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This Article Abstract Full Text (PDF) All Versions of this Article: 90/6/865    most recent expphysiol.2005.031484v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhou, S.-S. Articles by Ding, Y.-F. Search for Related Content PubMed PubMed Citation Articles by Zhou, S.-S. Articles by Ding, Y.-F. Related Collections Heart/Cardiac Muscle

¹ Institute of Basic Medical Sciences, Medical College, Dalian University, Dalian 116622, China ² Department of Physiology, Fourth Military Medical University, Xi'an 710032, China ³ Department of Physiology, Xinxiang Medical College, Xinxiang 453003, China

	Abstract

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The effects of Cl^– channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) and niflumic acid (NFA) on aconitine-induced arrhythmias were investigated. Left ventricular pressure and electrocardiogram were monitored in Langendorff-perfused rat hearts. Whole-cell patch-clamp and current-clamp techniques were used to measure sodium current (I_Na) and action potential (AP), respectively, in single rat cardiac ventricular myocytes. Addition of the Na⁺ channel agonist aconitine (0.1 µM) to the perfusion solution produced polymorphic ventricular arrhythmias with a latent period of 25.5 ± 6.3 s. NPPB could reverse aconitine-induced arrhythmias. A similar effect was observed by using NFA. NPPB and NFA reversibly depressed the upstroke of the AP in a dose-dependent manner with IC₅₀ values of 12.3 and 73.1 µM, respectively, without significantly affecting the resting potential of rat ventricular myocytes. Both Cl^– channel blockers inhibited I_Na and induced a leftward shift of the steady-state inactivation of I_Na. In conclusion, the results of this study demonstrate that NPPB as well as NFA can suppress aconitine-induced arrhythmias in rat hearts mainly by inhibiting cardiac I_Na.

(Received 5 July 2005; accepted after revision 16 August 2005; first published online 23 August 2005)
Corresponding author S.-S. Zhou: Institute of Basic Medical Sciences, Medical College, Dalian University, Dalian 116622, China. Email: zhouss{at}dlu.edu.cn

	Introduction

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The voltage-gated Na⁺ channel is primarily responsible for the generation and propagation of the action potential (AP) in excitable tissues. In the heart, disturbances of the activity of voltage-gated Na⁺ channels markedly influence the excitation of cardiac myocytes, which is crucial in the genesis of arrhythmias. For example, aconitine, a specific Na⁺ channel agonist able to prolong the open state of the channel (Peper & Trautwein, 1967; Wright, 2002; Wang & Wang, 2003), may induce intracellular Na⁺ accumulation (Peper & Trautwein, 1967; Sawanobori et al. 1987) and intracellular Ca²⁺ overload, and may eventually result in polymorphic arrhythmias, including ventricular bigeminy, tachycardia and ventricular fibrillation. Therefore, aconitine has been widely used experimentally as a tool to induce cardiac arrhythmias in various animals (Winslow, 1980; Lu & De Clerck, 1993; Amran et al. 2004).

Chloride channel blockers available for the investigation of Cl^– channels are notorious for their non-specific property, i.e. they also markedly affect other ionic channels besides blocking Cl^– channels (Hume et al. 2000; Jentsch et al. 2002). In the heart, Cl^– channel blockers are found to inhibit hyperpolarization-activated current (Accili & DiFrancesco, 1996), transient outward K⁺ current (Wang et al. 1997), L-type Ca²⁺ current (Conforti et al. 1994; Walsh & Wang, 1996; Zhou et al. 2002) and sodium current (I_Na; Conforti et al. 1994; Liu et al. 1998). Our previous studies suggest that the non-specific effects of Cl^– channel blockers on cardiac transient outward K⁺ current and L-type Ca²⁺ current may involve Cl^– channels (Zhou et al. 2002; Lai et al. 2004). Chloride currents may play a role in the genesis of arrhythmias (Hiraoka et al. 1998), and Cl^– current blockade may potentially be antiarrhythmogenic (Verkerk et al. 2000). However, there is little known about the effects of Cl^– channel blockers on the arrhythmias induced by abnormal Na⁺ channel activity.

In the present study, the effect of Cl^– channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) and niflumic acid (NFA) on aconitine-induced arrhythmias was investigated. We demonstrated that NPPB as well as NFA could suppress aconitine-induced arrhythmias mainly by inhibiting cardiac I_Na in rat hearts.

	Methods

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Perfusion of isolated hearts and electrocardiographic recordings

All experiments were carried out in accordance with the guidelines of the local ethics committee. Adult Sprague–Dawley rats (200–250 g) of either sex were killed by decapitation, and the hearts were immediately removed and cannulated via the aorta. Retrograde perfusion was performed at 37°C in a Langendorff apparatus under constant pressure (80 mmHg), and measurement of left ventricular pressure (LVP) was conducted as previously described (Kupriyanov et al. 1995). In brief, a water-filled balloon was inserted through the mitral valve and secured in the left ventricle. The balloon was connected to a pressure transducer and a physiological recorder (AP-621G, Nihon Koden Co., Tokyo, Japan) to monitor LVP. The end-diastolic pressure was set to approximately 5 mmHg. Electrocardiogram (ECG) was recorded via electrodes placed on the apical region of the hearts and the aortas. Coronary flow rate was measured from a collection of coronary sinus effluent. To eliminate the possible changes in Cl^––HCO₃^– exchange induced by Cl^– channel blockers, Hepes-buffered Tyrode solution bubbled with 100% O₂ was used to perfuse the hearts. All hearts were initially equilibrated for 30 min before recordings.

Cell preparations

Ventricular myocytes were enzymatically isolated from adult Sprague–Dawley rats (200–250 g) of either sex as reported previously (Zhou et al. 2002). Briefly, the hearts were removed immediately after decapitation and perfused in retrograde fashion at 37°C in turn with the following solutions: Tyrode solution (5 min), Ca²⁺-free Tyrode solution (5 min), Ca²⁺-free Tyrode solution containing 0.5 mg ml^–1 collagenase (type I, Sigma) and 1 mg ml^–1 bovine serum albumin (35 min), and Kraft-Brühe (KB: high K⁺) medium (5 min). After dissociation and collection, the isolated cells were maintained in KB medium at room temperature (23–25°C) for electrophysiological recordings.

Whole-cell patch-clamp and current-clamp experiments

Aliquots of cell suspension were transferred into a perfusion chamber on the stage of an inverted microscope. Pipettes had tip resistances of 2–2.5 M when filled with internal solution. Whole-cell recordings were performed using a patch-clamp amplifier (Axopatch 200B, Axon Instruments, Union City, CA, USA). The offset potentials between both electrodes were zeroed before the pipette touched the cell. The liquid junction potential between bath and internal solutions was corrected according to the calculation method of the JPCalc program within Clampex 8.1 (Axon Instruments). Whole-cell series resistance was compensated to more than 80%. Whole-cell I_Na was elicited from a holding potential of –90 mV to test potentials ranging from –90 to +30 mV in 5 or 10 mV increments. The current signals were low-pass filtered at 2 kHz and digitized with an analog-to-digital converter (Digidata 1322) and pCLAMP 8.1 software (Axon Instruments) at a sampling rate of 10 kHz. I_Na was calculated as the difference between the peak inward current and the holding current level. The voltage-dependent steady-state inactivation of I_Na was determined by the application of a 500 ms preconditioning pulse ranging from –140 to 0 mV in 10 mV increments, followed by a 30 ms test pulse to –30 mV. The data were fitted using a Boltzmann distribution equation:

where I_Na,max is the maximum I_Na, V_m is the preconditioning pulse potential, V¹/₂ is the membrane potential at half-maximum inactivation of I_Na and k is the slope factor.

Current-clamp experiments were conducted using an EPC-9 amplifier (HEKA Elektronik, Lambrecht, Germany), controlled by a personal computer and the Pulse-Software (HEKA Elektronik). Action potentials were elicited in current-clamp mode by applying an 8 ms stimulus pulse of 1 nA at a frequency of 1 Hz. Whole-cell patch-clamp and current-clamp experiments were performed at room temperature (23–25°C).

Solutions

The Tyrode solution contained (mM): NaCl, 143; KCl, 5.4; MgCl₂, 0.5; CaCl₂, 1.8; NaH₂PO₄, 0.3; glucose, 5; and Hepes, 5 (pH adjusted to 7.4 with NaOH). The nominally Ca²⁺-free Tyrode solution was prepared by removing CaCl₂ from the Tyrode solution. The KB solution contained (mM): potassium glutamate, 70; KCl, 25; taurine, 20; KH₂PO₄, 10; MgCl₂, 3; EGTA, 0.5; glucose, 10; and Hepes, 10 (pH adjusted to 7.35 with KOH). For AP recordings, the bath solution was the Tyrode solution. The pipette solution for AP recordings contained (mM): K-aspartate, 120; KCl, 20; MgCl₂, 1; Mg-ATP, 5; EGTA, 0.05; phosphocreatine, 5; GTP, 0.1; and Hepes, 5 (pH adjusted to 7.2 with KOH).

The pipette solution for recording I_Na contained (mM): Cs-aspartate, 110; MgCl₂, 2; Na₂ATP, 5; tetraethylammonium chloride, 20; EGTA, 5; and Hepes, 5 (pH adjusted to 7.2 with CsOH). The standard bath solution for whole-cell I_Na recordings contained (mM): N-methyl-D-glucamine chloride, 80; NaCl, 10; CsCl, 5; MgCl₂, 2; CaCl₂, 1; CoCl₂, 2; Hepes, 10; glucose, 10; and sucrose, 80 (pH adjusted to 7.4 with N-methyl-D-glucamine).

Chemicals

NPPB, NFA and aconitine were purchased from Sigma (St Louis, MO, USA). Stock solutions of NPPB (100 mM) and NFA (500 mM) in DMSO were diluted to the desired final concentrations immediately before use. DMSO at a final concentration of 0.1% in the bath solution had no effect on I_Na, AP or aconitine-induced arrhythmias (data not shown). NPPB (20 µM) or NFA (25 µM) was applied soon after the onset of aconitine-induced arrythmias by switching the perfusion solution to aconitine-containing solution plus NPPB or NFA.

Statistical analysis

The data are presented as means ± S.E.M. Statistical differences in the data were evaluated by paired Student's t test or ANOVA, as appropriate, and were considered significant at values of P < 0.05.

	Results

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Effects of Cl^– channel blockers on aconitine-induced arrhythmias

Figure 1 shows the effect of NPPB and NFA on aconitine-induced ventricular arrhythmias of Langendorff-perfused rat hearts. Addition of aconitine (0.1 µM) to the perfusion solution produced polymorphic ventricular arrhythmias with a latent period of 25.5 ± 6.3 s (n = 10, Fig. 1A). The initial arrhythmia induced by aconitine was bigeminy, followed by paroxysmal ventricular tachyarrhythmias. The arrhythmias which continued for > 15 min after washout of the compound (n = 10, Fig. 1A). Aconitine did not significantly alter the heart rate and coronary flow before the onset of bigeminy (n = 10). No significant changes of left ventricular end-diastolic pressure were observed at the onset of aconitine-induced arrhythmias (Fig. 1A, B and C). Application of NPPB (20 µM) to the perfusion solution restored aconitine-induced arrhythmias to sinus rhythm within 1 min (n = 5, Fig. 1B). NPPB slightly increased the coronary flow (from 8.5 ± 0.5 to 8.7 ± 0.5 ml min^–1, n = 5, P < 0.05). The Cl^– channel blocker NFA (25 µM) produced an effect similar to that of NPPB (Fig. 1C, n = 5). NFA increased the coronary flow from 8.6 ± 0.5 to 9.0 ± 0.4 ml min^–1 (n = 5, P < 0.05). In addition, both NPPB and NFA significantly suppressed LVP (Fig. 1B and C, upper panels), which is in good agreement with the previous observation that these compounds can reduce the contraction of single isolated rat ventricular myocytes (Zhou et al. 2002). These data indicate that the Cl^– channel blockers NPPB and NFA can effectively antagonize aconitine-induced arrhythmias.

View larger version (44K): [in this window] [in a new window]   Figure 1.  Effect of NPPB and NFA on aconitine-induced arrhythmias A, representative traces of left ventricular pressure (LVP, upper panels) and electrocardiogram (ECG, lower panels) recorded simultaneously in a rat heart. Aa, control; Ab, c and d, 20 s, 2 min and 5 min exposure to 0.1 µM aconitine, respectively; Ae, 15 min after washout of aconitine. B and C, examples of suppression of aconitine-induced arrhythmias by NPPB (B) and NFA (C). The lower panels in B and C are ECG traces corresponding to the LVP traces (upper panels in B and C) indicated by the open bars. Application of aconitine, NPPB and NFA is indicated by horizontal filled bars.

Because the arrhythmogenic action of aconitine is related to a specific modification of cardiac Na⁺ channels (Friese et al. 1997), the antiarrhythmic effect of NPPB and NFA implies that the cardiac Na⁺ channel may be involved. Therefore, we observed the effect of the Cl^– channel blockers on the cardiac ventricular AP. Figure 2A and B, respectively, shows the reversal effect of NPPB and NFA on the AP of rat ventricular myocytes. NPPB significantly suppressed AP amplitude without inducing a notable alteration in the resting membrane potential. Myocytes failed to generate APs in response to the same electrical stimulation 2 min after exposure to 50 µM NPPB (Fig. 2A, n = 10). NPPB reduced AP amplitude in a dose-dependent manner with an IC₅₀ of 12.3 µM (Fig. 2C). Similarly, NFA also suppressed AP amplitude (IC₅₀ 73.1 µM, Fig. 2B and C). These results indicate that the Cl^– channel blockers have a significant influence on the morphology of cardiac ventricular AP.

View larger version (12K): [in this window] [in a new window]   Figure 2.  Effects of NPPB and NFA on AP of rat cardiac ventricular myocytes A and B, representative traces of action potential in the absence and presence of NPPB (A) and NFA (B). AP was elicited in current-clamp mode by applying an 8 ms stimulus pulse of 1 nA. C, concentration–response relation for the inhibitory effect of NPPB and NFA on rat ventricular AP amplitude. Results are means ± S.E.M. of 4–6 cells for each concentration.

Figure 3A and B shows an example of the effect of NPPB on I_Na of rat ventricular myocytes. Under control conditions, the maximum sodium current (I_Na,max) was observed at –30 mV (n = 12). Exposure of the myocytes to NPPB (50 µM) reduced I_Na,max by 66.3 ± 3.5% (n = 6, P < 0.01, Fig. 3A), without significantly altering the threshold for activation and the reversal potential of the current (n = 6, Fig. 3B). Addition of 100 µM NFA to the superfusion solution decreased I_Na,max by 54.2 ± 4.1% (n = 6, P < 0.01, Fig. 3C and D), which is in good agreement with the observation reported by Conforti et al. (1994). The effect of NPPB on the steady-state inactivation of I_Na in rat ventricular myocytes is shown in Fig. 4A and B. NPPB (50 µM) reduced the maximum available I_Na and shifted the V¹/₂ by 8.1 ± 1.4 mV towards more negative potentials (n = 8, P < 0.01, Fig. 4A and B). No significant changes in the slope factor of the inactivation curve were observed in the presence of NPPB. A similar effect was observed when the myocytes were exposed to NFA (Fig. 4C and D). NFA (100 µM) reduced the steady-state Na⁺ channel availability and shifted the V¹/₂ of steady-state inactivation by 14 ± 2.5 mV towards more negative potentials (n = 5, P < 0.01).

View larger version (20K): [in this window] [in a new window]   Figure 3.  Effects of NPPB and NFA onINa of rat cardiac ventricular myocytes A, representative recordings of INa recorded in control conditions (a) and 3 min after addition of 50 µM NPPB (b). C, representative traces of INa recorded in control conditions (a) and 3 min after addition of 100 µM NFA (b). Whole-cell INa was elicited from a holding potential of –90 mV to test potentials ranging from –90 to +30 mV in 10 (A) or 5 mV increments (C). B and D, I–V relations for INa corresponding to the records in A and C, respectively.

View larger version (23K): [in this window] [in a new window]   Figure 4.  Effects of NPPB and NFA on the steady-state inactivation ofINa of rat ventricular myocytes A and C, original current traces recorded before (Aa and Ca) and after application of 50 µM NPPB (Ab) and 100 µM NFA (Cb). INa was activated by 30 ms test pulses to –30 mV from holding potentials ranging from –140 to –10 mV in 10 mV increments. B and D show the currents in A and C, respectively, expressed as fractions of maximal INa (INa/INa,max) and plotted as a function of membrane potential.

	Discussion

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The voltage-gated Na⁺ channel, a crucial determinant of the excitability of cardiac ventricular myocytes, is the primary target of neurotoxins and therapeutic drugs. Aconitine, an alkaloid neurotoxin derived from the aconite plant, can bind to receptor site 2 on the voltage-gated Na⁺ channel and modify the channel kinetics (Wright, 2002; Wang & Wang, 2003), and consequently induce ventricular arrhythmias (Peper & Trautwein, 1967; Tai et al. 1992; Lu & De Clerck, 1993). Site 2 neurotoxins generally modify the Na⁺ channel kinetics in an irreversible manner (Wright, 2002). This property was also observed in the present study. Aconitine-induced ventricular tachyarrhythmias lasted for > 15 min after washout with drug-free solution. In contrast, aconitine-induced ventricular arrhythmias could be reversed by the Cl^– channel blockers NPPB and NFA.

Aconitine can reduce the inactivation of I_Na (Peper & Trautwein, 1967) and prolong repolarization, and consequently induce after-depolarization with triggered automaticity of cardiac myocytes (Tanz et al. 1973; Sawanobori et al. 1987). The prolongation of the open state of Na⁺ channels may lead to an accumulation of intracellular Na⁺ (Peper & Trautwein, 1967; Sawanobori et al. 1987) and may eventually result in intracellular Ca²⁺ overload via a Na⁺–Ca²⁺ exchange (NCX) mechanism. The NCX mechanism may play a role in delayed after-depolarizations and cardiac arrhythmias (Lu & De Clerck, 1993). However, the effects of NCX blockers on aconitine-induced arrhythmias are still controversial. Recent evidence suggests that the involvement of the NCX system plays an insignificant role in the aconitine-induced arrhythmias (Amran et al. 2004). It appears from the present data that an elevation in diastolic intracellular Ca²⁺ concentration, if it occurs, is small because the left ventricular end-diastolic pressure is not significantly altered at the onset of aconitine-induced bigeminy (Fig. 1). Our previous study has revealed that NPPB and NFA can inhibit L-type Ca²⁺ current of rat ventricular myocytes (Zhou et al. 2002). Since modifications of intracellular calcium movements are the main determinants of the triggered activity (Swynghedauw, 1999), and inhibition of the L-type Ca²⁺ channel may reduce intracellular Ca²⁺ overload (Fleckenstein & Fleckenstein-Grun, 1988), the inhibition of L-type Ca²⁺ current induced by the Cl^– channel blockers may be responsible for the suppression of aconitine-induced arrhythmias. However, block of the L-type Ca²⁺ channel by its specific blockers such as verapamil does not prevent aconitine-induced arrhythmias (Winslow, 1980; Sawanobori et al. 1987; Bazzani et al. 1989; Lu & De Clerck, 1993). Thus, it seems unlikely that the inhibitory effect of NPPB and NFA on aconitine-induced arrhythmias is due to a direct influence on Na⁺–Ca²⁺ exchange or an inhibition of the L-type Ca²⁺ channel.

Studies have revealed that aconitine-induced ventricular arrhythmias can be suppressed by class I antiarrhythmic agents, Na⁺ channel blockers (Sawanobori et al. 1987; Bazzani et al. 1989; Lu & De Clerck, 1993), whereas sympatholytic agents (class II drugs), drugs that prolong repolarization (class III, K⁺ channel blockers) and Ca²⁺ channel blockers (class IV) are ineffective (Winslow, 1980; Sawanobori et al. 1987; Lu & De Clerck, 1993). The present data reveal that NPPB and NFA bear some similarity to Na⁺ channel blockers. Indeed, the present data reveal that AP amplitude and I_Na are significantly reduced in the presence of the compounds. Taken together, it appears that the effect of NPPB and NFA on aconitine-induced ventricular arrhythmias is mainly related to the inhibition of cardiac voltage-gated Na⁺ channels.

In conclusion, the results of this study demonstrate that the putative Cl^– channel blockers NPPB and NFA can suppress aconitine-induced arrhythmias in rat hearts. The antiarrhythmic effect of the Cl^– channel blockers may be mainly due to the inhibition of cardiac I_Na.

	References

Top Abstract Introduction Methods Results Discussion References

 
Accili EA & DiFrancesco D (1996). Inhibition of the hyperpolarization-activated current (i_f) of rabbit SA node myocytes by niflumic acid. Pflugers Arch 431, 757–762.[Medline]

Amran MS, Hashimoto K & Homma N (2004). Effects of sodium-calcium exchange inhibitors, KB-R7943 and SEA0400, on aconitine-induced arrhythmias in guinea pigs in vivo, in vitro, and in computer simulation studies. J Pharmacol Exp Ther 310, 83–89.[Abstract/Free Full Text]

Bazzani C, Genedani S, Tagliavini S & Bertolini A (1989). Putrescine reverses aconitine-induced arrhythmia in rats. J Pharm Pharmacol 41, 651–653.[Medline]

Conforti L, Sumii K & Sperelakis N (1994). Diphenylamine-2-carboxylate blocks voltage-dependent Na⁺ and Ca²⁺ channels in rat ventricular cardiomyocytes. Eur J Pharmacol 259, 215–218.[CrossRef][Medline]

Fleckenstein A & Fleckenstein-Grun G (1988). Mechanism of action of calcium antagonists in heart and vascular smooth muscle. Eur Heart J 9 (Suppl. H), 95–99.

Friese J, Gleitz J, Gutser UT, Heubach JF, Matthiesen T, Wilffert B & Selve N (1997). Aconitum sp. alkaloids: the modulation of voltage-dependent Na⁺ channels, toxicity and antinociceptive properties. Eur J Pharmacol 337, 165–174.[CrossRef][Medline]

Hiraoka M, Kawano S, Hirano Y & Furukawa T (1998). Role of cardiac chloride currents in changes in action potential characteristics and arrhythmias. Cardiovasc Res 40, 23–33.[Abstract/Free Full Text]

Hume JR, Duan D, Collier ML, Yamazaki J & Horowitz B (2000). Anion transport in heart. Physiol Rev 80, 31–81.[Abstract/Free Full Text]

Jentsch TJ, Stein V, Weinreich F & Zdebik AA (2002). Molecular structure and physiological function of chloride channels. Physiol Rev 82, 503–568.[Abstract/Free Full Text]

Kupriyanov VV, Stewart LC, Xiang B, Kwak J & Deslauriers R (1995). Pathways of Rb⁺ influx and their relation to intracellular [Na⁺] in the perfused rat heart. A ⁸⁷Rb and ²³Na NMR study. Circ Res 76, 839–851.[Abstract/Free Full Text]

Lai XG, Yang J, Zhou SS, Zhu J, Li GR & Wong TM (2004). Involvement of anion channel(s) in the modulation of the transient outward potassium channel in rat ventricular myocytes. Am J Physiol 287, C163–C170.

Liu J, Lai ZF, Wang XD, Tokutomi N & Nishi K (1998). Inhibition of sodium current by chloride channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) in guinea pig cardiac ventricular cells. J Cardiovasc Pharmacol 31, 558–567.[CrossRef][Medline]

Lu HR & De Clerck F (1993). R 56 865, a Na⁺/Ca²⁺-overload inhibitor, protects against aconitine-induced cardiac arrhythmias in vivo. J Cardiovasc Pharmacol 22, 120–125.[Medline]

Peper K & Trautwein W (1967). The effect of aconitine on the membrane current in cardiac muscle. Pflugers Arch 296, 328–336.[CrossRef]

Sawanobori T, Hirano Y & Hiraoka M (1987). Aconitine-induced delayed afterdepolarization in frog atrium and guinea pig papillary muscles in the presence of low concentrations of Ca²⁺. Jpn J Physiol 37, 59–79.[Medline]

Swynghedauw B (1999). Molecular mechanisms of myocardial remodeling. Physiol Rev 79, 215–262.[Abstract/Free Full Text]

Tai YT, But PP, Young K & Lau CP (1992). Cardiotoxicity after accidental herb-induced aconite poisoning. Lancet 340, 1254–1256.[CrossRef][Medline]

Tanz RD, Robbins JB, Kemple KL & Allen PA (1973). Pharmacology of aconitine-induced automaticity of cat papillary muscle. I. Effect of dose, tension, rate and endogenous catecholamines. J Pharmacol Exp Ther 185, 427–437.[Abstract/Free Full Text]

Verkerk AO, Veldkamp MW, Bouman LN & van Ginneken AC (2000). Calcium-activated Cl^– current contributes to delayed afterdepolarizations in single Purkinje and ventricular myocytes. Circulation 101, 2639–2644.[Abstract/Free Full Text]

Walsh KB & Wang C (1996). Effect of chloride channel blockers on the cardiac CFTR chloride and L-type calcium currents. Cardiovasc Res 32, 391–399.[Abstract/Free Full Text]

Wang HS, Dixon JE & McKinnon D (1997). Unexpected and differential effects of Cl^– channel blockers on the Kv4.3 and Kv4.2 K⁺ channels. Implications for the study of the I_to2 current. Circ Res 81, 711–718.[Abstract/Free Full Text]

Wang SY & Wang GK (2003). Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins. Cell Signal 15, 151–159.[CrossRef][Medline]

Winslow E (1980). Evaluation of antagonism of aconitine-induced dysrhythmias in mice as a method of detecting and assessing antidysrhythmic activity. Br J Pharmacol 71, 615–622.[Medline]

Wright SN (2002). Comparison of aconitine-modified human heart (hH1) and rat skeletal (µ1) muscle Na⁺ channels: an important role for external Na⁺ ions. J Physiol 538, 759–771.[Abstract/Free Full Text]

Zhou SS, Gao Z, Dong L, Ding YF, Zhang XD, Wang YM, Pei JM, Gao F & Ma XL (2002). Anion channels influence excitation-contraction coupling by modulating L-type Ca²⁺ channel in ventricular myocytes. J Appl Physiol 93, 1660–1668.[Abstract/Free Full Text]

	Acknowledgements

 
This research was funded by the National Natural Science Foundation of China (Grant nos 39870318 and 30270602). We thank Yue-Min Wang for his technical assistance.

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This Article Abstract Full Text (PDF) All Versions of this Article: 90/6/865    most recent expphysiol.2005.031484v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhou, S.-S. Articles by Ding, Y.-F. Search for Related Content PubMed PubMed Citation Articles by Zhou, S.-S. Articles by Ding, Y.-F. Related Collections Heart/Cardiac Muscle