Institute of Pharmacology and Toxicology Consejo Superior de Investigaciones Científicos, Universidad Complutense de Madrid, School of Medicine, Universidad Complutense, Madrid, Spain
Submitted 27 January 2005 ; accepted in final form 28 June 2005
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ABSTRACT |
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K+ channel; membrane currents; ion channels; arrhythmia; antiarrhythmics
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METHODS AND MATERIALS |
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Electrophysiological recording.
The intracellular pipette-filling solution contained (in mM) 80 K-aspartate, 50 KCl, 3 phosphocreatine, 10 KH2PO4, 3 MgATP, 10 HEPES-K, and 5 EGTA and was adjusted to pH 7.25 with KOH. The bath solution contained (in mM) 130 NaCl, 4 KCl, 1.8 CaCl2, 1 MgCl2, 10 HEPES-Na, and 10 glucose, and was adjusted to pH 7.4 with NaOH. AA, DHA, and 5,8,11,14-eicosatetraynoic acid (ETYA) (Sigma, St. Louis, MO) were dissolved in ethanol at concentrations of 56.5, 52.5, and 10 mM, respectively. Experiments were performed to test the potential effects of ethanol (30 µl/100 ml) on HERG channels. Ethanol, at this concentration, did not modify the outward maximum current (56.3 ± 10.3 vs. 52.7 ± 11.2 pA; n = 7, P > 0.05) nor the maximum peak tail current (68.7 ± 16.4 to 63.6 ± 16.7 pA; n = 7, P > 0.05). AA and DHA were stored under argon atmosphere and maintained in sealed ampoules protected from light at 40°C to prevent oxidation. HERG currents were recorded at room temperature (2123°C) using the whole cell patch-clamp technique (13) with an Axopatch 200A patch-clamp amplifier (Axon Instruments, Foster City, CA). Micropipettes were pulled from borosilicate glass capillary tubes (GD-1; Narishige, Tokyo, Japan) on a programmable horizontal puller (Sutter Instrument, San Rafael, CA) and heat polished with a microforge (Narishige). Micropipette resistance was 13 M. Maximum HERG tail-current amplitudes averaged 717 ± 123 pA, mean uncompensated access resistance was 1.5 ± 0.5 M
, and cell capacitance 29.8 ± 2.0 pF (n = 11). Thus no significant voltage errors (<5 mV) were expected. HERG currents were filtered at 100 Hz and sampled at 200 Hz. Cells were held at 80 mV. After control data were obtained, bath perfusion was switched to fatty acid-containing solution. The effects of drug infusion were monitored with test pulses to 10 mV applied every 30 s until steady state was obtained. Steady-state current-voltage relationships (I-V) were obtained by averaging the current over a small window (25 ms) at the end of 5-s depolarizing pulses. Between 80 and 50 mV only passive linear leak was observed and least squares fit to these data were used for passive leak correction. Deactivating tail currents were recorded at 60 mV. The activation curves were obtained from the tail current amplitude measured at the maximum peak value. The inactivation curves were obtained from the maximum current amplitude measured at a test pulse at +30 mV applied after a two-pulse protocol that consisted of a 1-s depolarizing pulse from 80 mV to +30 mV followed by a second pulse of 20 ms in duration to different membrane potentials between 120 mV and +10 mV. Other pulse protocols are described in RESULTS. Command potentials and data acquisition were generated by using the CLAMPEX program of pCLAMP 6.0.1, 9.0.1 (Axon Instruments). Data analysis was performed using the CLAMPfit program of pCLAMP 9.0.1, Origin 7.0.3 (Microcal Software, Northampton, MA), and other custom-made analysis programs. Deactivation was fitted to a biexponential process
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Statistical methods. Results are expressed as means ± SE. Direct comparisons between mean values in control conditions and in the presence of drug for a single variable were performed by paired Student's t-test. Differences were considered significant if P < 0.05. Comparisons between the three groups were performed by a one-way ANOVA, with a posterior Newman-Keuls test if P < 0.05.
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RESULTS |
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Voltage-dependent block of HERG channels induced by AA and DHA. Figure 1A shows HERG currents obtained after applying 5-s pulses from a holding potential of 80 to +50 mV in 10-mV steps in the absence and in the presence of 10 µM AA or DHA. Deactivating tail currents were measured at 60 mV. Figure 1B shows the I-V relationships obtained by plotting the amplitude of the HERG current measured at the end of the 5-s pulses vs. membrane potential in the absence and in the presence of AA (Fig. 1B, left) or DHA (Fig. 1B, right). Under control conditions, the I-V exhibits the characteristic bell shape that increases from 50 mV to 10 mV (12.4 ± 1.8 mV, n = 19) and, due to the fast C-type inactivation of HERG channels, it decreased with further depolarizations (38, 39). Thus steady-state drug-induced block was measured at the end of 5-s pulses to 10 mV. Blockade induced by AA (37.7 ± 2.4%, n = 10) was similar to that produced by DHA (50.2 ± 8.1%, n = 7; P > 0.05). However, block induced by DHA was higher than that produced by AA measured at the maximum peak of the tail current recorded at 60 mV after applying a 5-s depolarizing test pulse to 0 mV (47.4 ± 4.2%, n = 10, vs. 58.3 ± 2.7%, n = 7, in the presence of AA and DHA, respectively; P < 0.05). AA and DHA shifted the midpoint of activation curves without modifying the slope factors, being the voltage shift induced by DHA higher than that produced by AA (11.2 ± 1.1 mV, n = 7 vs. 5.1 ± 1.8 mV, n = 10; P < 0.05) (Fig. 1C). These results, 1) the higher degree of block observed in the tail currents, and 2) the negative shift of the activation curve, suggest an open-channel block mechanism.
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AA metabolism occurs via three principal pathways: cyclooxygenase, lipooxygenase, and epoxygenase catalysis. To test whether the AA effects were due to its direct interaction with HERG channels or to the actions of some of its metabolites, the electrophysiological effects of its nonmetabolizable analog ETYA were analyzed (Fig. 2). ETYA (10 µM) inhibited HERG current by 37.4 ± 3.7% and 42.5 ± 5.8%, measured at the end of 5-s pulses to 10 mV and at the maximum peak tail currents, respectively (n = 7; P > 0.05), similar to the inhibition produced by AA at the same concentration. Moreover, as it can be observed in Fig. 2, BD, the kinetics of block induced by ETYA was similar to that observed in the presence of AA. Therefore, these results suggest that the AA effects observed on HERG channels are not due to AA metabolites.
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To analyze the effects of AA or DHA on the inactivation kinetics, the three-pulse protocol shown in the top of Fig. 4 was applied. Holding potential was maintained at 80 mV, and after a 2-s step to +40 mV that fully activates HERG channels, a 20-ms pulse to 120 mV that promotes the recovery from the fast inactivation of HERG channels was applied. Then, 20-ms test pulses to membrane potentials between 0 and +50 mV were applied. The degree of block induced by DHA when measured at the maximum peak current recorded during the application of the test pulse to 0 mV was higher than that induced by AA. Neither DHA nor AA modified the time constant of inactivation (Inac) at membrane potentials between 0 and +40 mV. However, at membrane potentials positive to +40 mV, AA and DHA increased the
Inac, which can be explained either by a fatty acid-induced stabilization of the open state of HERG channels or a destabilization of the inactivated state. Figure 4B shows the degree of block induced by AA and DHA at the end of 5-s pulses to 0 mV (End 5-s) and at the maximum peak current recorded during the application of the test pulse to 0 mV (Maximum). DHA induced a higher block (P < 0.05) when measured at the maximum peak current than at the end of 5-s depolarizing pulses, thus suggesting an open channel block. However, block of HERG channels induced by AA was similar under both experimental conditions.
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DISCUSSION |
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Effects of AA and DHA on HERG channels. AA and DHA block HERG channels in a voltage-, time-, and state-dependent manner, which is consistent with an open channel block mechanism. In fact, block induced by both PUFAs steeply increased in the range of membrane potentials that coincides with the range of HERG channel activation, suggesting that their binding may derive a significant fraction of its voltage sensitivity through coupling to channel gating. Unfortunately, at depolarized voltages the open and inactivated conformations of HERG channels are in rapid equilibrium, making it difficult to unequivocally identify the state(s) with which these two PUFAs interact.
Whereas AA induced a similar inhibition of the HERG current when measured at the end of depolarizing pulses to 10 mV and at the maximum tail currents, DHA inhibited this current to a higher extent when measured at the maximum tail current than at the end of depolarizing steps to 10 mV. During depolarization, HERG channels inactivate faster than they activate and thus the amplitude of the current is reduced. On repolarization, closed channels transit through the open state, resulting in tail currents with higher amplitude (38, 39). In agreement with these results, block induced by AA when measured at the maximum peak current of a test pulse to 0 mV applied after a hyperpolarizing pulse to 120 mV (that promotes the IO transition) was similar to that observed at the same voltage at the end of a 5-s depolarizing pulse. However, DHA-induced block, when measured at the maximum peak current of a test pulse to 0 mV applied after a hyperpolarizing pulse to 120 mV, was higher than that observed at the same voltage at the end of a 5-s depolarizing pulse. Block induced by AA and DHA was also time dependent, being evident after a prepulse to +180 mV, suggesting a rapid drug binding to activated HERG channels, as previously described for cocaine and bupivacaine-type local anesthetics (11, 44). This time dependency was also evident in the deactivation process of HERG channels that was accelerated in the presence of both AA and DHA. However, AA and DHA did not modify the onset kinetics of the inactivation process or the recovery process. The faster deactivation induced by both PUFAs, together with their lack of effect on the recovery kinetics, suggests that a very fast dissociation rate constant from HERG channels is consistent with an open channel block mechanism, as has been proposed for propafenone (2). Another piece of evidence of an open channel interaction between both PUFAs and HERG channels is the use-dependent inhibition of the current. Taken together, all these results suggest that both AA and DHA preferentially bind to the open state of HERG channels, and that DHA exhibits a higher affinity for this state of the channel.
We also observed that AA and DHA produced a positive shift in the inactivation curve. This could be explained either by 1) stabilization of the open state of HERG channels or 2) destabilizing the inactivation process; i.e., without modifying the onset but accelerating the offset of inactivation. In both cases, the shift of the inactivation curve would be the result of the interaction between PUFAs and a closed state of HERG channels (tonic block). This tonic block is likely to influence the apparent steady-state inactivation and perhaps the activation process because both PUFAs accelerate the deactivation process. All of these results suggest that AA and DHA preferentially block the open state of HERG channels, but also that they interact with a closed state, thus producing changes in channel gating. Finally, the similar degree of AA-induced inhibition of the current at the end of 5-s depolarizing pulses (when most channels are inactivated) and at the maximum tail current or at the maximum peak current after applying a 120 mV step cannot permit us to rule out an interaction between AA and the inactivated state of HERG channels. Moreover, it has been shown that AA regulates the inactivation process in other K+ channels in such a way that introduces rapid voltage dependent inactivation into noninactivating Kv channels (30). The authors explain these results under the framework that AA closes Kv channels by inducing conformational alterations in the selectivity filter region (30) and propose that Kv channel inactivation is lipid dependent and that this process has a high affinity, comparable to that of KATP channels for phosphoinositides (3). Oliver et al. (30) propose that AA inserts into the cell membrane from either side, interacts with the channel protein, and, allosterically, induces a fast closure of the open Kv channel pore through conformational modifications in the selectivity filter. Further studies are required to discern the possible role of AA on the inactivation of HERG channels.
Clinical implications of this study.
Many studies suggest that -3 fatty acids have beneficial effects on human health. In contrast, a diet enriched in
-6 fatty acids provokes atherosclerosis, carcinogenesis, and heart disease (20). In the present study we have demonstrated that AA and DHA block HERG channels. The plasma levels of these two PUFAs vary greatly depending on the hormonal, metabolic, and nutritional state of the individual. Around 99.9% of fatty acids are carried in plasma bound to albumin and the range of free AA and DHA in human plasma is 5.313.1 µM and <2.8 µM, respectively (6). The EC50 values calculated from the blockade produced by both PUFAs at 10 µM are well within their physiological plasma range. Therefore, we can conclude that both PUFAs block HERG channels at concentrations within their physiological plasma levels.
It has been described that AA is able to modulate several ion currents (28). In fact, AA decreases L-type ICa (ICa,L), T-type ICa (ICa,T), Ito, INa, and Kv1.5 currents (4, 14, 40, 41) and activates IK1 (25). AA plasma levels are known to be increased during ischemia and reperfusion at the intracellular and extracellular levels (19), which, in the light of previous and present results, could represent a "natural" protective mechanism to prevent arrhythmias under these pathological conditions. On the other hand, it has been shown that DHA exhibits potential cardioprotective effects that have been associated with their antiarrhythmic effects (21). DHAs antiarrhythmic effects have been attributed to its actions on the cardiac ion channels responsible for the onset and maintaining of the cardiac action potential, mostly on its inhibitory effects on Na+ and ICa,L channels (22, 42), because DHA has inhibitory effects on INa, but not on ICa,L, that are higher than those of AA (41). DHA inhibitory effects on INa and ICa theoretically should shorten the cardiac action potential duration. Moreover, DHA enhances IKs, which would further shorten the cardiac action potential duration (9). However, experiments performed in rat ventricular myocytes demonstrate that DHA slightly prolongs the rat cardiac action potential (4, 26). In the present study we have demonstrated that DHA blocks HERG channels. Most drugs that selectively block HERG channels prolong the cardiac action potential (34). However, interactions of nonselective HERG channel blockers with other cardiac ion channels may mitigate or exacerbate the prolongation of action potential duration (27, 31, 33). Because DHA inhibits INa and ICa and enhances IKs (effects that would shorten the cardiac action potential), but also inhibits Ito, IK,ur, and HERG (which should produce a lengthening of the action potential duration), the result should be a modest effect on the time of repolarization. Besides these effects on the action potential duration, it should be stated that its inhibitory effects on Na+, Ca2+, and several K+ channels (Kv4 and HERG channels) would result in a lengthening of the refractory period and a decrease of cardiac excitability, thus contributing to its antiarrhythmic effects.
To our knowledge, this is the first demonstration that HERG channels are modulated by AA and DHA. The -3 antiarrhythmic effects have been attributed to their availability to modulate cardiac ion channels involved in the genesis and maintenance of the cardiac action potential (21). Our results suggest that AA and DHA block HERG channels mainly by binding to the open state of the channel. These PUFAs actions on HERG channels have to be taken into account to explain the antiarrhythmic effects of AA during ischemia and those previously reported for DHA in subjects consuming a diet rich in fish and fish oils.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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