 ms; n = 6, P = not significant (NS)]. In Kir6.2 KO hearts, APD₉₀ shortening was not observed over 10 min (from 61.2 ± 3.4 to 84.0 ± 5.7 ms; n = 6, P = NS) and APD₉₀ was rather prolonged transiently at 1.5 min of ischemia (101.0 ± 5.3 ms, P < 0.05). RMP decreased markedly during the first 2 min and thereafter gradually declined during no-flow ischemia in WT hearts (from –74.0 ± 2.4 to –57.8 ± 2.7 mV; n = 7, P < 0.05). A similar time course of RMP changes was observed in both Kir6.2 KO (from –72.0 ± 0.8 to –57.9 ± 1.6 mV; n = 6, P < 0.05) and WT+Glb (from –74.8 ± 1.8 to –59.2 ± 1.5 mV; n = 6, P < 0.05) hearts, and there were no significant differences among the three groups.

View larger version (20K): [in this window] [in a new window]   Fig. 1. Representative recording of action potentials before (control, left) and after 2 (middle) and 10 (right) min of ischemia in wild-type (WT, A), Kir6.2-deficient [Kir6.2 knockout (KO), B], and glibenclamide-treated WT (WT+Glb, C) mouse hearts.

View larger version (26K): [in this window] [in a new window]   Fig. 2. Time course of the changes in action potential duration measured at 90% repolarization (APD90) during ischemia in WT (n = 6), Kir6.2 KO (n = 6), and WT+Glb (n = 6) mouse hearts. Values are expressed as means ± SE. *P < 0.01 vs. WT.

View larger version (19K): [in this window] [in a new window]   Fig. 3. Time course of the changes in resting membrane potential (RMP) during ischemia in WT (n = 7), Kir6.2 KO (n = 6), and WT+Glb (n = 6) mouse hearts. Values are expressed as means ± SE.

View larger version (27K): [in this window] [in a new window]   Fig. 4. Time course of the changes in extracellular K+ concentration ([K+]o) during ischemia in WT (n = 6), Kir6.2 KO (n = 6), and WT+Glb (n = 4) mouse hearts. Top: rate of change of [K+]o ([K+]o) during 2-min intervals. Values are expressed as means ± SE.

View larger version (27K): [in this window] [in a new window]   Fig. 5. A: superimposed action potentials obtained at before (C) and 8 min after (I) ischemia in WT, Kir6.2 KO, and WT+Glb mouse hearts. Action potentials are presented in reference to stimulus artifact. B: time course of the changes in conduction time during ischemia in WT (n = 5), Kir6.2 KO (n = 5), and WT+Glb (n = 5) mouse hearts. Values are expressed as means ± SE. *P < 0.01 vs. WT.

View larger version (18K): [in this window] [in a new window]   Fig. 6. Time course of the changes in effective refractory periods (ERPs, A) and ratio of ERP to APD90 (ERP/APD90, B) during ischemia in WT (n = 7), Kir6.2 KO (n = 6), and WT+Glb (n = 5) mouse hearts. Values are expressed as means ± SE. #P < 0.05, *P < 0.01 vs. WT.

	DISCUSSION

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The present experiments show that the ischemia-induced shortening of APD was not observed in Kir6.2 KO hearts (Figs. 1 and 2). In addition, glibenclamide greatly attenuated APD shortening during ischemia. Therefore, our data add further support to the widely accepted notion that activation of K_ATP channels is responsible for APD shortening during myocardial ischemia (18). Somewhat unexpectedly, we found that APD was rather prolonged transiently during the early phase of ischemia in Kir6.2 KO hearts. Apart from the activation of K_ATP channels, marked electrophysiological alterations occur in ischemic myocardium, thereby modulating action potential configuration (1). For example, lysophosphatidylcholine, a lipid metabolite, accumulates rapidly in ischemic myocardium and has been shown to inhibit inward rectifier K⁺ current (I_K1) (3, 12). The transient outward current (I_to) has been shown to decrease under condition of metabolic stress (25). Thus the inhibition of outward currents other than the K_ATP channel current might lead to the prolongation of APD when complete K_ATP channel blockade is achieved by the genetic deletion.

A rise in [K⁺]_o is a major factor contributing to the development of lethal ventricular arrhythmias during acute myocardial ischemia (6, 9). It has been reported that the change in [K⁺]_o typically occurs with triphasic time courses, the initial fast rise followed by a secondary plateau phase and a third slower increase (30). Because previous studies showed that the sulfonylureas modulate the initial rate of rise of [K⁺]_o (7, 11, 15, 27, 31), our attention has been focused primarily on the first two (initial rise and subsequent plateau) phases. In the present experiments, we continuously monitored [K⁺]_o for a period of 10 min of ischemia and found that [K⁺]_o increased in a biphasic manner comprising an initial rising phase and a second plateau phase. A third phase was observed when the monitoring was continued up to 20 min (data not shown). The most striking finding is that [K⁺]_o in Kir6.2 KO hearts increased during early ischemia in a manner similar to that of WT hearts (Fig. 4). Furthermore, glibenclamide did not affect extracellular K⁺ accumulation during early ischemia, despite effective suppression of the ischemia-induced shortening of APD (Figs. 2 and 4). Although major support for the K_ATP channel hypothesis has come from pharmacological studies, the suitability of glibenclamide for assessment of involvement of K_ATP channels has been seriously questioned (19). Our study using Kir6.2 KO mice definitely indicates that K_ATP channel activation is not the primary cause of the extracellular K⁺ accumulation. In terms of the mechanism(s) of ischemia-induced increase in [K⁺]_o, several possibilities such as activation of Na⁺-activated K⁺ channel (16), delayed rectifier K⁺ channel (29), K⁺-Cl^– cotransporter (33), Na⁺-K⁺-2Cl^– cotransporter (16), and lactate transport (21) have been raised. Recently, Shivkumar et al. (22) proposed that intracellular Na⁺ accumulation produces passive K⁺ loss in hypoxic myocardium and K⁺ channels including K_ATP channel function only as a K⁺ diffusion pathway. Our findings that extracellular K⁺ accumulation similarly occurred in K_ATP channel-deficient myocardium may be consistent with their hypothesis.

In the present investigation, the ischemia-induced depolarization of RMP occurred similarly in both WT and Kir6.2 KO hearts (Fig. 3). These findings can be interpreted as showing that the resulting [K⁺]_o increase then depolarizes RMP in ischemic hearts. In principle, the depolarization of RMP inactivates Na⁺ channels, thereby causing the conduction delay (9). In the present study, conduction time was prolonged in all groups, accompanied by the depolarization of RMP. However, it should be mentioned that, despite the fact that similar changes in RMP occurred in WT and Kir6.2 KO hearts, the conduction delay was more pronounced in Kir6.2 KO hearts. Propagation of electrical activity is dependent not only on the stimulatory current provided by the action potential upstroke but also on the resistive elements in the current circuit, i.e., gap junction resistance. An increase in the intracellular concentration of Ca²⁺ can lead to a reduction of gap junction conductance (4). Indeed, a previous study documented that cellular uncoupling occurs in ischemic myocardium and the Ca²⁺ antagonist verapamil prevents the ischemia-induced conduction slowing (8). We previously found (24) that it took more time for the cessation of ventricular contraction during global ischemia in isolated Kir6.2 KO hearts compared with WT hearts, probably because of the lack of APD shortening and resultant Ca²⁺ influx during plateau phase. In addition, the increase in left ventricular end-diastolic pressure during ischemia was more marked in Kir6.2 KO hearts than in WT hearts, suggesting that greater Ca²⁺ overload might occur in ischemic heart cells of Kir6.2 KO mice. Moreover, the third phase of K⁺ accumulation, which occurs with electrical cell-to-cell uncoupling (2), was observed earlier in Kir6.2 KO hearts. Therefore, it is reasonable to assume that the inhibition of gap junction caused by Ca²⁺ overload might produce a greater conduction delay in Kir6.2 KO hearts.

Activation of K_ATP channels can theoretically be expected to increase the incidence of reentrant arrhythmias in ischemic hearts, because of APD shortening and K⁺ efflux (32). However, we found that extracellular K⁺ accumulation is not primarily attributable to the activation of K_ATP channels. In addition, as evidenced in Fig. 6, opening of K_ATP channels did not shorten ERP but rather produced postrepolarization refractoriness (5, 13). Activation of K_ATP current might counteract the depolarizing current, thereby contributing to the establishment of postrepolarization refractoriness. As discussed above, activation of K_ATP channels may rather lead to a decrease in Ca²⁺ influx during ischemia, which in turn could prevent the conduction delay. Thus opening of K_ATP channels is by no means proarrhythmic and may rather reduce the incidence of arrhythmias by preventing early and delayed afterdepolarizations as well as producing postrepolarization refractoriness. Unfortunately, however, neither WT nor Kir6.2 KO mice developed ischemic ventricular arrhythmias in our experimental condition, perhaps because global ischemia produces little heterogeneity in the electrophysiological alterations. Further studies using larger mammals would be required to establish the contribution of K_ATP channels to ischemia-related arrhythmias.

It is well known that configuration of cardiac action potentials varies from species to species. Mouse ventricular cells show a relatively short action potential with negative plateau voltage. Because a different action potential configuration reflects a difference in the balance between inward and outward currents, the relative impact of K_ATP channel activation on APD shortening and extracellular K⁺ accumulation during myocardial ischemia may differ between mouse hearts and those of larger mammals. Therefore, the extrapolation of the results observed in this study to larger mammals including humans should be made with caution.

The most important conclusion of this study using the Kir6.2 KO heart is that K_ATP channel activation is not the primary cause of the extracellular K⁺ accumulation during early ischemia, although it contributes to the shortening of APD. These findings provide new insights concerning antiarrhythmic and arrhythmogenic potential of K_ATP channels in ischemic hearts.

	GRANTS

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This work was supported by Grants-in-Aid for Scientific Research, the K. Watanabe Research Foundation, and the Vehicle Racing Commemorative Foundation.

	ACKNOWLEDGMENTS

 
We are grateful to M. Tamagawa, Y. Reien, and I. Sakashita for excellent technical and secretarial assistance. We thank H. Uemura, T. Ogura, and M. Suzuki for giving a great suggestion.

Present address of S. Seino and T. Miki: Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.

	FOOTNOTES

 

Address for reprint requests and other correspondence: H. Nakaya, Dept. of Pharmacology, Chiba Univ. Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan (E-mail: nakaya{at}faculty.chiba-u.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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