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Anesthesiology:
Special Section: Anesthetic Preconditioning

Differential Modulation of the Cardiac Adenosine Triphosphate-sensitive Potassium Channel by Isoflurane and Halothane

Kwok, Wai-Meng Ph.D.*; Martinelli, Anne T. M.D.†; Fujimoto, Kazuhiro M.D., Ph.D.‡; Suzuki, Akihiro M.D.‡; Stadnicka, Anna Ph.D.§; Bosnjak, Zeljko J. Ph.D.∥

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Abstract

Background: The cardiac adenosine triphosphate–sensitive potassium (KATP) channel is activated during pathophysiological episodes such as ischemia and hypoxia and may lead to beneficial effects on cardiac function. Studies of volatile anesthetic interactions with the cardiac KATP channel have been limited. The goal of this study was to investigate the ability of volatile anesthetics halothane and isoflurane to modulate the cardiac sarcolemmal KATP channel.
Methods: The KATP channel current (IKATP) was monitored using the whole cell configuration of the patch clamp technique from single ventricular cardiac myocytes enzymatically isolated from guinea pig hearts. IKATP was elicited by extracellular application of the potassium channel openers 2,4-dinitrophenol or pinacidil.
Results: Volatile anesthetics modulated IKATP in an anesthetic-dependent manner. Isoflurane facilitated the opening of the KATP channel. Following initial activation of IKATP by 2,4-dinitrophenol, isoflurane at 0.5 and 1.3 mm further increased current amplitude by 40.4 ± 11.1% and 58.4 ± 20.6%, respectively. Similar results of isoflurane were obtained when pinacidil was used to activate IKATP. However, isoflurane alone was unable to elicit KATP channel opening. In contrast, halothane inhibited IKATP elicited by 2,4-dinitrophenol by 50.6 ± 5.8% and 72.1 ± 11.6% at 0.4 and 1.0 mm, respectively. When IKATP was activated by pinacidil, halothane had no significant effect on the current.
Conclusions: The cardiac sarcolemmal KATP channel is differentially modulated by volatile anesthetics. Isoflurane can facilitate the further opening of the KATP channel following initial channel activation by 2,4-dinitrophenol or pinacidil. The effect of halothane was dependent on the method of channel activation, inhibiting IKATP activated by 2,4-dinitrophenol but not by pinacidil.
VOLATILE anesthetics have cardiac depressant effects and inhibit various ion channels in the heart. However, multiple effects of volatile anesthetics on the myocardium suggest the complexity of the underlying cellular and molecular mechanisms. Inhibition of cardiac voltage-gated calcium and sodium channels by volatile anesthetics is well documented 1–3 and may lead to an increased propensity to arrhythmias. However, recent studies have convincingly shown that volatile anesthetics can also be cardioprotective. 4–8 This cardioprotection, termed anesthetic-induced preconditioning, mimics ischemic preconditioning, 9 whereby a small ischemic episode protects the myocardium from a subsequent, more devastating insult.
The underlying mechanisms involved in anesthetic-induced preconditioning have not been elucidated. Despite the potentially numerous targets of volatile anesthetics, including ion channels and intracellular second messenger systems, the adenosine triphosphate–sensitive potassium (KATP) channel has been hypothesized to be one of the major target proteins involved in anesthetic-induced cardioprotection. 5,10 The sarcolemmal KATP channel is an attractive target since it acts as a metabolic sensor, and its activation leads to shortening of the cardiac action potential. 11,12 This, in turn, would lead to decreased calcium entry via the voltage-gated calcium channels and preservation of high-energy phosphates. Recent studies have also shown that the KATP channel on the inner membrane of mitochondria plays a more pivotal role in cardioprotection, particularly in ischemic preconditioning. 13–15 Volatile anesthetics, isoflurane and sevoflurane, were also recently reported to induce a redox-dependent increase in mitochondrial flavoprotein oxidation, an indicator of mitochondrial KATP channel opening. 16 Consequently, anesthetic-induced and ischemic preconditioning likely involve complex pathways that may include both the mitochondrial and sarcolemmal KATP channels.
Evidence for the involvement of the sarcolemmal KATP channel in anesthetic-induced preconditioning is derived from infarct-size studies using whole animal models. 5 On the other hand, direct studies of volatile anesthetic effects on the KATP channel have been limited. In the present study, the effects of two volatile anesthetics, isoflurane and halothane, on the cardiac sarcolemmal KATP channel were investigated using the whole cell configuration of the patch clamp technique.
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Materials and Methods

Preparation of Isolated Cardiac Ventricular Myocyte
After approval was obtained from the Institutional Animal Care and Use Committee, cardiac myocytes were enzymatically isolated from guinea pigs weighing 200–300 g. The procedure of the cell isolation is a modification of that of Mitra and Morad 17 and has previously been reported. 3 In brief, the guinea pigs were anesthetized by intraperitoneal injection of 180 mg/kg pentobarbital sodium and injected with 1,000 U heparin to hinder coagulation. During deep anesthesia, the hearts were quickly excised and mounted via the ascending aorta on a Langendorff-type apparatus. Each heart was perfused retrogradely at a rate of 6–8 ml/min with Joklik's medium containing 2.5 U/ml heparin at pH 7.23. After 3–4 min to allow for clearing of blood, the perfusing solution was replaced with an enzyme solution containing Joklik's medium with 0.25 mg/ml collagenase (Gibco Life Technologies, Grand Island, NY), 0.13 mg/ml protease (Type XIV, Sigma, St. Louis, MO), and 1 mg/ml bovine serum albumin (Serologicals Proteins, Kankakee, IL) at pH 7.23. The perfusion solutions were oxygenated (95% O2–5% CO2) and maintained at 37°C. After 14 min of recirculating the enzyme solution, the ventricles were removed, cut into small fragments, and incubated for approximately 3–8 min in a shaker bath in the enzyme solution. The cell suspension was then filtered, centrifuged, and washed twice in Tyrode solution before the cells were ready for experiments. The cells were stored in Tyrode solution at room temperature (20–25°C) and used within 12 h after isolation. For the patch clamp experiments, cells were transferred to a recording chamber mounted on the stage of an inverted microscope.
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Solutions
The isolated myocytes were initially washed in a standard Tyrode solution that contained the following ingredients: 132.0 mm NaCl, 4.8 mm KCl, 1.2 mm MgCl2, 1.0 mm CaCl2, 5.0 mm dextrose, and 10.0 mm HEPES, with pH adjusted to 7.4 with NaOH. After establishing a gigaohm seal, the external Tyrode solution was changed to one appropriate for measurement of potassium channel currents and contained 132.0 mm N-methyl-d-glucamine (substitute for sodium), 1.0 mm CaCl2, 2.0 mm MgCl2, 10.0 mm HEPES, and 5.0 mm KCl, with pH adjusted to 7.4 with HCl. Nisoldipine (200 nm), supplied by Miles Pentex (West Haven, CT), was also added to block the L-type Ca channel current. To elicit activation of the KATP current, 2,4-dinitrophenol or pinacidil, a KATP channel opener, was used. 2,4-Dinitrophenol (Sigma Chemical) was added directly to the external buffer solution to obtain a desired concentration. Pinacidil (Sigma/RBI) was prepared as a 10-mm stock in dimethyl sulfoxide and diluted to the desired concentration in the external solution. In a specified set of experiments, bimakalim was used as a potassium channel opener. Bimakalim was supplied by Garrett Gross, Ph.D. (Professor, Department of Pharmacology and Toxicology, Medical College of Wisconsin) and was prepared in dimethyl sulfoxide. The final concentration of dimethyl sulfoxide (0.025%) had no effect on the whole cell K currents. The standard pipette solution contained 60.0 mm K-glutamate, 50.0 mm KCl, 1.0 mm CaCl2, 1.0 mm MgCl2, 11.0 mm EGTA, and 0.1–1.0 mm K2-ATP, with pH adjusted to 7.4 with KOH.
The volatile anesthetics, isoflurane (Ohmeda Caribe Inc., Liberty Corner, NJ) and halothane (Halocarbon Laboratories, River Edge, NJ), were mixed by adding known aliquots of concentrated anesthetics to graduated syringes with the appropriate bath solutions. Isoflurane and halothane superfusions were achieved using a syringe pump with a constant flow of 1 ml/min. Clinically relevant concentrations of isoflurane (0.5–1.3 mm, equivalent to 1.048–2.723 vol%) and halothane (0.4–1.0 mm, equivalent to 0.643–1.610 vol%) were used. To determine anesthetic concentrations, 1 ml of the superfusate was collected in a metal-capped 2-ml glass vial at the end of each experiment. The superfusate concentration of the anesthetic was then determined by gas chromatography (head-space analysis) utilizing flame ionization detection Perkin-Elmer Sigma 3B gas chromatograph.
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Electrophysiology
Adenosine triphosphate–sensitive potassium current (IKATP) was recorded in the whole cell configuration of the patch clamp technique. Pipettes were pulled from borosilicate glass capillary tubes (Garner Glass, Claremont, CA) using a horizontal two-stage puller (Sachs-Flaming PC-84; Sutter Instruments, Novato, CA) and heat polished (Narishige microforge; MF-83, Tokyo, Japan). In standard solutions, pipette resistance ranged from 2.5 to 3.5 MΩ. Current was monitored during 100-ms test pulses from −110 to +50 mV in 10-mV increments from a holding potential of −40 mV. During this recording condition, contributions from the cardiac delayed-rectifier potassium current was minimal due to its activation kinetics of several hundred milliseconds at room temperature. To monitor changes in current amplitude over time, IKATP was recorded every 15 s during a 100-ms test pulse to 0 mV from a −40-mV holding potential. IKATP amplitude was measured at the end of the 100-ms test pulse. Series resistance compensation was adjusted to give the fastest possible cell capacity transients without producing ringing. Current was measured with a List EPC-7 patch clamp amplifier (Adams & List Assoc., Great Neck, NY), and the output was lowpass filtered at 3 kHz to reduce high-frequency noise. Experiments were performed at room temperature (20–25°C). Data were acquired and analyzed with the pClamp software package (versions 6.02 and 8.0; Axon Instruments, Inc., Foster City, CA) and ORIGIN (OriginLab, Northampton, MA).
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Statistics
Data are expressed as means ± SEM. Statistical differences were determined using paired or unpaired Student t test. Differences were considered statistically significant at P < 0.05.
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Results

Effect of 2,4-Dinitrophenol on Whole Cell K+ Current
Fig. 1
Fig. 1
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The effect of 2,4-dinitrophenol on whole cell K+ current recorded from a cardiac myocyte is demonstrated in figure 1. During control conditions, the only prominent K current was the inward-rectifier K+ current recorded at potentials negative to the potassium equilibrium potential, EK. In the presence of 2,4-dinitrophenol (120 μm), an outward current was elicited at potentials positive to EK. This current was identified as the sarcolemmal KATP current (IKATP) by its sensitivity to glibenclamide (200 nm). At potentials negative to EK, glibenclamide had no effect on the inward-rectifier K+ current.
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Volatile Anesthetic Effects on 2,4-Dinitrophenol–induced IKATP
Fig. 2
Fig. 2
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Fig. 3
Fig. 3
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The effects of isoflurane and halothane on the sarcolemmal KATP channel activated by 2,4-dinitrophenol were investigated in the next series of experiments, where we monitored KATP current amplitude every 15 s. IKATP was activated by 120 μm 2,4-dinitrophenol. The effects of the volatile anesthetics are demonstrated in figure 2. The current monitored at time t = 0 min was recorded immediately prior to the application of 2,4-dinitrophenol. The effects of isoflurane and halothane were recorded in the continued presence of 2,4-dinitrophenol but after the effect of 2,4-dinitrophenol has reached steady state. The example shows that isoflurane (1.3 mm) potentiated IKATP that was activated by 2,4-dinitrophenol. The increase in current amplitude was approximately 39%. In contrast, halothane (0.5 mm) had an inhibitory effect, decreasing current amplitude by approximately 45%. In both cases, the effects of the anesthetics were reversible. A summary of the effects of the volatile anesthetics on IKATP is shown in figure 3. At the concentrations tested, isoflurane further increased IKATP amplitude initially activated by 2,4-dinitrophenol, while halothane decreased 2,4-dinitrophenol–activated IKATP. For both the isoflurane and halothane groups, the anesthetic effects on IKATP had a tendency to be greater at the higher concentrations. However, within each anesthetic group, there were no significant concentration-dependent differences.
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Volatile Anesthetic Effects on Pinacidil-induced IKAPT
Fig. 4
Fig. 4
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The results from the 2,4-dinitrophenol studies showed differential and contrasting effects of isoflurane and halothane on IKATP. The effects of these anesthetics can possibly be due to the method of KATP channel activation. The activation of the KATP channel by 2,4-dinitrophenol is due to the uncoupling of oxidative phosphorylation, leading to decreased intracellular ATP. 2,4-Dinitrophenol has also been shown to directly interact with the KATP channel protein, leading to opening of the channel. 18 Consequently, to test whether the anesthetic effects were unique to 2,4-dinitrophenol–activated IKATP, experiments using pinacidil, a KATP channel opener, were carried out. Figure 4 demonstrates the effects of isoflurane on a pinacidil-activated IKATP. Whole cell current trace was recorded during a test-pulse potential of 0 mV from a −40-mV holding potential. During control, 25 min was allowed to elapse before the extracellular application of pinacidil to allow for diffusional exchange of 0.5 mm ATP between the recording pipette and the cell's interior. At this concentration of ATP, the KATP channel remained inhibited. In figure 4, the time t = 0 min denotes current recordings in control immediately prior to application of pinacidil. In the presence of pinacidil, KATP current was activated. After the effect of pinacidil reached steady state, 0.6 mm isoflurane was applied in the continued presence of pinacidil, resulting in a further increase in IKATP. The isoflurane-potentiated current was inhibited by glibenclamide. The effect of isoflurane on pinacidil-activated IKATP was also reversible (fig. 4).
Fig. 5
Fig. 5
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In 8 cells, isoflurane at 0.6 mm further increased KATP current amplitude in the presence of pinacidil, as summarized in figure 5. This result was similar to those observed with 2,4-dinitrophenol–activated IKATP. On the other hand, halothane had no significant effect on the pinacidil-activated current (fig. 5). This is in contrast to the inhibitory effects of halothane on the 2,4-dinitrophenol–activated current.
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The Effect of Isoflurane on Whole Cell IKATP
Fig. 6
Fig. 6
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The previous sets of experiments demonstrated that isoflurane can facilitate the further opening of the KATP channel after initial activation by either 2,4-dinitrophenol or pinacidil. Therefore, whether isoflurane alone can open the KATP channel was tested. A time-course experiment where IKATP amplitude was monitored at 15-s intervals is depicted in figure 6. After allowing for diffusional exchange of 1 mm ATP between the pipette solution and the cell's interior, isoflurane (0.6 mm) was applied extracellularly. However, during a 10-min application, isoflurane failed to elicit any outward current characteristic of IKATP. Upon washout of isoflurane, an application of a KATP channel opener, bimakalim, resulted in the activation of IKATP, confirming the functional existence of the KATP channel in this myocyte. In six cells tested, isoflurane failed to elicit KATP channel opening. Even after lowering the intracellular ATP to 0.5 mm, near the threshold for channel opening, isoflurane failed to activate IKATP (data not shown).
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Discussion

The results from this study show that volatile anesthetics, isoflurane and halothane, have differential effects on the sarcolemmal KATP channel in guinea pig ventricular myocytes. During conditions where IKATP was initially activated by 2,4-dinitrophenol or pinacidil, isoflurane further increased KATP current amplitude. In contrast, halothane either inhibited or had no significant effects on 2,4-dinitrophenol– or pinacidil-activated IKATP, respectively. In addition, although isoflurane facilitated opening of the KATP channel, the anesthetic by itself was unable to directly activate IKATP. Thus, isoflurane alone is not an effective KATP channel opener.
Since the studies by Kersten et al. and Cason et al. reporting on the cardioprotective effects of volatile anesthetics that mimic ischemic preconditioning, anesthetic effects on the sarcolemmal KATP channels have been implicated. 5,6 However, direct evidence of volatile anesthetic modulation of the sarcolemmal KATP channels has been limited. 19,20 In the rabbit ventricular myocytes, isoflurane shifted the KATP channel's sensitivity to ATP and increased the mean closed time. 19 The net result of a decreased ATP sensitivity coupled with an increase in mean closed time is ambiguous. The results from the present study show that the net outcome is an increase in whole cell KATP current amplitude, specifically in guinea pig ventricular myocytes. Another recent evidence of volatile anesthetic action on the sarcolemmal KATP channel was reported in studies on human atrial trabecular muscles. 20 In these cells, halothane decreased and isoflurane had no effect on IKATP. Thus, the inhibitory effect of halothane on IKATP is similar for the human atrial and guinea pig ventricular myocytes. On the other hand, the effects of isoflurane were different. This cannot be attributed to differences in the method of KATP channel activation, where in both cases 2,4-dinitrophenol was used. It is conceivable that the difference is due to species or tissue differences. Whether the KATP channels in atrial myocytes are less sensitive to isoflurane than those in the ventricles remain to be determined. Our previous studies have shown that the L-type Ca channels in the guinea pig atria were more sensitive to isoflurane than those in the ventricles. 21 Thus, differential sensitivity to isoflurane may also be characteristic of KATP channels in the atria and ventricle.
The effects of isoflurane and halothane on the KATP channel showed no significant differences between the two concentrations tested. This suggests that the concentrations of volatile anesthetic used were at saturating levels of KATP channel modulation. On the other hand, the observed variability suggests the disadvantage and difficulty in controlling the effects of 2,4-dinitrophenol. The consequence of uncoupling oxidative phosphorylation by 2,4-dinitrophenol leads to a decrease in intracellular ATP concentrations. However, the rate of ATP decrease and the accompanying intracellular changes will differ from cell to cell. Given the complexity of KATP channel modulation, which is sensitive to ATP, ADP, Mg2+, and phospholipids, to name a few intracellular modulators, 12,22–24 the microenvironment surrounding the channel protein will likely differ from cell to cell. The isoflurane effect on the KATP channel may also be modulated by these agents. For example, at 1 mm ATP, isoflurane failed to open the KATP channel when applied alone. This showed that isoflurane alone was unable to overcome the inhibitory effect of ATP. However, during conditions where the KATP channel was initially activated, isoflurane facilitated its opening, leading to an increase in IKATP. It appears that prior channel opening is a “precursor” to the isoflurane effect. One possible underlying mechanism is that isoflurane may partially desensitize the channel to ATP, resulting in a greater current flow. However, since isoflurane alone was unable to elicit IKATP even during conditions of 0.5 mm ATP, which is close to the threshold for channel opening, other intracellular mechanisms are likely to be involved.
The pinacidil experiments showed that the effect of isoflurane on IKATP is independent of the method of channel activation. In contrast, the effect of halothane was dependent on the method of channel activation, suggesting that different mechanisms may underlie the actions of isoflurane and halothane on IKATP. Studies on a rabbit model have shown that halothane has cardioprotective effects mimicking ischemic preconditioning. 25 However, results from the human atrial studies suggest that halothane diminishes the protective effects of ischemic preconditioning, while isoflurane induces protection. 20 This discrepancy may be attributed to the different models used and may imply potential species-dependent differences in the mechanism underlying cardioprotection. For example, the action of 2,4-dinitrophenol on the mitochondria results in uncoupling of oxidative phosphorylation. Pinacidil acts directly on the sarcolemmal KATP channel but also opens the mitochondrial KATP channel. 26 Consequently, it is conceivable that the halothane effect may be differentially dependent on the intracellular changes resulting from alterations in mitochondrial function initiated by 2,4-dinitrophenol or pinacidil.
Cardioprotection by isoflurane mimicking ischemic preconditioning is well documented in laboratory and, more recently, clinical studies. 27 However, the underlying mechanism for this protection has not been elucidated. Earlier studies have hypothesized that the sarcolemmal KATP channel was the end effector in both ischemic and anesthetic preconditioning. Recent studies have demonstrated that the mitochondrial KATP channel may play a more significant role, particularly in ischemic preconditioning. 13,14,28 Diazoxide, a potassium channel opener more specific for the cardiac mitochondrial rather than the sarcolemmal KATP channel, can mimic ischemic preconditioning. Opening of the mitochondrial KATP channel may subsequently trigger intracellular changes, leading to cardioprotection. On the other hand, activation of the cardiac sarcolemmal KATP channel may play a larger role during reperfusion and reoxygenation. 28
Although recent evidence supports the greater role of the mitochondrial KATP channel, possible contributions by the sarcolemmal KATP cannot be entirely excluded. It has been demonstrated that transfecting a cell with the sarcolemmal KATP channel can lead to the protection against hypoxia. 29 In addition, the cardioprotective effects of desflurane were found to involve both the sarcolemmal and mitochondrial KATP channels. 30 Furthermore, although the pathways involved in ischemic preconditioning are better characterized than those for anesthetic preconditioning, that identical mechanisms are involved in the two types of cardioprotection has not been established. It is possible that divergent pathways are involved since the initial trigger mechanism, ischemic versus volatile anesthetic, is different. In addition, the result that isoflurane can facilitate the opening of the sarcolemmal KATP channel suggests that it may be involved in anesthetic preconditioning in conjunction with activation of the mitochondrial KATP channel. 16
In summary, the results from this study show differential effects of isoflurane and halothane on the cardiac sarcolemmal KATP channel. Isoflurane facilitated the opening of the KATP channel after prior activation by either 2,4-dinitrophenol or pinacidil. In contrast, halothane inhibited the 2,4-dinitrophenol–activated IKATP but had no significant effect on the pinacidil-activated IKATP.
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