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Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska 68198-4575
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The aim of the present study was to define the cellular mechanisms underlying changes in K+ channel function in the failing heart after myocardial infarction. Rats with left coronary artery ligation were prepared and allowed to recover for 16 wk before study. Animals with chronic infarction exhibited marked cardiac hypertrophy and signs of heart failure, as indicated by a nearly twofold increase in heart weight- and lung weight-to-body weight ratios, respectively, compared with time-matched controls. Cardiac hypertrophy was also evident by a 49% increase in whole cell capacitance of isolated left ventricular myocytes (P < 0.05). Voltage-clamp experiments revealed that the maximum density of the Ca2+-independent, transient outward current (Ito), measured at +60 mV, was 42% less in myocytes from infarcted hearts than in myocytes from control hearts (P < 0.05), whereas the inward rectifier current (IK1) density was not different between groups. The reduced Ito density in the infarcted group was reversed, however, in 4-5 h by treatment with exogenous dichloroacetate or pyruvate, both activators of pyruvate dehydrogenase. Moreover, control myocytes incubated for 6 h in the presence of an inhibitor of pyruvate dehydrogenase, 3-bromopyruvate, exhibited a concentration-dependent decrease in Ito density compared with untreated cells. The present data demonstrate that Ito density is reversibly decreased in surviving myocytes from infarcted hearts and suggest that mechanisms related to glucose metabolism via pyruvate dehydrogenase may be involved. These postinfarction changes in myocyte Ito channel function may relate to impaired contractility and arrhythmogenesis, which are characteristic of the intact, failing heart.
potassium channels; pyruvate dehydrogenase
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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THE DEPRESSED VENTRICULAR performance that characterizes clinical congestive heart failure is often accompanied by a high incidence of sudden cardiac death that may account for up to 50% of the annual deaths in this patient population (21). Sudden cardiac death in patients with heart failure is thought to result from ventricular arrhythmias, although the cellular mechanisms of arrhythmogenesis in this pathophysiological condition are poorly understood. One consistent finding that has emerged from several electrophysiological studies of this disease state and that may explain the high incidence of sudden death seen clinically is an abnormal prolongation in myocyte action potential duration relative to control (2, 8, 15, 19). From the standpoint of arrhythmogenesis, it may be postulated that abnormally delayed repolarization enhances dispersion of refractoriness and the propensity for reentrant arrhythmias, or it may initiate bradycardia-dependent triggered activity from early afterdepolarizations (21). In addition, delayed repolarization may influence the magnitude and kinetics of muscle contraction, thereby further altering ventricular performance (3, 10).
Explanations for delayed repolarization in the failing heart have focused on the probable imbalance of ionic currents flowing during the plateau phase of the action potential. Recent experimental data suggest that action potential prolongation in myocytes from animals with heart failure is due to a net decrease in outward repolarizing current and/or an increase in inward depolarizing current. A major outward current that controls action potential duration in ventricular myocytes is the Ca2+-independent, transient outward K+ current (Ito), which has been shown to be downregulated in experimental heart failure (8, 15, 19). This current also exists in the human heart, and recent studies suggest that reduced Ito may contribute to the prolonged action potential duration in myocytes from heart failure patients (3, 10). Nevertheless, the cellular mechanisms by which Ito or other ionic currents are altered in heart failure are unknown.
The present investigation studied ion channel function in ventricular myocytes isolated from rat hearts 16 wk after coronary artery ligation. We focused on the characteristics of two major K+ currents that control action potential duration: Ito and the inward rectifier current (IK1). In addition, we assessed the metabolic basis of some of the changes in electrophysiology in a subset of myocytes from infarcted hearts exposed to dichloroacetate (DCA) or exogenous pyruvate as activators of glucose oxidation at the level of pyruvate dehydrogenase (PDH).
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Coronary artery ligation. A chronic, postinfarction model of heart failure was used in the present investigation as described previously (12, 13). Briefly, male Sprague-Dawley rats (250-350 g) were intubated and artificially ventilated with a respirator under methohexital sodium (Brevital) anesthesia (50 mg/kg ip). A left thoracotomy was performed, and the left coronary artery was ligated by a suture positioned between the pulmonary artery outflow tract and the left atrium. The thorax was closed, and the rats were allowed to recover for ~16 wk (16.8 ± 1.7 wk) before in vitro experimentation. This ligation protocol as used in our laboratory produces infarcts in >30% of the left ventricle in ~80% of rats and is accompanied by physiological signs of heart failure after several weeks (12, 13).
Isolation of ventricular myocytes. Left ventricular myocytes of epi- and endocardial origin were dissociated from perfused hearts by a collagenase digestion procedure described previously (17-19). Dispersed myocytes were suspended in sterile-filtered Dulbecco's modified Eagle's medium-Ham's F-12 (1.8 mM Ca2+, 0.5 mM pyruvate) containing penicillin (100 U) plus streptomycin (100 µg/ml) and stored in an incubator at 37°C until used, usually within 6 h of isolation. Aliquots of myocytes were transferred to a cell chamber mounted on the stage of an inverted microscope and superfused with standard external solution containing (in mM) 138 NaCl, 4.0 KCl, 1.2 MgCl2, 1.8 CaCl2, 10 glucose, 5 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, pH 7.4, and 0.5 mM CdCl2 to block Ca2+ channels. The cell chamber was continuously perfused with external solution at a rate of 1-2 ml/min by a roller pump. All experiments were done at room temperature (22-25°C).
Recording techniques.
Ionic currents were recorded using the whole cell configuration of the
patch-clamp technique. Specifically, borosilicate glass capillaries
were pulled to an internal tip diameter of 1-2 µm and filled
with standard pipette solution containing (in mM) 135 KCl, 3 MgCl2, 10 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, 3 Na2-ATP, 10 ethylene
glycol-bis(
-aminoethyl
ether)-N,N,N',N'-tetraacetic acid, and 0.5 Na-GTP, with pH adjusted to 7.2 with KOH. Filled pipettes
with resistances of 1-2 M
were coupled to a patch-clamp amplifier (Axopatch 1C, Axon Instruments), and after seal formation the
membrane within the pipette was ruptured. Whole cell capacitance (Cm) was then
calculated as the area under the capacitative transient divided by the
amplitude (5 mV) of an applied test pulse, and series resistance was
compensated by ~60-80%. Given the average, residual series resistance of our recording system, the maximal, uncompensated voltage error was <6 mV for the largest currents recorded. A computer program (pClamp, Axon Instruments) controlled command potentials and acquired current signals that were filtered at 2 kHz using a four-pole low-pass Bessel filter. Currents were sampled by
a 12-bit resolution analog-to-digital converter (Tecmar Labmaster) and
stored on the hard disk of a 486 computer.
40 and +60 mV (0.2 Hz). The holding potential in these
experiments was 80 mV, and a 100-ms prepulse was applied to
60 mV to inactivate the fast
Na+ current. At each test
potential the amplitude of
Ito was measured as the difference between peak outward current and the current level at
the end of the depolarizing clamp pulse.
IK1 was also measured in some myocytes with 100-ms test pulses applied from a
prepulse potential of 30 mV (holding potential = 80 mV).
Current-voltage (I-V) data were
recorded by changing the test potential from 120 to 40 mV
in 10-mV steps (0.2 Hz), and the amplitude of
IK1 was measured
at the end of each test pulse. Data for all
K+ currents were normalized as
current densities by dividing measured current amplitude by
Cm (pA/pF).
Data analysis. Values are means ± SE. Statistical comparisons of two groups were made using a Student's t-test, whereas comparison of more than two groups was carried out by analysis of variance. When a significant difference among groups was indicated by the initial analysis, individual paired comparisons were made using a Bonferroni modified t-test (22). Differences were considered significant at P < 0.05.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Characteristics of the experimental model. Table 1 summarizes the characteristics of the rat postinfarction model used in the present study. Heart weight and heart weight-to-body weight ratio were significantly greater in rats with infarction than in controls, indicating the presence of cardiac hypertrophy in the former group. In agreement with this change in cardiac structure, the mean Cm was 49% greater for isolated myocytes from infarcted hearts than for control myocytes (P < 0.05; Fig. 1). From the measurement of infarct weight, obtained after collagenase digestion of the heart, the size of infarction was estimated to be 20% of the total heart weight. Although we did not measure hemodynamic parameters in this group of infarcted rats, previous studies using this model in our laboratory (12, 13) have documented marked elevations in left ventricular end-diastolic pressure and other indexes of heart failure. In agreement with these findings, the present study also found a significant increase in lung weight and lung weight-to-body weight ratio in rats with infarction (Table 1).
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K+ channel
function: IK1 and
Ito.
To determine whether myocardial infarction altered
K+ channel properties in surviving
myocytes, we first examined the inward rectifier,
IK1. Figure
2A
compares raw currents recorded at test potentials from 40 to
120 mV in a control myocyte
(Cm = 152 pF) and
a myocyte isolated from an infarcted heart
(Cm = 252 pF). Although the steady-state current amplitude at all potentials was
larger in the myocyte from the infarcted heart, there was little
difference in current density between the two cells: 17.8 and
18.1 pA/pF for control and infarcted, respectively, measured at
120 mV. This is further illustrated in Fig.
2B, which plots mean
I-V relationships of
IK1 density as
measured in several myocytes from control and infarcted hearts. Over
the voltage range of 120 to 40 mV, there was no
significant difference between the mean I-V curves from the two groups of
myocytes. This lack of change in
IK1 density in
myocytes from infarcted hearts occurred even though mean
Cm in this group
was significantly greater than control: 253.7 ± 15.9 vs. 173.6 ± 7.7 pF (P < 0.05).
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40 to +60
mV in a control myocyte
(Cm = 161 pF) and
a myocyte isolated from an infarcted heart
(Cm = 275 pF). In
these examples, maximum
Ito amplitude
(+60 mV) in the control cell was ~39% greater than in the myocyte
from the infarcted heart (3,750 vs. 2,292 pA), whereas maximum
Ito density was
64% greater (23.3 vs. 8.3 pA/pF). Figure
3B plots the mean
I-V relationships for each group of
myocytes and demonstrates that
Ito density was markedly less in myocytes from infarcted hearts than in myocytes from
control hearts. Specifically, when compared at the test potential of
+60 mV, mean Ito
density in myocytes from the infarcted group was 42% less than control
(P < 0.05). As in the previous
series of experiments, mean
Cm was
significantly greater in the infarcted group than in the controls:
230.7 ± 9.8 vs. 179.9 ± 8.4 pF
(P < 0.05). Moreover, mean
I-V relationships of the steady-state current density measured at the end of depolarizing pulses were not
different between the groups of myocytes studied (data not shown).
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Normalization of Ito density by DCA and pyruvate. We recently reported that reduced Ito density in ventricular myocytes from rats with diabetic cardiomyopathy could be reversed by agents that increase glucose oxidation (23), suggesting that a metabolic mechanism may underlie changes in Ito channel function in this experimental model. To test whether there was a similar metabolic basis to the decrease in Ito density in the present postinfarction model, subsets of myocytes from infarcted hearts were examined after incubation with DCA or exogenous pyruvate as activators of glucose oxidation at the level of the PDH complex (20).
An initial series of experiments was conducted to examine the time dependence of DCA effects by incubating myocytes from infarcted hearts with 1.5 mM DCA (added to the culture medium) and measuring Ito in samples of myocytes taken at hourly intervals. Data from these experiments are summarized in Fig. 4A, which expresses the DCA-induced change in Ito density as a percentage of the mean maximum Ito density (measured at +60 mV) in untreated myocytes from the same infarcted heart. These data illustrate that DCA markedly increased Ito density in these myocytes but that this effect was not immediate, requiring at least 4-5 h of exposure to reach significance. Figure 4B compares raw currents recorded from an untreated myocyte with those recorded from a myocyte pretreated with DCA for 4 h. Cm was similar in both myocytes (241 and 225 pF in untreated and DCA, respectively), but maximum Ito density (at +60 mV) in the DCA-treated myocyte was more than twofold greater than in the untreated cell: 24.0 vs. 11.6 pA/pF.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Myocardial infarction and heart failure. The rat model of chronic myocardial infarction has been a useful experimental tool to study mechanisms of cardiac and peripheral adjustments in response to a marked loss of contracting myocardium. Previous studies using this model (7, 12, 13, 15) have documented significant hemodynamic alterations indicative of heart failure as well as heart hypertrophy (7, 12, 15). In the present study we also found evidence of hypertrophy (Table 1, Fig. 1). Although we did not measure intraventricular pressures in our rats, we assume that our animals were in failure, since lung weights were significantly increased in coronary-ligated rats (Table 1). However, although hypertrophy is a fundamental compensatory mechanism sustaining cardiac output after infarction, it is likely that hypertrophy alone was not a prerequisite for the changes in ion channel function reported in this study. For example, we have documented similar electrophysiological changes in a rabbit pacing-induced model of heart failure that is characterized by marked dilatation but no hypertrophy (18). We propose, therefore, that postinfarction changes in myocyte electrophysiology are related to but not dependent on changes in myocyte morphology.
A metabolic basis for decreased Ito density. Although IK1 was not altered in our experiments (Fig. 2), we found that Ito density was significantly reduced in myocytes from infarcted hearts compared with control (Fig. 3). This marked change is similar to that found in other studies using animal models (8, 15, 19) and in myocytes from failing human hearts (3, 10). It has been proposed that a decrease in Ito density partly underlies the increase in action potential duration observed in other studies (3, 8, 10, 15, 19). That is, a reduced outward current during the plateau would be expected to augment the effects of inward currents, thus prolonging action potential duration. In addition, reduced Ito in myocytes is consistent with a diminished phase 1 of the action potential, which is known to be controlled by this current system (3, 8, 10, 15, 19). However, despite the apparent relationship between reduced Ito density and delayed repolarization, some limitations of this hypothesis should be kept in mind. First, regional variations in Ito density have been well documented in the hearts of several species, including the rat (4), which may account for some of the quantitative changes in Ito density reported in this and other studies of pathophysiological states (3, 8, 10, 15, 19). Although we studied only left ventricular myocytes, we did not further separate myocytes on the basis of their epi- or endocardial origin. Second, other plateau currents (e.g., ICa, IK1, and the delayed rectifier IK) may contribute to changes in action potential morphology, but their importance may be underestimated because of differences in species or in the experimental conditions used to study them (8, 9).
The mechanisms underlying the decrease in Ito density in myocytes from failing hearts are not known. In a dog model of pacing-induced heart failure, Kääb et al. (8) showed that reduced Ito density is due to a decrease in the number of functional Ito channels, whereas unitary current amplitude and open probability are unaltered. They propose that a decrease in the number of channels may be due to an alteration in gene regulation of the channel protein. In support of this hypothesis, Gidh-Jain et al. (6) reported that the expression of the K+ channel subunit mRNA for the putative Ito (Kv4.2) is significantly reduced in the rat heart 3 wk after myocardial infarction, a time at which Ito density is significantly reduced (15). In our experiments, done 16 wk postinfarction, we found that reduced Ito density could be normalized by DCA (Figs. 4 and 5A) or exogenous pyruvate (Fig. 5C). This raises the possibility that a metabolic mechanism, related to depressed glucose oxidation, may underlie the decrease in Ito density in this model, although it remains to be determined whether a change in the number of functional channels or in gene regulation of the channel protein was involved. Indeed, the fact that it took several hours for DCA (Fig. 4A) or pyruvate to normalize Ito density suggests that alterations in protein synthesis may play a role. Support for a metabolic basis of Ito regulation has recently come from our laboratory, where we have reported that DCA normalizes depressed Ito in ventricular myocytes from rats with diabetic cardiomyopathy (23), a pathophysiological condition with well documented changes in metabolism (16). DCA increases glucose utilization in cardiac preparations at steps distal to the glucose transporter, primarily by increasing the activity of a key, mitochondrial regulatory enzyme involved in glucose oxidation: the PDH complex (1, 5, 20). This enzyme complex is also activated by exogenous pyruvate, which concurrently increases the flux of acetyl CoA through the tricarboxylic acid cycle (20). The present study suggests that the PDH complex may also be involved in the regulation of Ito in the infarcted heart, since DCA and pyruvate normalized Ito density (Fig. 5) in this group of myocytes, whereas 3-BP, an inhibitor of the PDH complex (1, 5), significantly reduced density in control myocytes. It should be noted that all control and experimental incubations were done in the presence of culture medium containing a variety of inorganic salts, amino acids, vitamins, and other compounds, including pyruvate (0.5 mM). We have not tested the effects of DCA, pyruvate, or 3-BP in standard external solution to determine whether some component(s) of the culture medium may have been essential for upregulating Ito density. Nevertheless, our data suggest a functional link between PDH activity and Ito channels. Although the mechanisms of this interaction are unclear, possibilities include intracellular accumulation of glycolytic or fatty acid metabolites (14) or direct control of Ito channel function via metabolism-induced changes in ATP in the vicinity of the channel (11). In summary, our data demonstrate that Ito density is reversibly decreased in myocytes from infarcted hearts by a mechanism(s) related to glucose metabolism. This may be unique to this current system, since the density of another K+ current, IK1, is not altered in this model. These changes in myocyte Ito channel function may relate to the impaired contractility and arrhythmogenesis that are hallmarks of the intact, failing heart.| |
ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-48023, a Research Award from the American Diabetes Association, and the University of Nebraska College of Medicine.
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FOOTNOTES |
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Address for reprint requests: G. J. Rozanski, Dept. of Physiology and Biophysics, University of Nebraska College of Medicine, 600 South 42nd St., Omaha, NE 68198-4575.
Received 17 March 1997; accepted in final form 30 September 1997.
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Abstract
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Discussion
References
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 U. C. Hoppe, D. C. Johns, E. Marban, and B. O'Rourke Manipulation of Cellular Excitability by Cell Fusion : Effects of Rapid Introduction of Transient Outward K+ Current on the Guinea Pig Action Potential Circ. Res., April 30, 1999; 84(8): 964 - 972. [Abstract] [Full Text] [PDF]
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 Z. Xu and G. J. Rozanski K+ current inhibition by amphiphilic fatty acid metabolites in rat ventricular myocytes Am J Physiol Cell Physiol, December 1, 1998; 275(6): C1660 - C1667. [Abstract] [Full Text] [PDF]
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S. J. Rials, X. Xu, Y. Wu, R. A. Marinchak, and P. R. Kowey Regression of LV hypertrophy with captopril normalizes membrane currents in rabbits Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1216 - H1224. [Abstract] [Full Text] [PDF]
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G. J. Rozanski and Z. Xu Glutathione and K+ channel remodeling in postinfarction rat heart Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2346 - H2355. [Abstract] [Full Text] [PDF]
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