葛根素抑制大鼠心室肌细胞的钠电流

AIM: To study the effect of puerarin (Pue) on Na+ channel in rat ventricular myocytes. METHODS: Whole-cell patch-clamp technique was applied on isolated cardiomyocytes from rats. RESULTS: Pue inhibited cardiac INa in a positive rate-dependent and dose-dependent manner, with an IC(50) of 349 micromol/L. The kinetics of blockage of cardiac sodium channel by Pue resembled the ClassIa/Ic of antiarrhythmic agents. Pue 300 micromol/L did not alter the shape of the I-V curve of INa, but markedly shifted the steady-state inactivation curve of INa towards more negative potential by 15.9 mV, and postponed the recovery of INa inactivation state from (21.9+/-1.6) ms to (54.4+/-3.4) ms (P<0.01). It demonstrated that the steady state of inactivation was affected by Pue significantly. CONCLUSION: Pue protected ventricular myocytes against cardiac damage and arrhythmias by inhibiting recovery from inactivation of cardiac Na+ channels.     

A mutation in the local anaesthetic binding site abolishes toluene effects in sodium channels

Toluene is a solvent of abuse that inhibits cardiac sodium channels in a manner that resembles the action of local anaesthetics. The purpose of this work was to analyze toluene effects on skeletal muscle sodium channels with and without beta1 subunit (Nav1.4+beta1 and Nav1.4-beta1, respectively) expressed in Xenopus laevis oocytes and to compare them with those produced in the F1579A mutant channel lacking a local anaesthetic binding site. Toluene inhibited Nav1.4 sodium currents (IC50=2.7 mM in Nav1.4+beta1 and 2.2 mM in Nav1.4-beta1 in a concentration dependent way. Toluene (3 mM) blocked sodium currents in Nav1.4 channels proportionally throughout the entire current-voltage relationship producing inactivation at more negative potentials. Minimal inhibition was produced by 3 mM toluene in F1579A mutant channels. Recovery from inactivation was slower both in Nav1.4 and F1579A channels in the presence of 3 mM toluene. The solvent blocked sodium currents in a use-dependent and frequency-dependent manner in Nav1.4 channels. A single mutation in the local anaesthetic binding site of Nav1.4 channels almost abolished toluene effects. These results suggest that this site is important for toluene action.     

双苯氟嗪对豚鼠心室肌细胞膜钠电流的影响(英文)

目的观察双苯氟嗪对豚鼠心室肌细胞膜钠电流的影响。方法用酶解方法分离豚鼠心室肌细胞,全细胞膜片钳技术记录钠电流。结果将细胞钳制在-80mV,给(-80～+50)mV,50ms和步阶10mV的去极化脉冲,记录到的电流被河豚毒素10μmol·L-1完全抑制。在该刺激条件下,该电流最大激活电压在-20mV左右,翻转电压在+30mV左右,提示该电流为钠电流。双苯氟嗪可以浓度依赖性地抑制钠电流。双苯氟嗪对钠电流的抑制作用在冲洗后可部分恢复,表明其对钠通道的抑制作用具有可逆性。双苯氟嗪可使钠电流I-V曲线上移,但对钠电流的电压依赖性特征、最大激活电压和翻转电压无明显影响。在双苯氟嗪40μmol·L-1存在下,最大激活电压下的峰值电流下降约46%;双苯氟嗪可明显使钠电流稳态失活曲线左移,但不影响曲线的斜率因子。双苯氟嗪40μmol·L-1可使钠电流半数失活电压从(-73.0±4.6)mV减少到(-82.8±7.2)mV。但双苯氟嗪对钠电流稳态激活无明显影响,在双苯氟嗪40μmol·L-1存在下,半数激活电压(-33.7±3.6)mV和斜率因子(5.6±2.4)mV与对照组激活电压(-34.9±5.1)mV和斜率因子(6.0±4.8)mV相比无显著性差异。双苯氟嗪可以使钠电流从失活状态下恢复明显减慢,双苯氟嗪40μmo·lL-1可使恢复时间常数延长(79±28)vs(36±11)ms。结论双苯氟嗪可以浓度依赖性、使用依赖性和频率依赖性地抑制心肌钠电流,并且主要作用于钠电流的失活状态。     

花生四烯酸对兔心室肌细胞电压门控钠通道的影响

目的研究花生四烯酸(AA)对兔心室肌细胞电压门控钠通道(VGSC)的影响。方法酶解法分离兔心室肌细胞,采用标准全细胞膜片钳技术记录电压门控钠通道电流(INa)。结果AA可浓度依赖性抑制INa,使INa的I-U曲线上移,但其激活电位、电位峰值和反转电位保持不变;AA使INa稳态失活曲线左移,恢复曲线右移;但对INa的抑制作用不具有明显的频率依赖性。结论AA对INa具有浓度依赖性抑制作用,主要是通过抑制失活和失活后恢复过程而发挥作用。因此AA对INa的抑制作用可能是AA抗心律失常,保护心肌的作用机制之一。     

Electrophysiological effect of l-cis-diltiazem, the stereoisomer of d-cis-diltiazem, on isolated guinea-pig left ventricular myocytes

l-cis-Diltiazem, the stereoisomer of the L-type Ca(2+) channel blocker d-cis-diltiazem, protects cardiac myocytes from ischemia and reperfusion injury in the perfused heart and from veratridine-induced Ca(2+) overload. We determined the effect of l-cis-diltiazem on the voltage-dependent Na(+) current (I(Na)) and lysophosphatidylcholine-induced currents in isolated guinea-pig left ventricular myocytes by a whole-cell patch-clamp technique. l-cis-Diltiazem inhibited I(Na) in a dose-dependent manner without altering the current-voltage relationship for I(Na) (K(d) values : 729 and 9 microM at holding potentials of -140 and -80 mV, respectively). A use-dependent block of I(Na), the leftward shift of the steady-state inactivation curve and the delay of recovery from inactivation suggest that l-cis-diltiazem has a higher affinity for the inactivated state of Na(+) channels. In addition to I(Na), the lysophosphatidylcholine-induced currents were inhibited by l-cis-diltiazem in a similar concentration range. It is suggested that inhibition of both Na(+) channels and lysophosphatidylcholine-activated non-selective cation channels contributes to the cardioprotective effect of l-cis-diltiazem.     

Inhibition of cardiac Na+ current by primaquine

The electrophysiological effects of the anti-malarial drug primaquine on cardiac Na(+) channels were examined in isolated rat ventricular muscle and myocytes. In isolated ventricular muscle, primaquine produced a dose-dependent and reversible depression of dV/dt during the upstroke of the action potential. In ventricular myocytes, primaquine blocked I(Na)(+) in a dose-dependent manner, with a K(d) of 8.2 microM. Primaquine (i) increased the time to peak current, (ii) depressed the slow time constant of I(Na)(+) inactivation, and (iii) slowed the fast component for recovery of I(Na)(+) from inactivation. Primaquine had no effect on: (i) the shape of the I - V curve, (ii) the reversal potential for Na(+), (iii) the steady-state inactivation and g(Na)(+) curves, (iv) the fast time constant of inactivation of I(Na)(+), and (v) the slow component of recovery from inactivation. Block of I(Na)(+) by primaquine was use-dependent. Data obtained using a post-rest stimulation protocol suggested that there was no closed channel block of Na(+) channels by primaquine. These results suggest that primaquine blocks cardiac Na(+) channels by binding to open channels and unbinding either when channels move between inactivated states or from an inactivated state to a closed state. Cardiotoxicity observed in patients undergoing malaria therapy with aminoquinolines may therefore be due to block of Na(+) channels, with subsequent disturbances of impulse conductance and contractility.     

Study of the interaction of lubeluzole with cardiac sodium channels

The effects of lubeluzole on sodium currents were examined in guinea-pig isolated cardiac myocytes by use of the whole-cell patch clamp technique. Lubeluzole (0.01-100 microM) reduced peak Na+ current (INa) obtained at a holding potential of -80 mV with an IC50 value of 9.5 (3.5-21.9) microM and a Hill coefficient of 1.1. These effects were rapid and reversible. Lubeluzole (10 microM) produced a shift in the inactivation curve to hyperpolarized potentials (by -9.7 mV, P < 0.05), but produced no change in the voltage-dependence of activation. Lubeluzole (10 microM) produced significant tonic block of INa obtained at a holding potential of -120 mV (2.7 +/- 1.4% and 27.5 +/- 5.8% for control and lubeluzole, respectively; n = 6; P < 0.05). Use-dependent block of INa was also observed. Recovery from block was delayed by lubeluzole (10 microM; tau1=4.4 +/- 6.2, tau2=22.7 +/- 1.5 milliseconds for control and tau1=311 +/- 144, tau2 = 672 +/- 23 milliseconds for lubeluzole; n = 6; P < 0.001) confirming use-dependency of block. The results indicate that lubeluzole produces both tonic and use-dependent block of cardiac sodium channels at concentrations similar to those that block neuronal sodium channels, due mainly to interaction of the drug with channels in the inactivated state.     

Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes. Atrioventricular difference of moricizine block

The effects of moricizine on Na+ channel currents (INa) were investigated in guinea-pig atrial myocytes and its effects on INa in ventricular myocytes and on cloned hH1 current were compared using the whole-cell, patch-clamp technique. Moricizine induced the tonic block of INa with the apparent dissociation constant (Kd,app) of 6.3 microM at -100 mV and 99.3 microM at -140 mV. Moricizine at 30 microM shifted the h infinity curve to the hyperpolarizing direction by 8.6 +/- 2.4 mV. Moricizine also produced the phasic block of INa, which was enhanced with the increase in the duration of train pulses, and was more prominent with a holding potential (HP) of -100 mV than with an HP of -140 mV. The onset block of INa induced by moricizine during depolarization to -20 mV was continuously increased with increasing the pulse duration, and was enhanced at the less negative HP. The slower component of recovery of the moricizine-induced INa block was relatively slow, with a time constant of 4.2 +/- 2.0 s at -100 mV and 3.0 +/- 1.2 s at -140 mV. Since moricizine induced the tonic block of ventricular INa with Kd,app of 3.1 +/- 0.8 microM at HP = -100 mV and 30.2 +/- 6.8 microM at HP = -140 mV, and cloned hH1 with Kd,app of 3.0 +/- 0.5 microM at HP = -100 mV and 22.0 +/- 3.2 microM at HP = -140 mV, respectively, either ventricular INa or cloned hH1 had significantly higher sensitivity to moricizine than atrial INa. The h infinity curve of ventricular INa was shifted by 10.5 +/- 3.5 mV by 3 microM moricizine and that of hH1 was shifted by 5.0 +/- 2.3 mV by 30 microM moricizine. From the modulated receptor theory, we have estimated the dissociation constants for the resting and inactivated state to be 99.3 and 1.2 microM in atrial myocytes, 30 and 0.17 microM in ventricular myocytes, and 22 and 0.2 microM in cloned hH1, respectively. We conclude that moricizine has a higher affinity for the inactivated Na+ channel than for the resting state channel in atrial myocytes, and moricizine showed the significant atrioventricular difference of moricizine block on INa. Moricizine would exert an antiarrhythmic action on atrial myocytes, as well as on ventricular myocytes, by blocking Na+ channels with a high affinity to the inactivated state and a slow dissociation kinetics.     

Biphasic effects of haloperidol on sodium currents in guinea pig ventricular myocytes

Aim： To study the effects of haloperidol on sodium currents （INa） in guinea pig ventricular myocytes. Method： Whole-cell patch clamp technique was employed to evaluate the effects of haloperidol on INa in individual ventricular myocytes. Results： Haloperidol （0.1-3 wnol/L） inhibited INa in a concentration-dependent manner with an IC50 of 0.253±0.015 larnol/L. The inhibition rate of haloperidol （0.3 μmol/L） on INa was 22.14%±0.02%, and the maximum conductance was reduced. Haloperidol significantly reduced the midpoints for the activation and inactivation of INa by 2.09 and 4.09 mV, respectively. The time constant of recovery was increased. The increase in time intervals could only recover by 90.14%±1.4% （n=6）; however, haloperidol at 0.03 μmol/L enhanced INa conductance. The midpoints for the activation and inactivation Of INa were shifted by 1.38 and 5.69 mV, respectively, at this concentration of haloperidol. Conclusion： Haloperidol displayed a biphasic effect on INa in guinea pig cardiac myocytes. High concentrations of haloperidol inhibited INa, while lower concentrations of haloperidol shifted the activation and inactivation curve to the left. Full recovery of recovery curve was not achieved after 0.3 μmol/L haloperidol administration, indicating that the drug affects the inactivated state of sodium channels.     

四肽FMRFa对大鼠心室肌Na^＋／Ca^2＋交换的抑制

目的　研究四肽FMRFa对大鼠单个心室肌细胞Na /Ca2 交换的作用。方法　用膜片钳全细胞记录法测定成年大鼠心室肌细胞Na /Ca2 交换电流 (INa /Ca2 )和其他离子通道电流。结果　FMRFa对大鼠心室肌细胞INa /Ca2 呈浓度依赖性抑制 ,10 0 μmol·L-1浓度时抑制内向和外向INa /Ca2 密度分别达 6 0 1%和 5 6 5 % ,对内向电流及外向电流的IC50 分别为 2 0 μmol·L-1和 34μmol·L-1。FMRFa 5 μmol·L-1抑制INa /Ca2 内向和外向电流密度分别为 38 7%和 34 9% ,但FMRFa 5 μmol·L-1及 2 0 μmol·L-1对L型钙电流、钠电流、瞬时外向电流和内向整流钾电流均无显著抑制作用。结论　FMRFa对大鼠心室肌细胞是一个特异性Na /Ca2 交换抑制剂。     

Isoflurane and propofol inhibit voltage-gated sodium channels in isolated rat neurohypophysial nerve terminals

Mounting electrophysiological evidence indicates that certain general anesthetics, volatile anesthetics in particular, depress excitatory synaptic transmission by presynaptic mechanisms. We studied the effects of representative general anesthetics on voltage-gated Na+ currents (INa) in nerve terminals isolated from rat neurohypophysis using patch-clamp electrophysiological analysis. Both isoflurane and propofol inhibited INa in a dose-dependent and reversible manner. At holding potentials of -70 or -90 mV, isoflurane inhibited peak INa with IC50 values of 0.45 and 0.56 mM, and propofol inhibited peak INa with IC50 values of 4.1 and 6.0 microM, respectively. Isoflurane (0.8 mM) did not significantly alter the V1/2 of activation; propofol caused a small positive shift. Isoflurane (0.8 mM) or propofol (5 microM) produced a negative shift in the voltage dependence of inactivation. Recovery of INa from inactivation was slower from a holding potential of -70 mV than from -90 mV; isoflurane and propofol further delayed recovery from inactivation. In conclusion, the volatile anesthetic isoflurane and the intravenous anesthetic propofol inhibit voltage-gated Na+ currents in isolated neurohypophysial nerve terminals in a concentration- and voltage-dependent manner. Marked effects on the voltage dependence and kinetics of inactivation and minimal effects on activation support preferential anesthetic interactions with the fast inactivated state of the Na+ channel. These results are consistent with direct inhibition of oxytocin and vasopressin release from the neurohypophysis by isoflurane and propofol. Inhibition of voltage-gated Na+ channels may contribute to the presynaptic effects of general anesthetics on nerve terminal excitability and neurotransmitter release.     

Modes of the Na channel blocking action of pilsicainide, a new antiarrhythmic agent, in cardiac cells.

Using a whole cell clamp technique, the blockade of sodium currents (INa) by pilsicainide, a new antiarrhythmic agent, applied either intracellularly or extracellularly, was studied in single myocytes isolated from guinea pig right ventricle. Pilsicainide applied extracellularly inhibited the peak amplitude of INa in concentration- (from 10(-5) M to 10(-4) M) and rate- (from 0.5 Hz to 3.0 Hz) dependent manners. The onset rate of the blockade in INa was almost constant, independent of frequency of stimulus, but higher at high concentration of pilsicainide. The time constant in the recovery phase from INa inactivation remained almost constant (65 to 75 msec) in the range of concentrations used. Similar results were obtained by intracellular application of 10(-3) M pilsicainide. Pilsicainide applied intracellularly inhibited INa in a rate-dependent manner. The blocking potency of internally applied pilsicainide almost corresponded to that of external 10(-5) M pilsicainide. The onset rate of INa inactivation (from 0.098/pulse to 0.130/pulse) and the recovery time constant (77 msec) was similar to those of external 10(-5) M pilsicainide. These results suggest that pilsicainide, irrespective of intra- or extracellular application, shares a common binding site to block INa in cardiac myocytes.     

Effects of amlodipine on native cardiac Na+ channels and cloned alpha-subunits of cardiac Na+ channels.

The inhibitory effects of amlodipine besilate (CAS 11470-99-6) on the native Na+ current (INa) and cloned human cardiac Na+ channel alpha subunit (hH1) were studied by whole cell patch clamp techniques. Amlodipine produced tonic block of INa in a concentration- and holding potential (HP)-dependent manner with hyperpolarization of H infinity. Amlodipine produced phasic blockade of INa, which was dependent on HP and pulse duration. Amlodipine produced tonic blockade of hH1 in a concentration-dependent manner with 1 : 1 stoichiometry, and phasic blockade of hH1 which was dependent on the pulse duration. Amlodipine blocked INa in a voltage- and frequency-dependent manner via affinity to the resting as well as inactivated conformations of the alpha subunit.     

六肽FRCRSFa对大鼠心室肌Na^＋／Ca^＋交换的抑制

AIM: To study the effect of Phe-Arg-Cys-Arg-Ser-Phe-CONH2 (FRCRSFa) on Na+/Ca2+ exchange and its specificity in rat ventricular myocytes. METHODS: Na+/Ca2+ exchange current (INa+/Ca2+) and other currents were measured using whole-cell voltage clamp technique. RESULTS: A concentration-dependent inhibition of hexapeptide FRCRSFa on Na +/Ca2+ exchange was observed in rat ventricular myocytes. IC50 of inward and outward INa+/Ca2+ were 2 and 4 micromol/L, respectively. FRCRSFa 5 micromol/L did not affect L-type Ca2+ current, voltage-gated Na+ current, transient outward K+ current, and inward rectifier K+ current. CONCLUSION: These data indicate that FRCRSFa is an available inhibitor of Na+/Ca2+ exchange with relative selectivity and m ay be valuable for studies of the Na+/Ca2+ exchange in cardiac myocytes.     

Differential modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by the local anesthetic lidocaine

1 Voltage-gated Na+ channels are transmembrane proteins that are essential for the propagation of action potentials in excitable cells. Nav1.7 and Nav1.8 dorsal root ganglion Na+ channels exhibit different kinetics and sensitivities to tetrodotoxin (TTX). We investigated the properties of both channels in the presence of lidocaine, a local anesthetic (LA) and class I anti-arrhythmic drug. 2 Nav1.7 and Nav1.8 Na+ channels were coexpressed with the beta1-subunit in Xenopus oocytes. Na+ currents were recorded using the two-microelectrode voltage-clamp technique. 3 Dose-response curves for both channels had different EC50 (dose producing 50% maximum current inhibition) (450 microm for Nav1.7 and 104 microm for Nav1.8). Lidocaine enhanced current decrease in a frequency-dependent manner. Steady-state inactivation of both channels was also affected by lidocaine, Nav1.7 being the most sensitive. Only the steady-state activation of Nav1.8 was affected while the entry of both channels into slow inactivation was affected by lidocaine, Nav1.8 being affected to a larger degree. 4 Although the channels share homology at DIV S6, the LA binding site, they differ in their sensitivity to lidocaine. Recent studies suggest that other residues on DI and DII known to influence lidocaine binding may explain the differences in affinities between Nav1.7 and Nav1.8 Na+ channels. 5 Understanding the properties of these channels and their pharmacology is of critical importance to developing drugs and finding effective therapies to treat chronic pain.     

Use- and voltage-dependent depression by ethmozine (moricizine) of the rapid inward sodium current in single rat ventricular muscle cells

Effects of ethmozine (moricizine) on the rapid inward sodium current (INa) were studied in freshly isolated single cells of rat ventricular myocardium. INa was measured by means of a patch clamp method for observing integral ionic currents. Ethmozine was applied extracellularly to a small cell membrane patch at concentrations of 10, 20, and 40 microM. At a stimulation frequency of 0.1 Hz the drug decreased the peak INa without producing a shift of the current-voltage curve, but shifted the V0.5 of the steady-state inactivation curve by -6 mV. At frequencies of 2-5 Hz the ethmozine-induced block exhibited a prominent use dependence, with trains of depolarizing clamp pulses 5-50 ms in duration eliciting maximal INa from holding potentials at which the steady-state inactivation variable h infinity was close to 1. The use-dependent inhibition of INa became more pronounced with an increase in both stimulation rate and pulse duration. In contrast to what has been observed in the node of Ranvier of the frog, the present results indicate that ethmozine binds to both inactivated and open Na+ channels, but that the contribution of the open channel block to the overall block at depolarizing clamp step durations of several hundred milliseconds is small in comparison with the contribution of the block of inactivated channels.     

Interaction between DPI 201-106 enantiomers at the cardiac sodium channel

The modification of cardiac sodium channels by DPI 201-106, its S-enantiomeric form (S)-DPI, and its R-enantiomeric form (R)-DPI was investigated with whole-cell voltage-clamp recording in single cultured ventricular myocytes obtained from late-fetal rats. From a holding potential of -100 mV, depolarizing pulses to -30 mV of 50-msec duration were applied at 0.2 Hz. Extracellular [Na] was reduced to 70 mM; temperature was 20 degrees. Drugs were administered directly on the cell by a double-barrelled microsuperfusion system. Sodium current inactivation was progressively slowed when the concentration of DPI 201-106 was increased from 0.3 to 3 microM. At 10 microM DPI 201-106, this effect was followed by a blocking effect on peak inward sodium current (INa), and at 30 microM inward sodium current was fully blocked within 2 min. The slowing of inactivation was produced by (S)-DPI (maximally effective at 3 microM), whereas (R)-DPI had little effect on inactivation at 3 microM. Conversely, (R)-DPI reduced INa at 10 microM, whereas (S)-DPI did not reduce INa at 3 microM. The effects of both (S)-DPI and (R)-DPI were partially reversed by washout. (R)-DPI retained its blocking activity on INa when the interval between depolarizing pulses was prolonged to 90 sec. In order to test whether the different sodium channel modifications produced by (S)-DPI and (R)-DPI were mutually exclusive, the INa-reducing activity of (R)-DPI was measured in the absence of (S)-DPI and after equilibration with a maximally effective (S)-DPI concentration. In the absence of (S)-DPI, 3 microM (R)-DPI reduced INa by 35% and in the presence of 3 microM (S)-DPI, by 51%. Thus, modification by (S)-DPI of sodium channels did not prevent their block by (R)-DPI. The INa-reducing activity of (R)-DPI was even significantly augmented by (S)-DPI after a 1-sec depolarization to -30 mV. During such prolonged pulses, (R)-DPI accelerated the monoexponential decay of the (S)-DPI-induced slow phase of sodium current inactivation. The results are consistent with an irreversible binding reaction between (R)-DPI and (S)-DPI-modified open sodium channels (association rate constant, 4.7 x 10(5) M-1sec-1). We conclude that (R)-DPI reduces INa by interacting both with resting sodium channels and with (S)-DPI-modified open sodium channels. The corresponding receptor site is stereoselective and distinct from and allosterically coupled to the (s)-DPI receptor that mediates slowing of inactivation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Use-dependent blockade of sodium channels by local anaesthetics and antiarrhythmic drugs. Effects of chloramine-T and calcium ions

Voltage clamp studies were carried out of the effects of chloramine-T(CT) and external Ca++ on the blocking interactions of local anaesthetics (LAs) and antiarrhythmic drugs (lidocaine, tetracaine, N-propyl ajmaline, compound KC 3791) with Na+ channels in frog Ranvier nodes. The results obtained provided direct evidence for the notion that: LAs interact preferentially with inactivated Na+ channels and stabilize their inactivated conformation ("drug-induced slow inactivation": SI); and SI underlies the cumulative inhibition of INa during repetitive membrane stimulation. Normal inactivation is not indispensable, but plays an auxiliary role in the mechanism of cumulative inhibition of INa by drugs interacting with open Na+ channels. This block results mainly from accumulation of the channels in the resting blocked state (due to the inability of charged drugs to leave the channel via a "hydrophobic pathway"). The contribution of the blockade-inactivated state to this type of block may depend on some properties of the drug and the holding membrane potential. The problem of the location of the binding site responsible for LA-induced SI requires further investigation in view of the fact that in the myocardium, along with LA, the lipid-insoluble tetrodotoxin (TTX) induces a pronounced SI.     

Esmolol inhibits Na+ current in rat ventricular myocytes

Esmolol is a unique cardioselective, intravenous, ultra-short acting, beta1-adrenergic blocking agent. It has been widely applied in treating ventricular and supraventricular arrhythmias, especially in emergency situations. In this study the effects of esmolol on sodium current (I(Na)) were investigated by the whole cell patch-clamp recording technique in isolated adult rat ventricular myocytes. The results indicated that esmolol reversibly inhibited I(Na) in a concentration-dependent manner, with an IC50 of 74.2 +/- 0.60 micromol l(-1) with a Hill coefficient of 1.02 +/- 0.04. This inhibition was voltage- and frequency-dependent. Esmolol decreased the peak of the I-V relationship curve at -35 mV from 16.97 +/- 1.68 pA/pF to 6.96 +/- 0.51 pA/pF. The steady-state inactivation curve of I(Na) was shifted to more negative potentials, the voltage at half-inactivation changing from -78.75 +/- 2.3 mV in control to -85.94 +/- 3.2 mV in the presence of esmolol. The development of resting inactivation from closed states was accelerated by esmolol, the time constant was shortened from 62.75 +/- 3.21 ms to 24.93 +/- 2.43 ms, whereas the activation curve was not altered. I(Na) from inactivation could not be recovered completely in the presence of esmolol. These results suggest that esmolol inhibits I(Na) through sodium channel in rat ventricular myocytes by mechanisms involving preferential interaction with the inactivated state and acceleration of the development of inactivation directly from resting state. Therefore, the effect of inhibitory sodium of esmolol may play a vital role in its antiarrhythmic efficacy.     

海葵毒素anthopleurin—Q对豚鼠心室肌细胞钠电流的作用

目的:研究从海葵(Anthopleura xanthogrammica)提取的毒素anthopleurin-Q(AP-Q)对豚鼠心室肌钠电流(I_(Na))的作用。方法:用酶消化法分离豚鼠单个心室肌细胞,用全细胞膜片箝技术记录心室肌细胞钠电流。结果:AP-Q 3-30nmol/L浓度依赖性地增大I_(Na),EC_(50)、为104nmol/L(95％可信范围:78-130nmol/L)。AP-Q 300nmol/L使I-V曲线左移,使半数激活电压从(-36.3±2.3)mV变为(-43±23)mV(n=6,P<0.01),半数失活电压从(-75±6)mV变为(-59±5)mV(n=6,P<0.01)。AP-Q 300nmol/L使I_(Na)半数恢复时间从(114±36)ms缩短为(17±2)ms(n=6,P<0.01),并明显减慢I_(Na)的快速失活时间常数(τ_f)。结论:AP-Q对I_(Na)有促进作用并减慢其失活过程。