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The Effects of Halothane, Isoflurane, and Sevoflurane on Ca2+ Current and Transient Outward K+ Current in Subendocardial and Subepicardial Myocytes from the Rat Left Ventricle

Rithalia, Amber PhD*; Hopkins, Philip M. MD; Harrison, Simon M. PhD*

doi: 10.1213/01.ANE.0000138422.40560.A9
Cardiovascular Anesthesia: Case Report
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Halothane, isoflurane, and sevoflurane abbreviate ventricular action potential duration (APD), and for halothane this effect is greater in the subendocardium than in the subepicardium. In this study we investigated mechanisms underlying the regional effects of these anesthetics on APD. The effect of 0.6 mM halothane, isoflurane, and sevoflurane on the action potential, L-type Ca2+ current, transient outward K+ current (Ito), and steady-state current was recorded in rat left ventricular subendocardial and subepicardial myocytes. Halothane and isoflurane (but not sevoflurane) reduced APD significantly (P < 0.05), more in subendocardial than subepicardial myocytes. Peak L-type Ca2+ current did not differ between regions and, compared with control, was reduced significantly in both regions by 40% (P < 0.001), 20% (P < 0.001), and 12% (P < 0.01) by halothane, isoflurane, and sevoflurane, respectively. Ito was greater in subepicardial (3.95 ± 0.29 nA) than subendocardial (1.12 ± 0.05 nA) myocytes. In subepicardial myocytes, peak Ito was reduced significantly by halothane (P < 0.01) and isoflurane (P < 0.05) (by 8% and 7%, respectively) but was unaffected by sevoflurane. No significant reduction of Ito was observed in subendocardial myocytes with the three anesthetics. The steady-state current was increased significantly (P < 0.05), but the extent of this increase did not differ between the two regions or among the three anesthetics. Therefore, greater inhibition of Ito in subepicardial than subendocardial myocytes by halothane and isoflurane could underlie their transmural effects on APD.

IMPLICATIONS: Halothane, isoflurane, and sevoflurane reduce action potential duration (APD) by virtue of inhibitory effects on membrane currents, principally the calcium current. The differential effects of anesthetics on APD in the subepicardium and subendocardium appear to be due to their inhibitory action on the transient outward K+ current.

*School of Biomedical Sciences and †Academic Unit of Anaesthesia, University of Leeds, Leeds, United Kingdom

Supported by the British Heart Foundation, London, UK.

Accepted for publication June 18, 2004.

Address correspondence and reprint requests to Simon M. Harrison, PhD, School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JT, UK. Address e-mail to S.M.Harrison@Leeds.ac.uk.

The volatile general anesthetics halothane, isoflurane, and sevoflurane, as well as having potent negative inotropic effects on the heart (1), also abbreviate ventricular action potential duration (APD) (2–4). This is thought to result from the effect of these drugs on membrane currents such as the L-type Ca2+ current (ICa) (5–10) and the transient outward K+ current (Ito) (10,11). The APD is reduced, suggesting that blockade of the inward current contributes the most to this effect. Rithalia et al. (12) reported that halothane inhibited contraction and APD to a greater extent in the ventricular subendocardium than the subepicardium; this may reflect regional variations in anesthetic-sensitive currents that contribute to the action potential. Membrane currents that play an important role in determining the duration of the ventricular action potential in rat myocardium include ICa, which contributes to the high plateau; repolarizing K+ currents; Ito; and the composite steady-state current (ISS). Ito underlies the initial phase of repolarization and is expressed to a greater degree in the ventricular subepicardium than the subendocardium (13–18), whereas other currents (e.g., ICa) are uniformly distributed across the ventricular wall. As a consequence of the greater expression of Ito in the subepicardium, repolarization is accelerated and APD is shorter than in the subendocardium. Both ICa and Ito have been reported to be sensitive to volatile anesthetics (see above), and the regional variation in the density of Ito across the ventricular wall represents a possible mechanism that could underlie the transmural variation in the effects of halothane on APD described previously (12). The aim of these studies was to record the effects of halothane, isoflurane, and sevoflurane on APD, ICa, Ito, and ISS in cells derived from the left ventricular subepicardium and subendocardium, to investigate potential mechanisms responsible for transmural effects on APD.

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Methods

These experiments were performed on Wistar rats (∼250 g; Central Biomedical Services, University of Leeds) that were given access to food and water ad libitum and maintained under a 12-h light/dark cycle. Animals were killed in accordance with UK government Home Office guidelines (Schedule 1 techniques sanctioned in the Animals Procedures Act, 1986). The heart was rapidly excised and placed into isolation solution (see below for composition) supplemented with 750 μM CaCl2 and equilibrated with 100% oxygen. The coronary arteries were flushed of blood by perfusion via the aorta with the above solution and then perfused for 4 min with the isolation solution, to which 100 μM Na2 EGTA was added (19). The heart was then perfused for 7 min with the isolation solution supplemented with 1 mg/mL collagenase (Type I; Worthington Biochemical Corp., Lakewood, NJ) and 0.1 mg/mL protease (Type XIV; Sigma, Poole, Dorset, UK), after which the ventricles were cut from the heart. The left ventricular free wall was then separated from the septum, and tissue was dissected from the subendocardium and subepicardium. Samples from both regions were then finely chopped and shaken in the collected enzyme solution (to which 1% bovine serum albumin was added) for 5-min intervals. Dissociated myocytes were harvested by filtration at the end of each 5-min digestion, and any remaining tissue was returned for further enzyme treatment. The dissociated myocytes from each region were centrifuged at 40g for 1 min, resuspended in the Ca2+-containing isolation solution, and stored at room temperature until required.

The isolation solution was composed of the following (mM): NaCl 130, KCl 5.4, MgCl2 1.4, NaH2PO4 0.4, HEPES 5, glucose 10, taurine 20, and creatine 10, pH 7.1 (NaOH), at 37°C. After dissociation, myocytes were superfused with a physiological salt solution of the following composition (mM): NaCl 140, KCl 5.4, MgCl2 1.2, NaH2PO4 0.4, HEPES 5, glucose 10, and CaCl2 1, pH 7.4 (NaOH), at 30°C. Next, 0.6 mM halothane (Fluothane; Zeneca, Macclesfield, UK), isoflurane (Aerrane; Pharmacia Laboratories, Milton Keynes, UK), or sevoflurane (Abbott Laboratories, Queenborough, UK) was added to the above solution from a 0.5 M stock solution made up in dimethyl sulfoxide. Anesthetic-containing solutions contained ≤0.12% dimethyl sulfoxide, a concentration that had no significant effect on the electrical activity of the myocytes. The 0.6 mM concentration of all 3 anesthetics equates to ∼2 times the minimum alveolar concentration for the rat (20) and therefore represents physiologically relevant and approximately equianesthetic concentrations. In previous studies (2), we verified anesthetic concentrations in the superfusate by gas liquid chromatography and found that the aqueous concentration was as expected and was well maintained over time. Unless stated otherwise, all solution constituents were from Sigma.

Action potentials were recorded with the perforated patch-clamp technique in current clamp mode (Axoclamp 200; Axon Instruments, Inc., Foster City, CA). The tip of each patch pipette was filled with a solution of the following composition (mM): KCl 140, NaCl 10, MgCl2 1, CaCl2 1, and HEPES 10, pH 7.1 (KOH), at 30°C, and the pipette was then back-filled with the above solution supplemented with amphotericin B 400 μg/mL. After the formation of a gigaseal, cells were left for up to 15 min until access resistance had decreased to <30 MΩ. Action potentials were evoked in response to current pulses of 1 nA (2 ms in duration) at a frequency of 1 Hz. Voltage traces were filtered at 1 kHz and digitized at 5 kHz, and the time course of the action potentials was analyzed with pClamp software (Axon Instruments Inc.). Action potential configuration was analyzed by measuring APD from the peak of the action potential to 25%, 50%, and 90% of repolarization.

Ito and ICa were recorded by using the whole-cell patch-clamp configuration. For Ito, the pipette solution contained the following (mM): K-aspartate 120, KCl 20, MgCl2 4, Na2 adenosine triphosphate 3, HEPES 5, and EGTA 10, pH 7.1 (KOH), at 30°C, and Ito was evoked by 200-ms depolarizing pulses to +80 mV, from a holding potential of −80 mV. Nifedipine 10 μM was added to the superfusion solution (see above) to block ICa. The pipette solution for recording ICa contained the following (mM): CsCl 80, TEA-Cl 20, MgCl2 4, Na2 adenosine triphosphate 3, HEPES 5, and EGTA 10, pH 7.1 (CsOH), at 30°C. ICa was evoked by 200-ms depolarizing pulses to 0 mV from a holding potential of −40 mV, and the superfusion solution was supplemented with 20 mM CsCl to minimize contaminating K+ currents. For both Ito and ICa, patch electrode resistance was 2–4 MΩ.

Once stable electrophysiological recordings were achieved, cells were exposed to 0.6 mM halothane, isoflurane, or sevoflurane for 1 min, during which a new steady state was achieved. For both action potentials and membrane currents, traces were averaged by using pClamp software to generate representative traces under control conditions and during anesthetic exposure. All experimental protocols were conducted at 30°C because at this temperature, run-down of membrane current was greatly reduced compared with 37°C, and electrophysiological recordings were more stable and reproducible over time and between cells. However, it should be noted that APD and membrane current magnitude would differ from those recorded at 37°C. For the measurement of each variable, each cell acted as its own control and was exposed to only one anesthetic, such that randomization of anesthetic exposure was not required.

Statistical analysis was performed in SigmaStat 2.0 (Jandel Scientific) by using Student’s paired or unpaired t-tests or analysis of variance as appropriate. Graphs were prepared with SigmaPlot 2000 (Jandel Scientific). Data are presented as mean ± sem.

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Results

Table 1 illustrates that there were significant differences in the peak voltage, amplitude, and duration of the action potential (measured at 25%, 50%, and 90% repolarization; P < 0.01 for all cases) but no differences in resting membrane potential between subepicardial (n = 17) and subendocardial (n = 16) cells. Under control conditions, the duration of the action potential at 90% repolarization (APD90) was 33.6 ± 2.9 ms and 68.0 ± 6.9 ms in subepicardial and subendocardial cells, respectively, such that the mean transmural difference in APD90 was 34 ms.

Table 1

Table 1

Figure 1, A and B illustrate action potential recordings from representative subepicardial and subendocardial cells, respectively. In subepicardial cells, 0.6 mM halothane significantly reduced APD90 (Fig. 1C), an effect that was modest and apparent only in the late phase of repolarization (Fig. 1A). In subendocardial cells, however, halothane had a much more profound effect on APD that was evident throughout the repolarization phase (Fig. 1B). Mean data in Figure 1D illustrate that halothane led to a 25% compared with a 37% shortening of APD90 in subepicardial (n = 6) and subendocardial (n = 7) cells, respectively. The result of this effect was to reduce the transmural gradient in APD90 in this subset of cells from 38 to 20 ms, a decrease of 47%.

Figure 1

Figure 1

Isoflurane significantly reduced APD90 from 27.1 ± 2.3 ms to 24.7 ± 1.9 ms in subepicardial cells (P < 0.05; n = 7) and from 62.8 ± 9.6 ms to 47.1 ± 5.8 ms in subendocardial cells (P < 0.01; n = 8). Similarly, sevoflurane significantly reduced APD90 in both regions: in subepicardial cells, APD90 was reduced from 30.4 ± 3.4 ms to 27.9 ± 2.8 ms (P < 0.05; n = 10), and in subendocardial cells it was reduced from 48.9 ± 6.0 ms to 42.3 ± 5.0 ms (P < 0.01; n = 7). Figure 1D shows mean data describing the extent to which APD90 (expressed as a percentage of control) was abbreviated in subepicardial and subendocardial cells by the three anesthetics. Halothane and isoflurane abbreviated APD90 to a significantly greater extent in subendocardial than subepicardial cells, but this did not reach significance with sevoflurane. The transmural gradient of APD90 was reduced by 37% by isoflurane and was affected least by sevoflurane (22%).

Figure 2 illustrates records of ICa under control conditions and in the presence of 0.6 mM isoflurane in representative subepicardial (Fig. 2A) and subendocardial cells (Fig. 2B). Isoflurane significantly (P < 0.001) decreased peak ICa (measured as peak current minus current at the end of the pulse) and accelerated current inactivation during the pulse (Table 2) in both cell types. Table 2 shows that there was no significant difference in the peak current magnitude or the inactivation time constant between subepicardial and subendocardial cells under control conditions. All three anesthetics decreased peak current (Table 2); current inactivation was accelerated (9,21) in all cases except in subepicardial cells with sevoflurane (Table 2). Figure 2C illustrates that each anesthetic inhibited peak current to the same extent in subepicardial and subendocardial cells; halothane had the greatest inhibitory effect, reducing peak ICa by ∼40% of control with isoflurane and sevoflurane having lesser effects (a reduction of 20% and 12% of control, respectively).

Figure 2

Figure 2

Table 2

Table 2

Figure 3 illustrates current records during voltage clamp pulses from −80 to +80 mV to evoke Ito. The rapidly inactivating component of membrane current most evident in Figure 3A was blocked by 5 mM 4-aminopyridine (not shown). Under control conditions, Ito (measured as peak current minus current at the end of the pulse) was significantly greater in subepicardial cells (3.95 ± 0.29 nA; n = 32) than in subendocardial cells (1.12 ± 0.05 nA; n = 19; P < 0.001). In subepicardial cells (Fig. 3A) exposed to halothane, Ito was reduced significantly (Table 3; mean reduction of 8.3% ± 1.7%), whereas in subendocardial cells, current was unaffected by halothane exposure (mean reduction of −1.3% ± 2.0%; Table 3, Fig. 4A). It was apparent, however, that the sustained current (ISS) at the end of the pulse was increased during halothane exposure in both subepicardial and subendocardial cells (Table 3). Figure 3B illustrates in subendocardial cells that this current was enhanced to the same extent throughout the clamp pulse. These data suggest that halothane inhibited Ito (in subepicardial cells) but also led to the enhancement (or activation) of a noninactivating or sustained component of current in both cell types.

Figure 3

Figure 3

Table 3

Table 3

Figure 4

Figure 4

Like halothane, isoflurane significantly reduced Ito in subepicardial cells (mean change of −7.3% ± 2.1%) but had no effect on subendocardial cells (mean change, −1.3% ± 1.3%; Table 3). ISS was also increased by isoflurane in both cell types, but this achieved significance (P < 0.05) only in subepicardial cells. Table 3 also shows that sevoflurane had no significant effect on Ito in either region but enhanced ISS in both regions.

Figure 4B compares the effects of all three anesthetics on Ito in subepicardial and subendocardial cells. Halothane and isoflurane had similar effects in percentage terms, inhibiting Ito to a greater extent in the subepicardium, whereas sevoflurane had only a small effect on Ito that was not significantly different from control or between the two regions.

Figure 4C illustrates that ISS at the end of the pulse was significantly enhanced in both cell types by halothane (Table 3), and Figure 4D shows that there were no differences in the extent to which ISS was enhanced by the three anesthetics or between the two regions (analysis of variance).

The increase in ISS could have been due to an anesthetic-induced increase (or slowing of inactivation) of a component of outward current that was previously active or, alternatively, the opening of a different class of ion channel activated by anesthetics (e.g., twin pore domain K+ channels). Figure 3B illustrates that in subendocardial cells, halothane enhanced current to the same extent throughout the pulse. This suggests that this component of current is rapidly activated and shows little inactivation during the pulse. Figure 5A illustrates current-voltage relationships for end current in the absence and presence of 0.6 mM halothane in subepicardial cells. Current was significantly enhanced by halothane at all voltages positive to −20 mV. A similar relationship was observed in subendocardial cells (not shown); i.e., there was no transmural difference in the extent of halothane-induced end current. Figure 5B shows the voltage dependence of the halothane-induced increase in end current for seven cells. This relationship appears to have a linear or weak outward rectifying voltage dependence and reverses at approximately −40 mV, close to the equilibrium potential for chloride ions (−44 mV in these experiments).

Figure 5

Figure 5

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Discussion

These data illustrate that both halothane and isoflurane abbreviate APD to a greater extent in subendocardial than in subepicardial cells. Sevoflurane reduced APD the least, and no significant transmural difference was observed in its effects. The aim of these experiments was to identify possible mechanisms underlying the transmural effects on APD of these anesthetics. The main reason for the longer action potential in the subendocardium is the relative paucity of Ito in this region compared with the subepicardium (13–18). Figures 3 and 4 illustrate that halothane and isoflurane inhibited this current to a significantly greater extent in cells from the subepicardium than the subendocardium, whereas no transmural difference was observed in the effects of sevoflurane. As such, the varying degree of inhibition of Ito represents a possible mechanism to explain the regional differences in the effect of halothane and isoflurane on APD, given that ICa does not change across the ventricular wall and is inhibited to the same extent in subendocardium and subepicardium (Fig. 2).

The regional difference in the effects of halothane and isoflurane on APD could be explained in terms of the inhibitory effects of halothane on ICa and Ito. Blockade of ICa in isolation, by halothane or isoflurane, would induce a shortening of APD. Figure 2 illustrates that there is no difference in the density of ICa across the ventricular wall, and this confirms previous reports (14,18,22,23). Therefore, one would expect similar action potential-abbreviating effects to result from halothane- or isoflurane-induced inhibition of ICa in the subendocardium and subepicardium. Inhibition of Ito alone by halothane (11) or isoflurane would be expected to prolong APD. However, because Ito is inhibited to a greater extent in subepicardial than subendocardial cells by halothane and isoflurane (Fig. 4), then inhibition of this current would be expected to have a greater action potential-prolonging effect in the subepicardium than the subendocardium. Combining the inhibitory action of halothane and isoflurane on these two currents in subepicardial myocytes, where Ito density is high, would lead to simultaneous inhibition of outward current (Ito) and inward current (ICa) and result in only a small net change in the balance of inward and outward currents and, consequently, only a modest effect on the APD. Reduction of APD in subepicardial cells by all three anesthetics suggests that inward current is inhibited to a greater extent than outward current (i.e., the inhibitory effect of halothane on ICa is greater than on Ito under these experimental conditions). In contrast, in subendocardial myocytes, where Ito density is much lower (Fig. 3), halothane and isoflurane would lead to only a small inhibition of outward current, whereas inward ICa would be inhibited to the same degree as in subepicardial cells. Thus, inward current (ICa) would be inhibited to a greater extent than outward current (Ito), with the result that APD would be abbreviated to a greater extent. The effect of an increase in ISS by all three anesthetics would contribute to the reduction in APD induced by these anesthetics. However, these data suggest that this would not contribute to the regional effects of these drugs, because this current was enhanced to the same degree by halothane, isoflurane, and sevoflurane in both subepicardial and subendocardial cells.

This proposed mechanism correlates well with the relative potencies of the three anesthetics on APD and the membrane currents studied: of the three, halothane had the greatest effect on both ICa and Ito and induced the largest transmural difference in APD. In contrast, sevoflurane, which had only a modest effect on ICa and Ito, led to the least change in APD.

In the clinical situation, use of volatile anesthetics—halothane in particular—is associated with more arrhythmias (24,25). Because these drugs lead to a decrease in Ca2+ influx via ICa and reduced Ca2+ transient and contraction (1), it is unlikely that such arrhythmias are secondary to a state of Ca2+ overload and are more likely due to altered electrical properties of the myocardium. These data presented here show that one consequence of the regional effects of these anesthetics on the action potential is that the transmural difference in APD is reduced. The transmural gradient in APD, which exists in vivo, is considered to underlie the positive going T-wave on the electrocardiogram (26) and is important for normal transmural dispersion of repolarization/refractoriness, which helps prevent reentrant arrhythmias. Under control conditions, the difference between the mean subendocardial and subepicardial APD90 was 38 ms, but this was reduced to 20 ms (a reduction of 47%) by halothane. This contrasts with isoflurane and sevoflurane, which reduced transmural APD by 37% and 22%, respectively. Drugs that affect the normal passage of repolarization and/or transmural dispersion of refractoriness are known to predispose to reentrant arrhythmias (27).

Our data suggest that, in vivo, the transmural dispersion of repolarization would be reduced during exposure to anesthetics that generally would be considered to be antiarrhythmic. However, it is possible that in vivo, where the transmural gradient in APD is smaller than recorded in isolated cells (because of electrotonic coupling between cells), the greater action potential-shortening effect of halothane and isoflurane on the subendocardium could collapse the normal transmural gradient of repolarization. Given the complex architecture of the heart, in terms of fiber orientation and impulse propagation, a potential consequence of altered repolarization would be an enhanced prospect of collision of repolarization wave fronts that would induce local conduction block (28). Thus, halothane especially, but also isoflurane, by altering normal repolarization, may modulate the vulnerability of the heart to arrhythmias induced by additional stimuli, such as a premature ventricular excitation (29), and could contribute to the increased incidence of arrhythmias observed in the clinical situation.

Figure 4D illustrates that all three anesthetics enhance current at the end of the pulse. Figures 3B and 5B suggest that the halothane-induced current has rapid activation kinetics, displays a linear or weak outward-rectifying voltage dependence, reverses at approximately −40 mV, and is still present after application of 10 mM 4-aminopyridine (not shown). The voltage dependence and estimated reversal potential are not consistent with activation of a K+ conductance such as TASK1 and suggest that the three anesthetics may enhance a chloride conductance (ECl was −44 mV in these experiments), although further experimentation is required to confirm this.

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