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Abstract |
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The cellular mechanisms that underlie general anesthetic actions on the inward rectifier K+ current (IKir), a determinant of the resting potential in myocardium, are not fully understood. Using the whole-cell patch clamp technique, therefore, we investigated the effects of halothane and isoflurane on IKir in guinea pig ventricular myocytes. At membrane potentials negative to the equilibrium potential for potassium both anesthetics decreased amplitude of the steady-state inward IKir in a concentration- and voltage-dependent manner. The slope conductance was reduced, but the activation kinetics of the inward current were not altered. At potentials positive to the equilibrium potential for potassium, the outward current was increased by both anesthetics, which also caused small depolarizing shifts in the activation curve. With high internal magnesium concentration, the outward current increase by isoflurane was abolished, and the inward current block by halothane was attenuated. Spermine prevented the effects of both anesthetics on IKir at all membrane potentials tested. The results show voltage-dependent modulation of cardiac IKir channel by volatile anesthetics. Distinct modification of anesthetic effects by inward rectification gating agents, magnesium and spermine, suggests anesthetic interactions with the IKir channel protein.
Implications: Differential modulation of myocardial inward rectifier potassium current by volatile anesthetics under normal and altered rectification may contribute to the mechanism of dysrhythmic actions by these anesthetics.
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Introduction |
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Modern volatile anesthetics have numerous effects on various body systems. Because of considerable clinical importance of these secondary effects, the mechanisms underlying anesthetic actions are widely investigated. The membrane effects of volatile anesthetics involve multiple interactions with the lipid bilayer and proteins, with ion channels being primary targets (1,2). Numerous potassium channel currents described in the heart are critical to the regulation of the cardiac action potential duration, repolarization, and resting potential (3). A potential target for anesthetics is the inward rectifier potassium (IKir) channel that sets and maintains the resting potential of myocardial cells near the equilibrium potential for potassium, controls excitability, and is responsible for fast repolarization during the final phase of the action potential. A characteristic feature of this channel is the ability to conduct current more readily in the inward rather than the outward direction. This inward rectification results from channel blockade by intracellular Mg2+ and endogenous polyamines (4–9), which interact with the intrinsic gate of the channel (10). At membrane potentials more depolarized than -40 mV, rectification caused by channel block by intracellular Mg2+ and polyamines prevents intracellular K+ loss and repolarization (11).
Volatile anesthetics appear to have predominant inhibitory effects on the majority of potassium currents (12–15). Studies from this laboratory, however, demonstrated a unique modulation of cardiac ventricular IKir by sevoflurane that caused a decrease in the inward current at membrane potentials negative to the equilibrium potential for potassium (EK) but increased the outward current at potentials more positive than EK (16). The results were interpreted to reflect the polar nature of sevoflurane contributing to the biphasic effect. We tested the hypothesis that other volatile anesthetics have similar effects on IKir. The results show that, in cardiac ventricular myocytes, isoflurane and halothane have voltage-dependent biphasic effects on IKir. Differential modifications of these effects by magnesium and spermine suggest that volatile anesthetics may interact with the Kir channel protein.
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Methods |
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All experiments conformed to the National Institutes of Health guidelines for the care and use of laboratory animals and were approved by the Animal Care and Use Committee of the Medical College of Wisconsin.
Cell Isolation
The method for the isolation of ventricular myocytes from guinea pig hearts was described in detail previously (16). Briefly, Langendorff retrograde perfusion of the heart with the Joklik medium (GibcoBRL; Life Technologies, Grand Island, NY) containing collagenase (Type II; GibcoBRL) and protease (Type XIV; Sigma, St Louis, MO) was used to dissociate myocardial tissue and obtain single ventricular cells. The cells were stored in the modified Tyrode solution at room temperature (20°–22°C), and were used for experiments within 6 to 10 h after isolation.
Solutions
The modified Tyrode solution contained (mM): NaCl 132, KCl 4.8, MgCl2 1.2, CaCl2 1, HEPES 10, and glucose 5, at pH 7.35 adjusted with NaOH. The pipette solution for recording whole-cell IKir contained (mM): KCl 50, K glutamate 60, MgCl2 1, HEPES 10, CaCl2 1, EGTA 11, and K2ATP 5, at pH 7.4 adjusted with KOH. The bath solution contained (mM): N-methyl-D-glucamine (NMDG) 132, CaCl2 1, MgCl2 2, HEPES 10, glucose 5, and KCl 5, at pH 7.4 adjusted with HCl. Substituting NMDG for sodium chloride eliminated the contribution of sodium currents. Cadmium chloride (0.2 mM) added to the bath solution blocked the L-type Ca2+ current. A holding potential of -40 mV was selected to inactivate the rapid transient inward sodium current. The ATP-sensitive potassium channel current was suppressed by the addition of 5 mM K2ATP to the pipette solution.
Spermine tetrahydrochloride (Aldrich-Sigma, Milwaukee, WI) or magnesium chloride was added to the pipette solution. Isoflurane or halothane was sonicated into the bath solution, which was then delivered to the recording chamber from glass syringes. The millimolar concentrations of anesthetics in the bath solution were determined by gas chromatography by using a Sigma 3B gas chromatograph (Perkin-Elmer, Norwalk, CT). Averaged concentrations of halothane were 0.43 ± 0.04, 0.63 ± 0.04, 1.30 ± 0.07, 1.87 ± 0.10, and 2.10 ± 0.1 mM equivalent to 0.67, 0.98, 2.02, 2.91, and 3.26 vol%, respectively. The concentrations of isoflurane were 0.40 ± 0.05, 0.61 ± 0.05, 1.08 ± 0.15, 1.81 ± 0.15, and 2.3 ± 0.2 mM equivalent to 0.80, 1.22, 2.17, 3.63, and 4.61 vol%, respectively. The highest concentrations of 2.1 mM halothane and 2.3 mM isoflurane were used to determine the saturating maximum depressant effect by anesthetics.
Electrophysiologic Recordings
The whole-cell voltage clamp configuration of the patch clamp technique (17) was used to record IKir from ventricular myocytes at room temperature (20°–22°C). The cells were placed in a flow-through chamber mounted on the stage of an inverted microscope (Olympus IMT-2, Tokyo, Japan) and initially superfused with the Tyrode solution at a flow rate of 1–2 mL/min (Minipuls3 peristaltic pump, Gilson, Middletown, WI). Patch pipettes were pulled from borosilicate glass capillaries (Garner, Monrovia, CA) with a multistage puller (Sachs PC-84; Sutter, Novato, CA) and heat polished by using a microforge (MF-83; Narishige, Tokyo, Japan). The resistance of pipettes filled with internal solution and immersed in the Tyrode solution was 3–4 M
. After a gigaohm seal between the tip of the pipette and the cell membrane was established and whole-cell configuration was formed, the Tyrode solution was replaced with the external solution isolating for IKir. Series resistance compensation was adjusted electronically to give the fastest capacity transient without producing noise. Whole-cell membrane currents were recorded by using a List EPC-7 patch-clamp amplifier (Adam & List, Great Neck, NY), and low-pass filtered at 3 kHz. Data were digitized by using pCLAMP software (Axon Instruments, Foster City, CA) and stored electronically for off-line analyses. Voltage protocol generation, data acquisition, and data analyses were performed by using pCLAMP (Axon Instruments) and Origin (Microcal, Northampton, MA) software.
Voltage-clamp Protocols
Whole-cell currents were elicited by 10-mV voltage steps from a holding potential of -40 mV to test potentials varying from -110 mV to +50 mV. Duration of the voltage steps was limited to 50 ms to avoid overlap from the delayed rectifier potassium current which, in guinea pig ventricular cells, activates with a delay of 200 ms. The current-voltage (I–V) relationships were determined from the steady-state current amplitude measured at the end of the voltage steps.
Whole-cell currents were also recorded by using the ramp voltage clamp protocol in which voltage commands changed linearly from -110 mV to +50 mV as a function of time (1-s duration). Holding potential was -40 mV. Ramp data were plotted as current versus voltage relationship.
The slope conductance was determined from the steady-state inward current. Because the steady-state inward currents were linear over the range of -110 mV to -80 mV, the maximal slope conductance was defined as the slope of the linear regression fitted through these points.
To determine the rate of current activation, time constants for the inward current activation (
act) were obtained by fitting a single exponential function to current traces recorded at selected voltages negative to EK (-110, -100, and -90 mV).
The steady-state activation curves were obtained by calculating conductance (GK) from GK = IK/(V–EK), where IK is the current amplitude measured at the end of a test pulse, V is the test potential, and EK is the equilibrium potential for potassium. Normalized conductance (GK/GKmax) was plotted versus test voltages, and the relationship was fitted to a Boltzmann equation: 
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The dose-response curves for the steady-state block of inward current by anesthetics were fitted with the modified Hill equation:
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Data were expressed as mean ± SEM. Each cell served as its own control. The paired Student’s t-test was used to compare steady-state effects of each anesthetic to corresponding controls. Differences between groups were evaluated by using analysis of variance for repeated measures. Differences were considered significant at P 
0.05.
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Results |
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Voltage and Concentration-Dependent Effects of Halothane and Isoflurane on IKir
Figure 1A shows current traces of the whole-cell IKir recorded from a ventricular myocyte in the presence and absence of halothane. At hyperpolarized membrane potentials negative to EK, 1.3 mM halothane caused a reversible suppression of the inward current. Similar effects were observed for isoflurane. At potentials positive to EK, both halothane and isoflurane enhanced IKir. The ramp voltage-clamp recordings shown in Figure 1B clearly demonstrate that, between -70 and -40 mV, the outward IKir was increased in the presence of 1.3 mM halothane and 1.1 mM isoflurane.
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= control, 
= anesthetics.The concentration- and voltage-dependent effects of anesthetics on IKir are shown in Figure 2. Current amplitude was measured at the end of 50-ms test pulses to the potentials shown, and changes from corresponding controls were determined. When monitored at -110 mV, the inward current block by 1.3 and 1.87 mM halothane showed dependence on the membrane potential increasing with hyperpolarization. At all concentrations tested, halothane increased the outward current positive to EK. Isoflurane decreased the amplitude of the inward current in a voltage-dependent manner, and similar to halothane, increased the outward current amplitude as monitored at -50 mV. Compared with corresponding controls, the dose-dependent effects of both anesthetics on the inward current and effects on the outward current were statistically significant at P
0.05.
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), and 1.87 (
) mM halothane. B, Data for 0.40 (Halothane and isoflurane decreased K+ conductance when measured between -110 and -80 mV. The slope conductance (averaged control 84 ± 3 nS, n = 43) was decreased in a dose-dependent manner from 2.4% ± 2.4% to 21.6% ± 2.4% with 0.43 to 1.87 mM halothane, and from 6.6% ± 2.4% to 23.7% ± 4.5% with 0.4 to 1.81 mM isoflurane.
Both anesthetics produced small, concentration-dependent depolarizing shifts in V1/2 of the steady-state activation curves. From control, V1/2 was shifted by 1.6 ± 0.3 to 3.6 ± 0.4 mV in the presence of 0.43 to 1.87 mM halothane (n = 5 in each group). In the presence of 0.40 to 1.81 mM isoflurane (n = 5 in each group), the rightward shifts in V1/2 ranged from 2.6 ± 0.4 to 3.1 ± 0.4 mV. The slope factor, k, was not altered by either anesthetic.
The activation kinetics of the inward current were not altered by anesthetics. The time constants for activation of the inward current, act, measured in the absence and presence of 0.63 mM halothane (n = 5) were 2.5 ± 0.1 and 2.4 ± 0.3 ms at -110 mV, 2.9 ± 0.2 and 2.8 ± 0.2 ms at -100 mV, and 3.7 ± 0.3 and 4.1 ± 0.2 ms at -90 mV, respectively. The act values for control and 0.61 mM isoflurane (n = 5) were 2.3 ± 0.2 and 2.4 ± 0.2 ms at -110 mV, 2.8 ± 0.3 and 2.8 ± 0.2 ms at -100 mV, 3.3 ± 0.1 and 3.3 ± 0.2 ms at -90 mV, respectively.
Voltage-Dependent Potency of Anesthetic Block
To evaluate the relationship between anesthetic concentration and suppression of the inward current, concentration-response curves for the block of the steady-state IKir amplitude measured at potentials of -110, -100, and -90 mV were fitted with the modified Hill equation (Figure 3A). For the inhibitory effects of halothane, the concentrations for half-maximal effect, Kd, and the Hill coefficients, n, were 0.89 ± 0.31 mM and 1.9 ± 0.75 at -110 mV, 0.88 ± 0.33 mM and 1.9 ± 0.79 at -100 mV, and 0.87 ± 0.32 mM and 1.9 ± 0.83 at -90 mV. For isoflurane, the respective Kd and n values were 0.68 ± 0.07 mM and 2.7 ± 0.65 at -110 mV, 0.70 ± 0.07 mM and 2.6 ± 0.59 at -100 mV, 0.87 ± 0.14 mM and 2.3 ± 0.57 at -90 mV. The results show that the potency of isoflurane block increased at more hyperpolarized membrane potentials. In contrast, the potency of halothane block was not dependent on membrane potential. This is further demonstrated in Figure 3B where -log Kd is plotted versus membrane potentials. The -log Kd of isoflurane block shows a negative slope linear relationship with the membrane potential.
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) against various concentrations of halothane and isoflurane (n = 5 in each group). To establish the plateau of anesthetic effects, additional data points were obtained in the presence of 2.1 mM halothane (n = 3) and 2.3 mM isoflurane (n = 3). The relationship between percent change in current amplitude and anesthetic concentration was fitted with the Hill equation. B, Voltage-dependent potency of halothane and isoflurane block was determined from a linear regression fit to the -log Kd values plotted against membrane voltages. The linear regression slope values were 0.52 x 10-3 ± 0.05 x 10-3 for halothane, and -8.27 x 10-3 ± 0.07 x 10-3 for isoflurane.Modification of Anesthetic Effects by Magnesium and Spermine
An increase in the outward IKir by anesthetics suggested altered channel rectification. Consequently, the gating agents for rectification, magnesium and a polyamine, spermine, were used to probe the mechanism of IKir modulation by anesthetics. The effects of halothane and isoflurane were examined in cells dialyzed with either 10 mM [Mg2+]i or 5 µM spermine. In the absence of anesthetics, 10 mM [Mg2+]i slowed activation kinetics of the inward current as compared with normal 1 mM [Mg2+]i. With 10 mM [Mg2+]i, differential effects of halothane and isoflurane on current activation kinetics were observed (Figure 4). In contrast to lack of the effects at 1 mM [Mg2+]i, in the presence of 10 mM [Mg2+]i, isoflurane further slowed the inward current activation kinetics. Halothane had no such effect on current activation kinetics at 10 mM [Mg2+]i.
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) and presence (•) of anesthetics; n = 6–7 cells in each group. *P < 0.05 versus isoflurane.The voltage-dependent biphasic effects of halothane and isoflurane were also differentially modulated at 10 mM [Mg2+]i (Figure 5A). The inhibitory effect of halothane at potentials negative to EK was significantly attenuated. The enhancement of IKir by halothane at potentials positive to EK was not significantly affected and similar to that at 1 mM [Mg2+]i. In contrast, the enhancement of IKir by isoflurane at potentials positive to EK was abolished. Furthermore, isoflurane block of IKir at potentials negative to EK was similar to that observed at 1 mM [Mg2+]i. With 10 mM [Mg2+]i, neither anesthetic caused depolarized shifts in the activation curve that were observed with 1 mM [Mg2+]i (data not shown).
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After cell dialysis with the internal solution containing spermine (5 µM), the amplitude of current negative and positive to EK and the activation kinetics of inward current remained unaltered (data not shown). However, in the presence of spermine, halothane at 0.63 and 1.3 mM and isoflurane at 0.61 and 1.08 mM did not produce changes in the amplitude of the steady-state IKir (Figure 5B). In addition, no depolarizing shifts in the steady-state activation curve were observed (data not shown). Thus, spermine prevented the effects of both anesthetics on IKir at all tested membrane potentials.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The principal finding of our study is that halothane and isoflurane modulate the cardiac ventricular inward-rectifier K+ current in a voltage-dependent, biphasic manner. Both anesthetics decreased the amplitude of the inward current at hyperpolarized potentials negative to EK, but enhanced the outward current at more depolarized potentials positive to EK. The inhibition of inward current was concentration-dependent, although increase in the outward current was independent of the anesthetic concentrations. The inhibitory effects were associated with decreased K+ conductance, but the inward current activation kinetics were not affected. Anesthetics also caused a slight positive shift of voltage dependence of activation. Magnesium and spermine, the gating agents for rectification, differentially modified the anesthetic effects. High intracellular magnesium attenuated the halothane block of IKir at hyperpolarized potentials and abolished the isoflurane induced enhancement of IKir at potentials positive to EK. Spermine prevented the effects of both halothane and isoflurane on IKir at all tested membrane potentials.
Although halothane and isoflurane had similar effects on IKir, the results from the magnesium experiments suggest that the mechanisms of action may differ between anesthetics. High intracellular magnesium concentration prevented the block of IKir by halothane at potentials negative to EK without significantly affecting the activation kinetics. Thus, it appears that high intracellular magnesium concentration may prevent halothane from accessing its interaction site at or near the channel. However, the effects of halothane at potentials positive to EK were not significantly affected by intracellular magnesium. This indicates that the mechanism of current enhancement at potentials above EK is distinct from that of current inhibition at hyperpolarized membrane potentials.
Modulation of isoflurane effects by magnesium contrasts that of halothane. High intracellular magnesium did not prevent the inhibitory effects of isoflurane at potentials negative to EK. Thus, in contrast to halothane, magnesium does not prevent isoflurane from reaching its inhibitory interaction site. The current activation kinetics, however, were slowed by isoflurane at these hyperpolarized potentials. Activation kinetics of IKir below EK have been reported to involve a relief from magnesium block (18,19) and intrinsic transition from the closed to open state (20). At 1 mM [Mg2+]i, isoflurane did not change activation kinetics, which indicates that the anesthetic does not interfere with the channel gating. In the presence of 10 mM [Mg2+]i, however, isoflurane appears to impede the rate of unblock of magnesium ion from the channel pore. Although high intracellular magnesium concentration did not prevent isoflurane from inhibiting IKir, it did abolish the isoflurane-induced enhancement of current positive to EK. As with halothane, the differential effects of magnesium suggest distinct mechanisms for the voltage-dependent modulation of IKir by isoflurane. Because intracellular magnesium alters the halothane effect at hyperpolarized potentials and the isoflurane effect at more depolarized potentials above EK, the role of magnesium differs between the two modes of anesthetic action.
Another gating agent for rectification, spermine, had identical effects on the actions of isoflurane and halothane on IKir. Spermine prevented the voltage-dependent inhibition and enhancement of IKir by both anesthetics. In addition, spermine prevented anesthetic-induced shifts in the steady-state activation curve. This contrasts with the differential effects of magnesium on anesthetic actions. Concentrations of polyamines in the intact cells may reach millimolar amounts, but most are bound to nucleic acids, nucleotides, and proteins (21), and only free cytosolic polyamines interact with ion channels (6,7,9,22). The molecular mechanism of channel block by spermine involves sequential insertion of at least two polyamine molecules into the pore. Spermine occludes the pore by forming a blocking complex with the intrinsic gate of the channel (9,10). The binding site for magnesium in the IKir channel pore is located approximately 35% into the channel pore from its intracellular opening (23). Consequently, the occlusion of a greater distance of the channel pore by two spermine molecules rather than by a magnesium ion may explain the total prevention of anesthetic effects by spermine compared with the partial effect by magnesium. By occluding the long pore of the channel, spermine may prevent the anesthetics from reaching the binding sites, which may be responsible for the voltage-dependent modulation of IKir. The occupancy of the pore by two spermine molecules may prevent conformational changes by anesthetics. Although magnesium and spermine modulate anesthetic effects, the exact molecular mechanisms underlying the inhibition and enhancement of IKir are not known. Further experiments at the single-channel level will be necessary to elucidate the mechanisms involved.
The Hill coefficients for anesthetic block of IKir obtained from fitting the concentration-response curves were different for both anesthetics and showed voltage dependence for isoflurane. These values suggest more than one interaction site at the channel for both anesthetics. However, the Hill coefficient is not an accurate measure of the number of binding sites, and the value of n is only a qualitative indicator of the degree of cooperativity. Thus, the differences in n values between halothane and isoflurane may not be indicative of the differences in the number of interaction sites. In both cases, however, the value of n > 1 suggests cooperativity between the interaction sites.
The effects of halothane and isoflurane on the cardiac IKir channel are similar to those reported previously for sevoflurane (16). All three anesthetics show a voltage-dependent biphasic effect on the channel. Spermine prevents the inhibitory and enhancing effects of all anesthetics. However, among these inhaled anesthetics, the mechanism of isoflurane action appears to be most similar to that of sevoflurane. The inhibitory potency of isoflurane is dependent on the membrane potential similarly to the potency of sevoflurane. In contrast, potency of halothane block is voltage-independent. The effects of high intracellular magnesium are similar for isoflurane and sevoflurane. These similarities in isoflurane and sevoflurane actions may be caused by a similar chemical structure. Moreover, both isoflurane and sevoflurane are more polar than halothane. In the sevoflurane study, an interaction site within the IKir channel’s electric field was proposed (16). A similar site may exist for isoflurane. The lack of voltage-dependent potency by halothane suggests that its interaction site may lie outside the channel’s electric field. Thus, even though the effects of the anesthetics on the IKir channel are similar, the underlying mechanism of action may differ.
Changes in myocardial calcium, sodium, and potassium channel function are responsible for ventricular dysrhythmias. A specific blockade of the IKir channels may contribute to early afterdepolarizations together with delayed rectifier and transient outward potassium and calcium channel blockade (24). Reduced K+ conductance through IKir channels may lead to increased excitability and triggered dysrhythmias. Lengthening of the late phase of repolarization may also have a pro-dysrhythmic effect (25). Under normal metabolic conditions, voltage-dependence of the inward IKir block by volatile anesthetics and its decrease at potentials near EK suggests minor effects on resting membrane potential. All tested anesthetics, however, increase K+ conductance in a limited range of membrane potentials positive to EK. This may accelerate the final phase of late repolarization and contribute to shortening of the action potential. However, volatile anesthetics simultaneously affect the function of multiple ion channels in the heart. Consequences of their profound depressant effects, for example, on calcium and sodium channels (26,27), will have a major impact on cell excitability. Modifications of anesthetic effects on IKir under altered inward rectification suggest that under pathophysiologic conditions such as ischemia, which is associated with increased free intracellular Mg2+, or cardiac hypertrophy with elevated polyamine levels, volatile anesthetics effects on ventricular IKir will be diminished.
In summary, this study demonstrates biphasic, voltage-dependent effects of halothane and isoflurane on IKir. The anesthetic actions are similar to those reported previously for sevoflurane.
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Acknowledgments |
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Supported in part by the National Institutes of Health, Grant HL 34708.
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