(Circulation. 2000;102:1165.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Nicotine Is a Potent Blocker of the Cardiac A-Type K+ Channels
Effects on Cloned Kv4.3 Channels and Native Transient Outward Current
From the Department of Medicine and Research Center, Montreal Heart Institute, University of Montreal (H.W., H.S., L.Z., M.P., S.N., Z.W.), and Department of Pharmacology and Therapeutics, McGill University (S.N.), Montreal, Quebec, Canada, and the Department of Pharmacology, Harbin Medical University, Harbin, China (B.Y., Z.W.).
Correspondence to Dr Zhiguo Wang, Montreal Heart Institute, 5000 Belanger E, Montreal, Quebec, Canada H1T 1C8. E-mail wangz{at}icm.umontreal.ca
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Abstract |
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Background—Nicotine is a main constituent of cigarette smoke and smokeless tobacco, known to increase the risk of sudden cardiac death. This study aimed at establishing ionic mechanisms underlying potential electrophysiological effects of nicotine.
Methods and Results—Effects of nicotine on Kv4.3 and Kv4.2 channels expressed in Xenopus oocytes were studied at the whole-cell and single-channel levels. The effects of nicotine on the transient outward K+ current (Ito) were studied by use of whole-cell patch-clamp techniques in canine ventricular myocytes. Nicotine potently inhibited Kv4 current. The concentration for half-maximal inhibition (IC50) was 40±4 nmol/L, and the current was abolished by 100 µmol/L nicotine. The IC50 for block of native Ito was 270±43 nmol/L. The steady-state activation properties of Kv4.3 and Ito were unaltered by nicotine, whereas positive shifts of the inactivation curves were observed. Of the total inhibition of Kv4.3 and Ito by nicotine, 40% was due to tonic block and 60% was attributable to use-dependent block. Activation, inactivation, and reactivation kinetics were not significantly changed by nicotine. Nicotine reduced single-channel conductance, open probability, and open time but increased the closed time of Kv4.3. The effects of nicotine were not altered by antagonists to various neurotransmitter receptors, indicating direct effects on Ito channels.
Conclusions—Nicotine is a potent inhibitor of cardiac A-type K+ channels, with blockade probably due to block of closed and open channels. This action may contribute to the ability of nicotine to affect cardiac electrophysiology and induce arrhythmias.
Key Words: nicotine • ion channels • potassium
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Introduction |
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Use of cigarettes and smokeless tobacco is a considerable public health problem. Conversely, nicotine also has the potential to be a valuable pharmacological agent.1 Nicotine is known to increase the risk of cardiovascular disease, sudden coronary death, hypertension, and stroke.2 3 4 5 It is believed that nicotine promotes sudden cardiac death by provoking lethal ventricular arrhythmias.6 7 8 Indeed, nicotine is implicated in a wide spectrum of cardiac rhythmic disorders, including transient sinus arrest and/or bradycardia, sinus tachycardia, atrial fibrillation, sinoatrial block, AV block, and ventricular tachyarrhythmias.3 6 7 8 9
Nicotine binds to the nicotinic cholinergic gating site on cation channels in receptors (nAChRs) throughout the body, stimulating the release of neurotransmitters, including catecholamines from the adrenal medulla. The cardiac effects of nicotine have been ascribed to this enhanced release of catecholamines.10 However, accumulating evidence has shown that nicotine can also exert its effects without involvement of nAChRs and catecholamine release. Studies under conditions devoid of nAChR stimulation demonstrated the ability of nicotine to alter action potential (AP) characteristics in guinea pigs,11 rabbits,12 and dogs13 in different tissues such as sinus node,14 atrium, ventricle, and Purkinje fibers. The most noticeable changes were decreases in resting potential and prolongation of later AP phases. It is therefore quite conceivable that nicotine might be able to interact directly with ion channels.
K+ currents are critical for membrane repolarization and maintaining resting potentials of cardiac cells.15 The A-type K+ current, also called transient outward K+ current (Ito), governs the initial phase of cardiac repolarization and influences the participation of other currents and membrane transport processes by affecting the voltage-time trajectory of the AP. Ito is altered in many heart diseases and is a target for many drugs. Native Ito is encoded by A-type K+-channel genes such as Kv1.4, Kv4.2, and Kv4.3.16 17 18 19 The participation of Kv4.3 has been convincingly demonstrated in rats,18 rabbits,16 dogs,17 and humans.16 In light of the ability of nicotine to prolong APD and to alter the propensity to arrhythmias, we hypothesized that nicotine might be able to block K+ channels. To explore whether the long-recognized effects of nicotine on cardiac electrophysiology could be accounted for, at least partially, by the effects of nicotine on A-type channels, we performed detailed analyses on Kv4.3 and Kv4.2 channels expressed in Xenopus oocytes and on native Ito.
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Methods |
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In Vitro Transcription and Functional Expression
Procedures for in vitro transcription and oocyte injection have been described previously.16 20 Kv4.2 (subcloned into PRC-CMV vector) and Kv4.3 (pSP64-A+ vectors) were kind gifts from Dr Jeanne Nerbonne, Washington University, St Louis, Mo. cRNAs were prepared with mMESSAGE mMACHINE (Ambion) using T7 (for Kv4.2) and SP6 (for Kv4.3) RNA polymerases. All whole-cell and single-channel recordings were obtained in stage V to VI Xenopus oocytes injected with 46 nL of cRNA.
Two-Electrode Voltage-Clamp Recording
Electrodes filled with 3 mol/L KCl had a resistance of 
1.0 to
1.5 M
when measured in the bath solution containing (in mmol/L)
NaCl 100, KCl 5, CaCl2 0.3,
MgCl2 2, and HEPES 10 (pH 7.4). Electrodes were
connected to a GeneClamp-500 amplifier (Axon). The pClamp suite of
programs was used for data acquisition and analysis.
Experiments were conducted at room temperature (22°C to 23°C). Leak
was subtracted for all current records. When the sustained current
component at the end of the 400-ms pulse was >10% of the total
current amplitude, the oocytes were rejected.
Single-Channel Recording
Single channels were recorded in cell-attached patches in
the inside-out mode.16 Fire-polished glass electrodes had
a tip resistance of 10 M when filled with the extracellular
solution, which had the same composition as the bath solution described
for the 2-electrode experiments. The bath solution (intracellular side)
contained (in mmol/L) NaCl 5, KCl 100, CaCl2
0.3, MgCl2 2, and HEPES 10. Data were digitized
at 10 kHz and filtered (2-kHz cutoff). Single-channel data were
analyzed with Fetchan, and open and closed transitions were
detected with half-amplitude threshold criteria.
Myocyte Isolation and Patch-Clamp Recording
Canine ventricular myocytes were isolated with
previously described techniques.21 Adult mongrel dogs (20
to 26 kg) were anesthetized with pentobarbital (30 mg/kg IV),
and the left ventricle was dissected and mounted via the right
coronary artery to a Langendorff perfusion system.
Collagenase (110 U/mL CLS II; Worthington) was used to
isolate subepicardial cells.
The patch-clamp recording techniques used have been described
in detail elsewhere.16 21 Borosilicate glass electrodes
had tip resistances of 1 to 3 M when filled with pipette solution
containing (in mmol/L) GTP 0.1, potassium aspartate 110, KCl 20,
MgCl2 1, MgATP 5, HEPES 10, and phosphocreatine 5
(pH 7.3). The Tyrode’s solution for cell isolation and whole-cell
patch-clamp recording at 36±1°C contained (in mmol/L)
NaCl 136, KCl 5.4, MgCl2 1, HEPES 5, glucose 10,
and CaCl2 1 (pH 7.4).
Series resistance and capacitance were compensated and leak currents subtracted. Sodium current was suppressed by holding cells at -50 mV. CdCl2 (200 µmol/L) was used to inhibit Ca2+ current and Ca2+-activated chloride current. ATP-sensitive current was blocked by glyburide (10 µmol/L) in the superfusate and ATP (5 mmol/L) in the pipette. Dofetilide (1 µmol/L)22 and 293B (20 µmol/L)23 were used to block delayed-rectifier K+ currents. APs were recorded in current-clamp mode and elicited by twice-threshold, 1.5-ms pulses.
Data Analysis
Group data are expressed as mean±SEM.
Ito amplitude was measured as the
difference between peak and residual currents at the end of
depolarizing pulses. Statistical comparisons among groups were
performed by ANOVA followed by t test with Bonferroni
correction. A 2-tailed P<0.05 was taken to indicate a
statistically significant difference. A nonlinear least-squares program
(CLAMPFIT or Graphpad Prism) was used for curve-fitting.
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Results |
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Effects of Nicotine on Kv4.3 and Kv4.2 Currents in Xenopus Oocytes
Superfusion for 10 minutes with nicotine at concentrations of 10 nmol/L to 100 µmol/L inhibited Kv4.3 currents (Figure 1
). Significant block was seen at 10
nmol/L, and complete inhibition was achieved at 100 µmol/L. The
IC50 was 40±4 nmol/L (Hill coefficient=0.3,
Figure 2).
4-Aminopyridine (4-AP), a prototype A-type
K+ current blocker, inhibited Kv4.3 with an
IC50 of 1.7±0.2 mmol/L (Hill
coefficient=0.5, Figure 2).
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The voltage-dependent activation curve was not significantly affected
by nicotine at concentrations up to 10 µmol/L (Figure 3A). On the contrary, inactivation was
shifted toward more positive potentials (Figure 3B).
Half-maximal inactivation voltage (V1/2)
values were -50±6, -42±4 (P<0.05 versus control),
-37±4 (P<0.01), and -32±3 (P<0.01,
n=6/group) mV for control, 0.1, 1, and 10 µmol/L nicotine,
respectively.
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The activation (Figure 4A) and
inactivation (Figure 4B) time constants were not altered by
nicotine at concentrations up to 10 µmol/L. Kv4.3 channel
reactivation (Figure 4C) was similarly unaffected (time
constant, 198±24 ms without and 224±27 ms with 10 µmol/L
nicotine, P>0.05, n=4).
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) calculated from currents recorded
with voltage protocols shown in Figure 1
The use-dependence of nicotine action was evaluated with 10 consecutive
pulses to +50 mV at 0.1, 1, and 2 Hz. The first pulse after a 60-second
quiescent period at a holding potential of -70 mV was taken as
tonic block, and the reduction in subsequent pulses was considered
use-dependent inhibition. There was a significant tonic block
(24%), as indicated by the reduced current amplitude in the first
pulse (Figure 5). Further decrease
in the current amplitude was observed with pulsing, but this
use-dependent inhibition was seen only at a frequency of 
1 Hz, and
statistical significance (P<0.01, ANOVA, F test, n=5) was
achieved only at 2 Hz (Figure 5B). The use-dependence was rapid
(rate constant of 0.3±0.0 pulses).
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Figure 6 summarizes the blocking
properties of nicotine on Kv4.2 channels. The current was diminished
42% at a concentration of 100 nmol/L and 82% at 100
µmol/L, similar to the effects on Kv4.3. No significant
endogenous currents were recorded in water-injected
oocytes before or after superfusion with nicotine (Figure 1A
).
Pretreatment with or coapplication of mecamylamine (100 µmol/L,
an nAChR antagonist),24 atropine (1
µmol/L, a muscayinic AChR antagonist), prazosin
(2 µmol/L, an 
1-adrenoceptor
antagonist), or propranolol (1 µmol/L, a
ß-adrenoceptor inhibitor) did not alter the
inhibitory effects of nicotine on Kv4 channels.
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Effects on Single-Channel Currents
Depolarization of cell-attached patches to potentials positive to
+30 mV produced brief channel openings at the onset of the voltage step
and infrequent subsequent reopenings (Figure 7A). The ensemble average of 200
consecutive recordings (Figure 7A, bottom) is typical of
Ito, with rapid activation and
inactivation. Nicotine suppressed single-channel and ensemble-average
currents (Figure 7A) and slightly reduced slope conductance
(from 18±3 to 13±3 pS, P<0.05, n=4, 0.1 µmol/L
nicotine, Figure 7B). Open probability was reduced (Figure 7C), closed time lengthened (Figure 7D) from 1.8±0.4 to
3.3±0.5 ms (P<0.05, n=4) for the fast component and from
16.5±2.6 to 19.2±3.1 ms for the slow component (P=NS), and
open time shortened (Figure 7E).
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Effects on Native Ito
Ten minutes after baseline recording, nicotine was applied
to the bath, and Ito recordings
were repeated after a 15-minute exposure period (Figure 8A). After we had verified that
mecamylamine (100 µmol/L, n=4 cells), atropine (1 µmol/L,
n=3), prazosin (2 µmol/L, n=3), and propranolol
(2 µmol/L, n=3) had no influence on the effects of nicotine,
these compounds were also included in the superfusate (Figure 8B). Approximately 15%, 25%, and 56% decreases in
Ito were seen with 0.01, 0.1, and 1
µmol/L nicotine, respectively (Figure 8C). The
IC50 (Figure 8D) averaged 0.39±0.05
µmol/L.
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Like its effects on Kv4.3, nicotine did not alter the activation
curve (V1/2 values, 6±1 and 9±2 mV for control
and 10 µmol/L nicotine, respectively, P>0.05, n=4).
The inactivation curve (Figure 9A and 9B)
was shifted to more positive potentials by nicotine
(V1/2=-33±4 and -20±3 mV for control and
1 µmol/L nicotine, respectively; P<0.05, n=5). No
significant changes in reactivation time constants were observed
(12.9±1.8 ms for control versus 15.4±2.3 ms for nicotine 1
µmol/L). Nicotine at concentrations up to 50 µmol/L did not
alter the activation and inactivation time courses determined by the
same methods as for Kv4.3.
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As with Kv4.3, nicotine produced 2 phases of block: tonic block
and use-dependent block (Figure 9C). The degree of tonic block
(determined from the current reduction with the first pulse of the
depolarizing train to +50 mV) was 12% at 0.1 µmol/L.
Use-dependent block with subsequent pulses quickly reached steady state
(23%), with a rate constant of 0.6±0.1 pulses.
Effects on Canine Ventricular APs
Nicotine caused a concentration-dependent (0.01 to 1
µmol/L) lengthening of AP duration (APD) and an elevation of the
plateau level (Figure 10).
APD50 (APD at 50% repolarization) increased from
70±9 ms (control) to 83±10 (P<0.05, n=3) and 102±12
(P<0.05) ms after 0.1 and 1 µmol/L nicotine,
respectively. APD90 was slightly but not
significantly lengthened (112±13 ms for control versus 124±27
[P>0.05] and 129±31 [P>0.05] ms for 0.1
and 1 µmol/L nicotine, respectively). The magnitude of phase 1
repolarization decreased from 39±5 mV (control) to 22±3
(P<0.05, n=3) and 17±2 (P<0.01) mV at 0.1 and
1 µmol/L nicotine, respectively.
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Discussion |
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We have performed a detailed characterization of nicotine block of Kv4.3 currents expressed in Xenopus oocytes and native Ito in canine ventricular myocytes at both the whole-cell and single-channel levels. Our major novel finding is that nicotine is a potent direct blocker of cardiac A-type channels and significantly delays canine ventricular repolarization.
Previous Studies of the Effects of Nicotine on K+
Channels
In our study, the effects of nicotine were not reversed by
mecamylamine (an nAChR antagonist),24 atropine
(a muscayinic AChR antagonist), prazosin (an
1-adrenoceptor antagonist), and
propranolol (a ß-adrenoceptor inhibitor).
These results indicate that nicotine block of A-type
K+ currents are most likely the consequence of
direct interactions between drug molecules and channel proteins.
Reports on the effects of nicotine on ion channels are sparse.
Hamon et al25 first reported that nicotine
inhibited slowly inactivating K+ currents in rat
cultured striatal neurons. The effects were attributed to stimulation
of nicotinic receptors, because the nicotinic antagonist
dihydro-ß-erythroidine reversed and nicotinic agonists reproduced the
block.25 Direct effects on K+
channels were not revealed until recently by Tang et al,26
who used vascular smooth muscle cells, and by our
laboratory.27 Tang et al found that nicotine caused dual
effects on the rapidly activating and slowly inactivating
K+ current in rat artery smooth muscle cells: an
increase in current amplitude at concentrations <0.3 mmol/L and a
decrease at >0.3 mmol/L.26 We have reported
preliminary findings27 that nicotine directly blocks
K+ currents, with effects on
IK1 and IKr at
much higher concentrations compared with those on
Ito.
To date, no detailed studies on the interactions between nicotine and cardiac K+ channels have been published. The present work provides insight into potential mechanisms underlying nicotine block of A-type currents. Approximately 40% of the total inhibition could be ascribed to tonic block, with the remainder (60%) due to use-dependent block, for both Kv4.3 and Ito. This would imply that nicotine binds to Ito channels in the closed state. A decrease in the slope conductance of Kv4.3 single channels and increases in closed times by nicotine are in line with this notion. Nicotine did not alter voltage-dependent activation, whereas the inactivation curve was shifted to more positive potentials and block was relieved slightly with more positive holding potentials that rendered more channels in the inactivated state. At the single-channel level, nicotine reduced the channel conductance, open time, and open probability but increased the closed time of Kv4.3. These data are consistent with the closed and open channel block indicated at the macroscopic level.
Potential Implications
It has been shown that the average blood concentration of nicotine
in regular smokers is 220 nmol/L and that the level can reach 440
nmol/L after consumption of a single cigarette.10 26 It
has been estimated that the typical single dose of nicotine in chewing
tobacco is 15 times greater than for an average-strength
cigarette.5 24 Moreover, for a daily intake of 100 mg
nicotine with regular nicotine chewing gum use, blood nicotine can
accumulate for 6 to 8 hours.28 Longer retention of
nicotine occurs in the heart, possibly accounting for the
predisposition of the heart to pathological
manifestations.29 30 Although we have shown that nicotine
blocks multiple K+ currents, the
IC50 values for other currents (4
µmol/L for IK1, 165 µmol/L for
Kir2.1, 1.3 µmol/L for IKr, and
17 µmol/L for HERG)27 are 10 times higher
than blood concentrations of nicotine. Only the concentrations of
nicotine effective in Kv4.3 and Ito
inhibition in our study are relevant to the blood levels in heavy
cigarette smokers and smokeless tobacco users.
It has been suggested that Kv4.3 and Kv4.2 are the major molecular constituents of native cardiac Ito.16 18 The ability of nicotine to block Kv4.3 and Kv4.2 might contribute to the previously observed lengthening of cardiac APD in many preparations.11 12 13 Nicotine preferentially prolongs initial repolarization and the subsequent plateau phases,11 consistent with the participation of Ito in early phases of repolarization. The ability of nicotine to slow repolarization was confirmed in our experiments. Blockade of Ito may also provide an explanation for the observed nicotine-induced alterations (morphology, height, and duration) in the T wave of the ECG,6 because Ito has been proposed to be responsible for cardiac memory,31 an altered T-wave morphology after tachycardia.
A-type K+ channels are not limited to cardiac cells. Both cloned and native A-type currents have been identified in a variety of tissues, including brain and vascular smooth muscle. The A-type K+ current in vascular smooth muscles is believed to act as a "brake" to counteract depolarizing influences that may induce spontaneous AP activity or oscillatory vasoconstriction.32 Nicotine is known to have vasoconstrictive properties that contribute to the elevation of blood pressure and stroke risks induced by this compound.3 4 5 7 8 Nicotine readily crosses the blood-brain barrier and is distributed throughout the brain. Impairment of the vascular brake due to inhibition of A-type K+ currents in vascular smooth muscle could contribute to the increased risk of hypertension and stroke after nicotine exposure. Future studies are warranted to clarify this notion.
To the best of our knowledge, nicotine is one of the most potent
blockers of A-type channels. 4-AP is in widespread use as a
pharmacological tool for its ability to inhibit A-type
K+ current selectively. However, as documented in
many previous reports, several hundred micromolar to several millimolar
concentrations of 4-AP are necessary to block Kv4.3 and
Ito.33 34 35 In the
present study, the potency of nicotine for Kv4.3 block was
4x104-fold higher than that of 4-AP
(IC50=40±4 nmol/L for nicotine versus
1.7±0.2 mmol/L for 4-AP, Figure 2). Phrixotoxins PaTx1 and
PaTx2, purified from the venom of the tarantula Phrixotrichus
auratus, probably represent the only substance with an
inhibitory potency for Kv4.3
(5<IC50<70 nmol/L)36
comparable to that of nicotine. Although we have shown that nicotine
blocks multiple K+ currents, the
IC50 values for other currents are 10 times
higher than that for Kv4.3/Ito. Thus,
nicotine can potentially be a useful pharmacological probe to study the
role of A-type channels in cardiac electrical activity and the outcome
of pharmacological interventions on A-type channels.
Potential Limitations
There are some unexplained issues in the present study.
Although blockade of A-type channels may account in part for the
ability of nicotine to broaden APD, our data did not allow us to draw
any conclusions as to whether this property is beneficial
(antiarrhythmic) or deleterious (proarrhythmic). Many antiarrhythmic
agents act by inhibiting Ito, and this
would imply that inhibition of Ito should
confer antiarrhythmic efficacy.37 38 39 40 However,
excessive block of Ito could also be
proarrhythmic. Obviously, the arrhythmic consequences of nicotine
action on A-type current await further study. Furthermore, the
observations on nicotine in in vitro conditions are not necessarily the
same as those in vivo. The effects of nicotine on A-type current could
be modulated by the action on Ito produced
by stimulation of 1-adrenoceptors by nicotine,
because it is known that nicotine can enhance release of
norepinephrine, and it has also been reported that
1-adrenergic stimulation can alter
Ito.10 41 In addition,
nicotine may also directly or indirectly affect other ion channels,
such as calcium and sodium channels. Thus, the overall outcome of
nicotine actions in in vivo situations would be determined by different
aspects of nicotine pharmacology and
pathophysiological conditions of the heart in an
integrated manner.
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Acknowledgments |
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This work was supported by the Smokeless Tobacco Research Council, Inc (grant 0739-01). Dr Wang is a research scholar of the Heart and Stroke Foundation of Canada. The authors wish to thank XiaoFan Yang for her excellent technical assistance.
Received December 31, 1999; revision received March 17, 2000; accepted April 6, 2000.
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