Anesth Analg 2006;102:98-103
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000184257.54917.99
ANESTHETIC PHARMACOLOGY
The Effects of Sevoflurane and Propofol on QT Interval and Heterologously Expressed Human Ether-A-Go-Go Related Gene Currents in Xenopus Oocytes
Masana Yamada, MD*,
Noboru Hatakeyama, MD, PhD*,
Anna P. Malykhina, PhD
,
Mitsuaki Yamazaki, MD, PhD*,
Yasunori Momose, PhD
, and
Hamid I. Akbarali, PhD
*Department of Anesthesiology, University of Toyama, Toyama, Japan, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Clinical Pharmacy, Toho University, Chiba, Japan
Address correspondence and reprint requests to Noboru Hatakeyama, MD, PhD, Department of Anesthesiology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama-shi, Toyama 930–0194, Japan. Address e-mail to nobo{at}ms.toyama-mpu.ac.jp.
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Abstract
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Sevoflurane can induce prolongation of the cardiac QT interval by inhibiting the repolarization phase of the action potential. This may occur as a result of inhibition of the human ether-a-go-go related gene (HERG) channel. To clarify the mechanisms of anesthetics on HERG channels, we monitored the electrocardiogram and measured QT intervals in the guinea pig in the presence of sevoflurane and propofol. Sevoflurane (1%–4%) prolonged QTc dose-dependently (7.5%–21.2%), but propofol did not affect it. Furthermore, HERG channels were expressed in Xenopus oocytes and outward HERG currents were obtained on step depolarization from a holding potential of –70 mV. Repolarization to –70 mV from positive test potentials resulted in large outward tail currents. Sevoflurane (1%–4%), in a dose-dependent manner, inhibited the HERG outward tail currents (9.7%–26.6%), whereas steady-state currents were inhibited only at large concentrations. The time constant of the converging current was decreased in the presence of sevoflurane, but the inactivation and activation curves were not shifted. Propofol did not affect these currents within the clinically relevant concentration. In conclusion, compared with steady-state currents, sevoflurane was more potent in inhibiting the outward tail currents, suggesting that sevoflurane may modulate the HERG channel kinetics in its inactivated state.
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Introduction
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Long QT syndrome (LQTS) is an arrhythmogenic cardiovascular disorder that manifests as QT interval prolongation on the electrocardiogram (ECG) and is caused by a prolongation of cardiac muscle repolarization. LQTS results in a ventricular arrhythmia that can degenerate into ventricular fibrillation and cause sudden death (1). Repolarization of cardiac ventricular myocytes depends mainly on the outward potassium currents (2), especially on the delayed rectifier potassium current, which is composed of rapidly (IKr) and slowly (IKs) activating components (3). IKr initiates repolarization and regulates the duration of the plateau phase of the cardiac action potential. IKr is encoded by the ether-a-go-go related gene (ERG) (4,5), and mutations in ERG result in LQTS (6).
In addition to the congenital form of LQTS, inhibition of ERG channel by several different drug classes also results in the acquired form of LQTS (7,8). It has been reported that volatile anesthetics such as halothane, enflurane, and isoflurane, when administered as the only drug for induction and maintenance of anesthesia, can prolong the QT interval in healthy humans (9). In addition, Li and Correa (10) reported that halothane inhibited human ERG (HERG) channels and that this mechanism played a role for QT interval prolongation. Sevoflurane is a popular volatile anesthetic because of its low blood-gas solubility, which leads to rapid induction and emergence from anesthesia. However, there is emerging evidence of QT prolongation by sevoflurane in both adults and infants (11–14). Kleinsasser et al. (11) and Kuenszberg et al. (12) reported that the administration of sevoflurane, but not propofol, significantly prolonged QTc in healthy female patients. Furthermore, Paventi et al. (14) concluded that the extent the sevoflurane-associated QT prolongation might be of clinical significance in some patients presenting with the LQTS, hypokalemia, or in presence of other drugs or factors that lengthen QT. The effect and mechanism of general anesthetics on the QT interval are not entirely clear but could involve actions on the HERG K+ channel. Park et al. (15) demonstrated inhibition of a delayed rectifier K+ channel by sevoflurane, although this effect was mainly limited to quite positive potentials and the slow voltage ramps may have masked effects on the HERG channel. We hypothesized that HERG channel current would play a major role in the prolongation of QT interval and that there would be a difference in the site of action on the repolarization phase between sevoflurane and propofol. In the present study, we examined the effects of sevoflurane and propofol on heterologously expressed HERG channels.
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Methods
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For the ECG recording, after obtaining approval from our local animal committee, guinea pigs of either sex (200–250g) were anesthetized with intraperitoneal injection of pentobarbital (0.2 mg/g). Then the trachea was cannulated and the lungs of the animals were ventilated mechanically, with monitoring of end-tidal CO2 (4.7–5.3 kPa). A femoral vein was cannulated for the administration of propofol. Sevoflurane (Abbott Japan, Tokyo, Japan) was administered by vaporizing with air using a dedicated vaporizer (Sevotec 3; Datex-Ohmeda, Helsinki, Finland) and the vaporized concentration was monitored with a gas monitor (Capnomac, Datex-Ohmeda). Propofol (Diprivan, AstraZeneca, Osaka, Japan) was administered by single injection into the femoral vein in 10 s. The ECG was monitored from a limb lead and continuously recorded during the experiments. For sevoflurane, the QT interval was measured between 10 and 15 min after the end-tidal concentration had stabilized at the selected concentration, and for propofol, the QT interval was measured between 3 and 10 min after administration. QTc was calculated using Bazett’s method: QTc = QT/
RR, where RR = interval between R waves.
The HERG channel was expressed in oocytes as previously described (16). Briefly, the HERG cDNA in Psp64PolyA vector was linearized with BamH1. The digested product was ethanol precipitated and the linearized template DNA was resuspended in autoclaved double-distilled water at a concentration of 1 µg/µL. MMessage mMachine kit containing SP6 RNA polymerase enzyme (Ambion, Austin, TX) was used to make cRNA from the linearized template DNA, according to the manufacturer’s instructions.
All protocols were approved by the University of Oklahoma IACUC Committee. Female Xenopus laevis (Nasco, Fort Atkinson, WI) were anesthetized by a 30-min exposure to 3-aminobenzoic acid ethylester (tricaine, Sigma, St. Louis, MO, 1.5 g/L in water). Ovarian lobes were removed through a small incision in the abdominal wall and washed in Ca2+-free OR-2 solution containing (in mM): 82.5 NaCl; 2 KCl; 1 MgCl2; 5 4-(2-Hydroxyethyl) piperazine-1-ethanesulfonic acid (HEPES, free acid) (pH adjusted to 7.6 with NaOH). Stage IV and V oocytes were defolliculated by treatment with 1 mg/mL collagenase (Type IA, Sigma) in Ca2+-free OR-2 solution for 1.5h. Oocytes were incubated at 18°C in modified Barth’s solution with antibiotics, containing (in mM): 96 NaCl; 2 KCl; 1 MgCl2; 1.8 CaCl2; 2.5 HEPES (free acid); 2.5 HEPES (sodium salt); and 0.1 g/L Streptomycin sulfate; 0.27 g/L Pyruvic acid (sodium salt) and 0.5 g/L Gentamicin sulfate. Twenty-four hours after the isolation procedure, oocytes were injected with 23 nL of HERG cRNA (1.1–1.6 µg/µL) using a automatic nanoliter injector (Nanoject II, Drummond Scientific, Broomall, PA).
Currents were expressed in Xenopus oocytes 2–4 days after injection of cRNA. Currents were measured using the two-electrode voltage clamp technique. Oocytes were perfused with modified Barth’s solution at room temperature (22°C–24°C). Glass microelectrodes (tip resistances were ranged between 0.7 and 2.0 M
) were filled with 3 M KCl. Oocytes were voltage-clamped with a GeneClamp 500B amplifier (Axon Instruments, Sunnyvale, CA) and protocols were generated with pClamp software (Axon Instruments, CA). The oocyte membrane potential was held at –70 mV between test pulses. Sevoflurane was vaporized through a dedicated vaporizer with oxygen and dissolved into the solution by bubbling. The concentration of dissolved sevoflurane in the bathing solution was measured by gas chromatography (1%: 0.14, 2%: 0.30, 4%: 0.65 mM). Propofol (Sigma-Aldrich) was dissolved (10–1 M) in dimethyl sulfoxide (DMSO), and then applied to the bathing solution in a designated concentration (10–6–10–4 M). DMSO itself did not affect the evoked currents within the tested concentration. HERG currents were evoked by 2 s depolarizing voltage steps ranging from –70 to + 50 mV in 10 mV increments. The current-voltage relationships were obtained by measuring the current amplitude at the end of the depolarizing steps and at the peak of tail currents. The dose-response relationship of sevoflurane on tail currents was obtained according to the equation (y = min + (max – min)/(1 + 10[log IC50 – x]) Hill slope) using Sigma Plot software (SPSS Inc., Chicago, IL). The activation curves were determined by fitting peak values of tail currents (I) versus test potential (Vt) to a Boltzmann’s function: I = Imax/(1 + exp [(V0.5 –Vt)/k]), where Imax is the maximum tail current. Furthermore, effects of sevoflurane and propofol on the decay of tail currents were measured by applying the single exponential fitting provided by Sigma Plot software.
The kinetics of HERG steady-state inactivation were determined using voltage protocols similar to that previously published (16). Results are expressed as mean ± se. Statistical significance was calculated by means of one-way repeated measures analysis of variance. Student-Newman-Keuls test for multiple comparisons was used to test the significance of dose-dependency. A value of P < 0.05 was considered statistically significant.
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Results
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ECG was recorded in 10 guinea pigs (5 for sevoflurane, and 5 for propofol). For both sevoflurane and propofol, a series of concentrations were administered cumulatively for all 5 guinea pigs. Sevoflurane (1%–4%) prolonged QTc in a dose-dependent manner (Fig. 1A), and the effect was reversible after 10 min of washout. The prolongation of QT started after 2 min and reached a plateau after 5 min of administration. In contrast, propofol had no effect on QTc at any time after administration (Fig. 1B).
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Figure 1. Effects of sevoflurane (A) and propofol (B) on QTc in guinea pig electrocardiogram recordings (n = 5, *P < 0.05 for dose dependency). A: Sevoflurane (1%–4%) prolonged QTc in a dose-dependent manner (1%: 107.5 ± 2.5, 2%: 113 ± 2.7, 4: 121.2 ± 3.5, washout: 102.2 ± 1.5% change, n = 5). Control QTc value was 0.35 ± 0.02 s. B: Propofol had no effect on QTc. (0.2 mg/kg: 101.2 ± 5.3, 0.5 mg/kg: 106.1 ± 2.9, 1.0 mg/kg: 98.4 ± 2.5, 2.0 mg/kg: 99.2 ± 2.1, 5.0 mg/kg: 97.5 ± 4.5, washout: 96.6 ± 3.7% change, n = 5). Control QTc value was 0.39 ± 0.03 s. QTc was measured 10 min after end-tidal concentration was stabilized for sevoflurane and after 3 min of injection for propofol. The concentrations of sevoflurane were 1%: 0.14, 2%: 0.30, and 4%: 0.65 mM.
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Depolarizing pulses from –70 to + 50 mV in 10 mV steps evoked outward K+ currents in Xenopus oocytes expressing HERG channels. Outward currents were activated slowly on depolarization up to 0 mV; thereafter peak current decreased. This reflects the inwardly rectifying property of HERG currents that is a result of fast inactivation at potentials positive to 0 mV (Fig. 2A and B). On repolarization to –70 mV, tail currents were evoked from the process of recovery from inactivation and as the channels pass through an open state before closing (Fig. 2A and C). The current-voltage relationship for the currents measured at the end of the test pulses showed the typical bell-shaped response of HERG channels. These currents were completely blocked in the presence of specific HERG channel inhibitor E-4031 (10–6 M). Sevoflurane did not affect this steady-state current at l% and 2%, but 4% sevoflurane inhibited the steady-state currents between –40 and +50 mV compared with the control currents (Fig. 2B). In contrast, tail currents were significantly inhibited in the presence of sevoflurane in dose-dependent and reversible fashion between 1% and 4% at test potentials positive to –10 mV (Fig. 2C). The concentration-dependent inhibition by sevoflurane was measured for tail currents obtained from a test potential of +40 mV, close to the plateau height of the cardiac action potential. The IC50 value calculated from the Hill equation was 4.32%. Propofol inhibited both the steady-state current and the tail current only at 10–4 M (Fig. 3A, B, C). These inhibitory effects of sevoflurane and propofol returned to 80%–90% of control after 10 min of washout. Sevoflurane (1%–4%) decreased the time constant of the decay in tail currents (Fig. 4A and C). Propofol inhibited it only at a large concentration (Fig. 4B and D). The voltage dependence of activation and inactivation were measured as the relative amplitudes of tail currents and plotted as a function of test potential. For activation, the isochronal activation curve had a V1/2 of –12.8 mV for control currents and did not shift in the presence of 5% sevoflurane (Fig. 5B). Furthermore, to examine the effects of sevoflurane on the voltage-dependence of channel inactivation, a three-pulse protocol was applied. The cell was depolarized to +20 mV for 5 s to establish inactivation, followed by a 30 ms prepulse to potentials between –140 and +20 mV to allow recovery from inactivation but little deactivation. The cell was then depolarized to a test potential of +20 mV to assess the relative number of channels that recovered from inactivation during the prepulse (18) (Fig. 5A). For the inactivation curve, the V1/2 was –49 mV for the control current. Sevoflurane (5%) shifted V1/2 positively by 4.2 mV, but the change was not significant (Fig. 5B).
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Figure 2. Effects of sevoflurane on HERG currents elicited by depolarizing voltage pulses in Xenopus oocytes. (A) Superimposed recordings elicited by depolarizing test pulses from –70 to +50 mV in 10-mV increments from a holding potential of –70 mV in control (upper) and in the presence of 4% sevoflurane (lower) from the same cell. (B and C) Current (I) – voltage (V) relationships for steady-state (B) and the tail (C) HERG current, obtained from the protocol described in the panel (A). Steady-state current amplitudes were measured at the end of depolarizing pulses (B) and the maximum amplitudes of tail currents (C) were plotted against the pulse potential before (closed circle) and after the application of sevoflurane (1%: open circle, 2%: closed triangle, 4%: open triangle, n = 10, *P < 0.05 versus control; **P < 0.05 for dose-dependency).
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Figure 3. Effects of sevoflurane on HERG currents elicited by depolarizing voltage pulses in Xenopus oocytes. (A) Superimposed recordings elicited by a depolarizing test pulse from –70 to +20 mV from a holding potential of –70 mV in control (upper) and in the presence of 10–4 M propofol (lower) from the same cell. (B and C) Current (I) – voltage (V) relationships for steady-state (B) and the tail (C) HERG current, elicited by depolarizing test pulses from –70 to +50 mV in 10-mV increments from a holding potential of –70 mV. Steady-state current amplitudes were measured at the end of depolarizing pulses (B) and the maximum amplitudes of tail currents (C) were plotted against the pulse potential before (closed circle) and after the application of propofol (10–6 M: open circle, 10–5 M: closed triangle, 10–4 M: open triangle, n = 6, *P < 0.05 versus control).
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Figure 4. Effects of sevoflurane and propofol on the decay of HERG tail current. Tail currents were recorded by the repolarization from +50 to –70 mV. Single exponential function was applied for the determination of time constant of the decay (Tau). A and B: Superimposed currents are shown in A (sevoflurane) and B (propofol). C: Sevoflurane (1%–4%) decreased the time constant of the decay (n = 8, *P < 0.05 versus control). D: Propofol, only at a large concentration (10–4 M), decreased the time constant of the decay (n = 5, *P < 0.05 versus control).
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Figure 5. Sevoflurane does not affect the voltage-dependence of channel inactivation nor activation. (A) Measurements of the steady-state inactivation at test potential of +20 mV after prepulse (30 ms) between –120 and +20 mV in 10-mV increments. Superimposed traces after hyperpolarization pulse of –110 mV are displayed before (solid line) and after application of 5% sevoflurane (dashed line). (B) Current (I) – voltage (V) relationships of normalized steady-state inactivation curves (control: closed circle with solid line, 5% sevoflurane: open circle with dotted line, n = 5) and the tail current activation curves (control: closed triangle with solid line, 5% sevoflurane: open triangle with dotted line, n = 10). I–V curves were fitted by Boltzmann relationship.
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Xenopus oocytes injected with either water or uninjected developed small currents on depolarization from –70 mV to +50 mV, which were unaffected by sevoflurane (4%) (data not shown).
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Discussion
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The present study demonstrates a novel effect of sevoflurane on cardiac HERG channels. Both clinical (9,11–14) and animal (19,20) studies have shown prolongation of the QT interval by sevoflurane, although the precise mechanism is not entirely clear. The result, that the prolongation of QTc was observed in the very early phase of administration, consistent with another study in humans (12), suggested that this inhibitory effect might be a direct effect on the HERG channel. The delayed rectifier potassium current in the myocardium consists of two components, IKr (rapid) and IKs (slow). IKr activates faster and at more negative potentials than IKs and displays an apparent inward rectification at potentials positive to 0 mV (19). Park et al. (15) showed that sevoflurane inhibited the delayed rectifier K+ current in isolated guinea-pig ventricular myocytes. Because this inhibitory effect was observed using voltage-ramp protocols at positive potentials, it was concluded that the major effect might be on IKs. However, because HERG channels are rapidly activating and inactivate at positive potentials, slow voltage ramps, such as those used by Park et al. (15), may mask the effects on the HERG channel that encodes IKr.
The results of our study demonstrate that sevoflurane has an IC50 value of approximately 4%, equivalent to 0.65 mM in the bathing solution; this is within clinically relevant concentrations (17). In addition, the inhibitory concentrations of sevoflurane may have been under-estimated because of the presence of a vitelline membrane of Xenopus oocytes. For instance, the class III antiarrythmic agent, BRL-32872, inhibits HERG channels expressed in mammalian cells with an IC50 value of 19.8 nM but requires an almost 12-fold increase in the inhibition of HERG channels in Xenopus oocytes (21).
The mechanism by which sevoflurane inhibits the HERG channel requires special mention. Compared with steady-state currents, sevoflurane was more potent in inhibiting the outward tail currents obtained on repolarization to potentials close to the resting membrane potential of native cardiac myocytes. Large outward tail currents are unique features of HERG channels and kinetically represent recovery of channels from inactivation, whereby channels pass through an open state before closing. This suggests that sevoflurane may modulate the HERG channel by stabilizing the channel in the inactivated state. This is quite different from the effect of dofetillide, a class III antiarrhythmic drug that has a much lower affinity for closed and inactivated channels (22). Interestingly, sevoflurane did not affect either the voltage-dependence of channel activation or the rates of inactivation and deactivation. It is interesting that halothane also inhibited HERG channels both on steady-state and tail currents by slowing activation and accelerating deactivation and inactivation (10). These results are different in the case of sevoflurane, which had an inhibitory effect mainly on tail currents. This suggests that sevoflurane may have less effect than halothane on HERG channels. Further studies are necessary to establish the kinetics of sevoflurane-induced inhibition of the HERG channel.
In contrast, propofol did not prolong QTc after a single administration between 0.2 and 5 mg/kg. This range includes clinically relevant dosages for the induction of anesthesia with propofol and suggests that propofol is a very safe drug in terms of QT prolongation. In the electrophysiological study, the concentration of propofol ranged between 10–6 and 10–4 M. The total plasma concentration of propofol during general anesthesia is 2.0–5.0 µg/mL, comparable to the concentrations used for this study. However, because of its high protein binding, the free propofol concentration in plasma during anesthesia will be much smaller than this. The bathing solution used in our electrophysiological study was free of protein, so that the free propofol concentration in the bathing solution will have been very much larger than that which occurs clinically. This further supports the suggestion that propofol is very safe with regard to QT prolongation.
There was no direct evidence that HERG channels were expressed on the oocytes in this system, but the fact that the specific HERG channel blocker, E-4031, blocked a similar system as reported in some studies (16,18) would strongly support the idea that expressed channels were HERG channels.
The QT interval is determined by the duration of the action potential, which is mainly regulated by a balance of the influx of Ca2+ via the L-type Ca2+ channel and outward K+ currents that define the repolarizing phase. Inhibition of the K+ currents alone induces the risk for torsade de pointes; however, this risk is reduced if there is concomitant inhibition of the Ca2+ currents. We have previously shown that sevoflurane inhibits Ca2+ currents in canine ventricular myocytes (23). This may be consistent with the possible less frequent incidence of torsade de pointes or severe arrhythmias with sevoflurane despite its HERG channel blocking activity. Therefore, the use of sevoflurane in patients with congenital LQTS, or those on ß-adrenoceptor antagonists, may be contraindicated.
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Footnotes
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Supported, in part, by Grant-in aid for scientific research 15591619 (NH) and National Institutes of Health grant DK46367 (HA).
Accepted for publication July 11, 2005.
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Abstract
Introduction
