葛根素对豚鼠心肌细胞动作电位及有效不应期的影响

目的　观察葛根素对豚鼠乳头肌动作电位及有效不应期的影响 ,以探讨其抗心律失常的作用机制。方法　采用标准玻璃微电极细胞内记录技术。结果　①葛根素 0 0 0 5 ,0 0 1,0 0 15mmol·L-1能使豚鼠心室肌细胞动作电位复极5 0 %时程 (APD50 )和复极 90 %时程 (APD90 )明显延长 ,APD50分别由 ( 176 4 3± 5 1 3 7)ms延长至 ( 192 86± 60 82 )ms(n=7,P <0 0 5 ) ,( 2 0 0 71± 63 0 8)ms和 ( 2 0 7 71± 65 4 5 )ms(n =7,P <0 0 1) ;APD90 分别由 ( 2 0 0 71± 5 9 75 )ms延长至 ( 2 2 1 4 3± 70 4 6)ms(n =7,P <0 0 5 ) ,( 2 3 5 0 0±5 8 88)ms和 ( 2 4 0 0 0± 5 8 4 5 )ms(n =7,P <0 0 1) ,并且这种延长呈现量效关系。②采用 0 2 ,0 5 ,1,2 ,4Hz频率的方波刺激 ,发现在 0 0 1mmol·L-1时葛根素延长心肌细胞APD50 有明显的非逆向频率依赖性。③使用双脉冲刺激发现在 0 0 1mmol·L-1时葛根素能明显延长心肌细胞的有效不应期 ,由 ( 98 0 0± 16 4 3 )ms延长至 ( 168 0 0± 13 0 4 )ms(n =5 ,P <0 0 1)。结论　葛根素能延长心肌细胞APD50 和APD90 以及心肌细胞有效不应期 ,其抗心律失常的机制源于此作用。     

Frequency-dependent acceleration of cardiac repolarization by progesterone underlying its cardiac protection against drug-induced proarrhythmic effects in female rabbits

Concurrent supplement of estradiol and progesterone has been shown to reduce the cardiac sensitivity to class III antiarrhythmic agent-induced arrhythmias in ovariectomized rabbits. To understand the underlying cardiac electrophysiological mechanisms of the hormones, present study explored the modulation of progesterone and estradiol on repolarization and its frequency dependence in papillary muscles of female rabbit right ventricles by glass microelectrode technique. Results showed that progesterone shortened action potential duration for 90% repolarization (APD(90)) whereas estradiol prolonged APD(90) and those actions on APD(90) were concentration-dependent for both hormones at 1.0-30 μM (P<0.05 or P<0.01). Further, the action of both hormones on APD(90) was found to be dependent on stimulation frequencies (0.2-3.3Hz). The shortening of APD(90) by progesterone (10 μM) was enhanced with the increase in frequencies reaching a statistic significance at frequencies ≥1.0 Hz, whereas the prolongation of APD(90) by estradiol (3 μM) was weakened with the increase in frequencies and the significant change was observed at frequencies ≤2.0 Hz (P<0.05 or P<0.01). More interestingly, the relative change of APD(90) and the incidence of early afterdepolarization induced after by dofetilide (0.1 μM), a class III antiarrhythmic agent, were significantly less or lower in the papillary muscles pretreated with progesterone than in those pretreated with estradiol (P<0.01 or P<0.05). In conclusion, progesterone has a reverse modulating affect on cardiac repolarization to that of estradiol. By acceleration of ventricular repolarization, progesterone may reduce the susceptibility of females to class III antiarrhythmic agents-induced proarrhythmic affection.     

幼猪心肌梗死后植入骨髓间充质干细胞对心室肌细胞复极活动的影响

目的调查心肌梗死后植入骨髓间充质干细胞(mes-enchymal stem cells,MSCs)对心室肌细胞复极活动的影响。方法取10只苏中幼猪作正常对照组(Control),另取23只通过球囊导管堵闭左前降支法建立心肌梗死(myocardial in-farction,MI)模型,并分别移植MSCs悬液(MSCs组,n=13)或等量生理盐水(MI组,n=10),6周后记录左室心内膜心肌细胞的单相动作电位(MAP),分析动作电位复极90%的时间(APD90)、复极时间(RT)、APD和RT离散度(APDd和RTd),APD重整曲线斜率及APD交替的阈值周长。结果(1)MI组和MSCs组APD90、RT、APDd和TRd值较Control组均延长(P均<0.01),但MSCs组较MI组缩短(P<0.05或0.01);(2)Control组APD重整曲线斜率<1(正常),而MSCs组和MI组重整曲线斜率均>1(异常),但前者斜率明显小于后者;(3)MSCs诱发APD交替的阈值周长虽高于Control组(P<0.01),却低于MI组(P<0.05)。结论 MI后心室复极离散度增大,MSCs可以减轻MI引起的复极紊乱,提示MSCs移植有助于降低MI后室性心律失常的风险。     

植物性雌激素金雀异黄素对家兔窦房结起搏细胞的电生理效应

目的:研究植物性雌激素金雀异黄素(genistein,GST)对家兔窦房结起搏细胞的电生理效应及其作用机制.方法:应用经典玻璃微电极方法.结果:GST(10-150μmol/L)不仅以剂量依赖性方式抑制窦房结起搏细胞的零相最大上升速度(V_(max)),舒张期除极速度(VDD),起搏放电频率(RPF)和动作电位幅度(APA),而且延长复极化90％时间(APD_(90)).提高灌流液中钙离子浓度以及应用L型钙通道开放剂Bay K8644(0.5μmol/L)均可逆转GST对起搏细胞的上述电生理效应,但NO合酶阻断剂L-NAME(1 mmol/L)对GST的效应并无影响.结论:GST对家兔窦房结具有负性变时作用,并可延长复极化时程.这些效应可能与其抑制钙离子内流及钾离子外流有关.     

牛磺酸镁配合物对获得性长QT综合征亚型8模型下L型钙通道作用研究

目的 观察不同浓度牛磺酸镁配合物（TMCC）对获得性长QT综合征亚型8的抗心律失常机制。方法 采用Langendorff逆行主动脉灌流酶解法,急性分离获得豚鼠单个心室肌细胞;建立表达CACNA1C基因的HEK293细胞模型。BayK 8644（10 nmol/L）用来建立LQT8模型,采用全细胞膜片钳技术记录TMCC （0.01、0.10、1.00 mol/L）对对照和LQT8模型下HEK293细胞L型钙通道（LTCC）电流、豚鼠心室肌细胞动作电位的影响。结果 在HEK293细胞细胞中,与对照组比较,0.1、1 mol/L TMCC组I_Ca,L电流密度显著减弱,差异有统计学意义（P<0.05、0.01）。与对照组比较,BayK 8644组I_Ca,L的电流-电压（I-V）曲线显著下移,电流密度显著增强（P<0.01）,使半数激活电压明显升高3.23倍,激活曲线左移,激活加快。TMCC （0.01、0.1、1 mol/L）可明显减弱BayK 8644对I_Ca,L电流的增强作用,使下移的I-V曲线上移,0.1、1 mol/L浓度组差异有统计学意义（P<0.05、0.01）;TMCC各浓度组均明显降低半数激活电压（P<0.05、0.01）,恢复左移的激活曲线,使激活减慢。在豚鼠心室肌细胞中,与对照组比较,BayK 8644显著延长30%、50%和90%复极化动作电位持续时间（APD₃₀、APD₅₀和APD₉₀）（P<0.01）;0.01、0.1、1 mmol/L TMCC均可以减弱BayK 8644对APD₃₀、APD₅₀和APD₉₀的延长作用,0.1、1 mmol/L浓度组差异显著（P<0.05、0.01）。结论 TMCC通过缩短动作电位时程,减弱被增强的I_Ca,L电流,发挥一定的抗LQT8的作用。     

Effects of desipramine and tramadol in a chronic mild stress model in mice are altered by yohimbine but not by pindolol

There are few investigations on azimilide effects during ischemia/reperfusion. We have therefore investigated low concentrations of azimilide (0.1 and 0.5 micromol/l) versus Controls on action potential parameters and occurrence of repetitive responses during simulated ischemia and reperfusion. An in vitro model of "border zone" in guinea-pig ventricular myocardium (n=30) was used. Azimilide 0.5 micromol/l lengthened action potential duration in normoxic but not in ischemic-like conditions. Therefore an increased dispersion of action potential duration at 90% of repolarization during simulated ischemia in presence of azimilide was seen. Upon reperfusion, both normal and reperfused myocardium showed azimilide-induced action potential duration increase. There was a neutral effect on the occurrence of arrhythmias during simulated ischemia; however azimilide showed significant (P=0.033) antiarrhythmic properties following reperfusion. To mimic I(Kr) and I(Ks) blocking properties of azimilide we further used dofetilide 10 nmol/l with HMR 1556 1 nmol/l (N=9), which was accompanied by less severe shortening (P<0.05) of action potential duration at 90% of repolarization at 30 min of ischemic-like conditions (-43+/-9%), as compared with azimilide 0.5 micromol/l (-64+/-5%) but similar to what seen with azimilide 0.1 micromol/l (-53+/-5%) and Controls (-52+/-6%). During reperfusion, 2/9 (22%) preparations had sustained activities, which was less than what observed in Controls (5/10, 50%) and with azimilide 0.5 micromol/l (0/10, 0%), although not statistically different (respectively, P=0.35 and P=0.21). Lack versus homogenous class III effects of azimilide in respectively simulated ischemia and reperfusion may explain its different efficacy on arrhythmias, although prevention of reperfusion arrhythmias calls for other than just its I(Kr) and I(Ks) blocking properties.     

Effects of Ginkgolide B on action potential and calcium, potassium current in guinea pig ventricular myocytes

INTRODUCTION Ginkgo biloba extract (GbE) is extracted fromthe leaves of Ginkgo biloba. GbE is a multicomponentdrug with a polyvalent action. In Germany and France,such extracts were used effectively to treat cerebraldysfunction and peripheral circulatory disturbances[1].The results of clinical trails support new indications forGbE in the treatment of cardiovascular disease, par-ticularly in the prevention of ischemic heart syndromes[2].The primary active constituents of GbE incl…     

KATP channels and 'border zone' arrhythmias: role of the repolarization dispersion between normal and ischaemic ventricular regions.

1. In order to investigate the role of KATP channel activation and repolarization dispersion on the 'border zone' arrhythmias induced by ischaemia-reperfusion, the effects of glibenclamide and bimakalim, agents modifying action potential (AP) duration, were studied in an in vitro model of myocardial 'border zone'. 2. The electrophysiological effects of 10 microM glibenclamide and 1 microM bimakalim (n=8 each), respectively KATP channel blocker and activator, were investigated on guinea-pig ventricular strips submitted partly to normal conditions (normal zone, NZ) and partly to simulated ischaemic then reperfused conditions (altered zone, AZ). 3. By preventing the ischaemia-induced AP shortening (P<0.0001), glibenclamide reduced the dispersion of AP duration 90% (APD90) between NZ and AZ (P<0.0001), and concomitantly inhibited the 'border zone' arrhythmias induced by an extrastimulus (ES), their absence being significantly related to the lessened APD90 dispersion (chi2=8.28, P<0.01). 4. Bimakalim, which also reduced the APD90 dispersion (P<0.005) due to differential AP shortening in normal and ischaemic tissues, decreased the incidence of myocardial conduction blocks (25% of preparations versus 83% in control, n=12, P<0.05) and favoured 'border zone' spontaneous arrhythmias (75% of preparations versus 25% in control, P<0.05). 5. During reperfusion, unlike bimakalim, glibenclamide inhibited the ES-induced arrhythmias and reduced the incidence of the spontaneous ones (12% of preparations versus 92% in control, P<0.05), this latter effect being significantly related (chi2=6.13, P<0.02) to the lessened ischaemia-induced AP shortening in the presence of glibenclamide (P<0.0001). 6. These results suggest that KATP blockade may protect the ischaemic-reperfused myocardium from 'border zone' arrhythmias concomitantly with a reduction of APD90 dispersion between normal and ischaemic regions. Conversely, KATP channel activation may modify the incidence of conduction blocks and exacerbate the ischaemia-induced 'border zone' arrhythmias.     

Effects of polychlorinated biphenyl 19 (2,2',6-trichlorobiphenyl) on contraction, Ca2+ transient, and Ca2+ current of cardiac myocytes.

Polychlorinated biphenyls (PCBs) have been known as serious environmental pollutants, causing developmental delays, motor dysfunction, and decrease in brain dopamine level in humans and animals. We have investigated the effects of a PCB congener, 2,2',6-trichlorobiphenyl (PCB 19) on contractile force, Ca2+ transient, and L-type Ca2+ current (I(Ca,L)) in guinea pig ventricular myocytes stimulated at a rate of 0.25-0.33 Hz. PCB 19 decreased contractile force in a concentration-dependent manner. During the negative inotropic response, the action potential duration at 20% (APD20), 90% of repolarization (APD90), and the action potential amplitude (APA) were decreased concentration dependently: 30 microM PCB 19 reduced APD20, APD90 and APA by 36.7 +/- 3.5%, 22.6 +/- 3.9%, and 2.4 +/- 0.6%, respectively (n = 11, p < 0.01). PCB 19 30 microM decreased the Ca2+ transient and the I(Ca,L) by 46.8 +/- 1.8% (n = 9, p < 0.01) and 47.1 +/- 3.1% (n = 9, p < 0.01), respectively. The results suggest that PCB 19 decreased the Ca2+ transient through inhibition of L-type Ca2+ channels and that the decreased Ca2+ transient consequently caused a negative inotropic effect in cardiac myocytes.     

Effects of ginkgo biloba extract and bilobalide,a main constituent,on the ionic currents in guinea pig ventricular cardiomyocytes

Effects of Ginkgo biloba extract (GBE, 0.01 to 1 mg/ml) and a main constituent, bilobalide (0.1 to 1 mumol/l), on the action potentials and the underlying ionic currents in guinea pig ventricular cardiomyocytes were investigated using a patch-clamp technique. Both GBE and bilobalide at high concentrations caused depressant actions on the action potential configuration. GBE (0.3 mg/ml) decreased the Vmax by 17.1 +/- 2.1% (n = 6, p < 0.05), and bilobalide (1 mumol/l) by 14.7 +/- 2.2% (n = 8, p < 0.05). GBE prolonged the action potential duration at 90% repolarization (APD90), by 70.6 +/- 2.8% (n = 6, p < 0.001) at 1 mg/ml; in contrast, bilobalide shortened APD, by 11.1 +/- 2.0% (n = 8, p < 0.05) at 3 mumol/l. In voltage-clamp experiments, GBE (1 mg/ml) markedly inhibited the Ca2+ current (ICa) at 10 mV by 90.1 +/- 3.0% (n = 6, p < 0.001), the delayed rectifier K+ current (IK) at 60 mV by 63.7 +/- 3.0% (n = 6, p < 0.01), and the inwardly rectifying K+ current (IK1) at -120 mV by 47.8 +/- 2.6% (n = 6, p < 0.01). On the other hand, bilobalide at 1 mumol/l enhanced the ICa by 40.0 +/- 2.3% (n = 6, p < 0.05), and the IK by 14.0 +/- 2.3% (n = 6, p < 0.05), concentration-dependently. The IK1 was unaffected. These responses were reversible (to approximately 50-80%) after 10- to 20-min washout. These results indicate that even after acute administrations, GBE and bilobalide produced active actions on the APD and the ionic currents in cardiomyocytes. Although each chemical exhibited the responses in opposite directions, GBE acts totally as a mixture.     

Potential cellular mechanisms of hydrogen peroxide-induced cardiac arrhythmias.

The electrophysiologic effects of hydrogen peroxide on the isolated guinea pig right ventricular free wall were studied using simultaneous recordings of action potentials from the epicardium and the endocardium. Exposure to hydrogen peroxide caused a time- and concentration-dependent change in action potential characteristics. Action potential durations at 50 and 90% of repolarization (APD50 and APD90, respectively) were significantly prolonged by hydrogen peroxide in both the epicardium and the endocardium. Although prolongation occurred at lower concentrations (0.5 mM) in the epicardium, increases in APD in response to higher concentrations of hydrogen peroxide (1 or 4 mM) were maintained for a longer period of time in the endocardium. In addition, hydrogen peroxide (1 or 4 mM) caused significant depolarization in the epicardium after 10 min, although this effect was observed only in the endocardium exposed to 4 mM hydrogen peroxide. Ventricular arrhythmias were observed in 5 of 7, 6 of 7, and 7 of 7 preparations exposed to 0.5, 1, and 4 mM hydrogen peroxide, respectively. The most frequently observed electrophysiologic abnormalities were associated with increased automaticity. Coupled beats, including clearly identifiable early and delayed depolarizations, were also observed. Verapamil (2 microM) and amiloride (0.1 mM) reduced both the incidence and the duration of hydrogen peroxide-induced arrhythmias but did not influence the effects on APD. This study is the first demonstration of hydrogen peroxide-mediated transmural dispersion in APD that could play an important role in the development of ventricular arrhythmias. In addition, our results demonstrate that hydrogen peroxide can induce ventricular arrhythmias through several cellular mechanisms, including increased automaticity, coupled beats, and triggered activity.     

蜂毒肽对豚鼠心室肌细胞钾电流和动作电位的影响(英文)

目的:研究蜂毒肽(Melittin,Mel)对豚鼠心室肌细胞钾电流和动作电位的影响.方法:全细胞膜片箝记录.结果:蜂毒肽可呈浓度依赖性促进延迟整流钾电流(I_k),在测定电压为40 mv时,0.05,0.1,0.2μmol·L~(-1)蜂毒肽分别使I_k从(295±109)增大到(371±142)(n=5 P<0.05),(467±180)(n=5,P<0.05),(552±248)pA(n=5,P<0.05).但药物在三个浓度时对内向整流钾电流(I_(k1))均无显著影响.蜂毒肽0.05,0.1,0.2 μmol·L~(-1)分别使动作电位APD_(50)由(520±55)减小到(459±91)(n=5,P>0.05),(385±102)(n=5,P<0.01),(281±81)ms(n=5,P<0.01),使APD_(90)由(613±96)减小到(536±93)(n=5,P>0.05),(467±96)(n=5,P<0.01),(354±95)ms(n=5,P<0.01).结论:蜂毒肽促进延迟整流钾电流,缩短动作电位时程.     

胍丁胺抑制兔房室结细胞的自发活动(英文)

目的:研究胍丁胺(Agm)对兔房室结细胞自发活动的影响及其作用机制.方法:应用玻璃微电极方法.结果:Agm不仅剂量依赖地抑制兔房室结细胞自发活动的V_(max),APA和VDD,RSF;而且延长APD_(90);idazoxan能明显抑制Agm的作用;而L-NAME不能影响Agm的作用;提高灌流液中的Ca~(2 )浓度可对抗Agm的作用;ATP-敏感性钾通道开放剂(lemakalim)可拮抗Agm延长APD_(90)的作用.结论:Agm对房室结细胞自发活动的抑制作用由咪唑啉受体和/或肾上腺素α_2-受体介导,并与Ca~(2 )内流和K~ 外流减少有关.     

Analysis of the electrophysiologic effects of short-term oxybutynin on guinea pig and rabbit ventricular cells

The objective of this study was to investigate the cardioactive properties of oxybutynin, a drug that is widely prescribed for management of voiding dysfunction. Membrane currents were recorded from whole-cell-configured guinea pig ventricular myocytes, and action potentials were recorded from guinea pig and rabbit papillary muscles. L-type Ca2+ current (I(Ca),L), inward-rectifier K+ current (I(K1)), and delayed-rectifier K+ current (I(K)) were unaffected by < or = 1 microM oxybutynin, and inhibited by higher concentrations. The concentrations that reduced the currents to one-half of predrug control amplitude (K0.5) were as follows: 1(Ca),L, 16.1 microM, I(K1), 18.2 microM, rapidly activating I(K)(I(Kr)), 11.4 microM, and slowly activating I(K)(I(Ks)), 28.7 microM. Action-potential durations at 20 and 90% repolarization (APD20, APD90) were unaffected by oxybutynin < or =3 microM in guinea pig papillary muscles driven at 1 Hz; higher concentrations selectively shortened the APD20 by as much as 25% (100 microM), and caused moderate reductions in maximal upstroke velocity. Changes in the action potentials of rabbit papillary muscles were even smaller than in the guinea pig muscles. Because the peak therapeutic plasma concentration of oxybutynin is in the 0.01-0.1 microM range, the results suggest that the drug is highly unlikely to have adverse effects on cardiac electrical activity.     

Effect of altered repolarization course induced by antiarrhythmic drugs and constant current pulses on duration of premature action potentials in canine cardiac Purkinje fibers

The purpose of this study was to elucidate the mechanism of the upward shift of the electrical restitution curve, i.e., the lengthening of premature action potential duration (APDt) expressed as percentage of basic APD, induced by class I antiarrhythmic drugs in dog Purkinje fibers. In this study, six class I antiarrhythmic drugs lengthened APDt at a diastolic interval of 20 ms by 2.5-14.1%. The drugs also decreased the ratio of APD at 50% to APD at 90% of repolarization from 70.8 +/- 1.8% (n = 60) to 47.4-60.8%. The relation between the decrease in the ratio of APD50 to APD90 of the basic AP and lengthening of the normalized APDt was linear (r = 0.92; p less than 0.01). We attributed the lengthening of normalized APDt to the decreased ratio of APD50 to APD90, and applied repolarizing current pulses in short (less than or equal to 2 mm) fibers to simulate the drug-induced decrease in the ratio of APD50 to APD90. The altered repolarization course of basic AP by the current pulse during late plateau and early phase 3 caused APDt lengthening. The relation between the current-induced decrease in the ratio of APD50 to APD90 of the basic AP and the lengthening of normalized APDt was linear (r = 0.91; p less than 0.01). The slope of regression line describing this relation was similar to that in the presence of drugs. These results suggest that lengthening of the normalized APDt by class I antiarrhythmic drugs results from a more rapid repolarization during phase 2 of the preceding basic AP, possibly due to lesser influence of the delayed outward rectifying current. The lengthening of APDt by class I drugs may contribute to their antiarrhythmic action.     

Effect of 4-Aminopyridine on Action Potential Parameters in Isolated Dog Purkinje Fibers

Introduction.  4-Aminopyridine (fampridine), a potassium channel blocker, has demonstrated efficacy in improving lower extremity strength and walking speed in patients with multiple sclerosis. Since in vitro electrophysiologic studies are recommended for evaluating a drug's potential to prolong the QT interval and induce such cardiac arrhythmias as Torsades de Pointes, we examined the electrophysiologic effects of 4-aminopyridine (0.5, 5.0, 50, and 500 µM) on isolated canine Purkinje fibers.
Methods.  Microelectrodes monitored the resting membrane potential, overshoot, amplitude of action potential (AP), and maximal rate of depolarization of the AP upstroke in Purkinje fibers stimulated at 0.5 and 1.0 Hz.
Results.  None of the above variables were altered in the presence of 4-aminopyridine. The AP duration at 30%, 50%, and 90% repolarization was also monitored, with only the 500-µM concentration at the 1.0-Hz frequency significantly increasing these values with respect to baseline ( P  < 0.05). However, the small sample size (N = 4) was small. The proportional increases, and their 95% confidence intervals, were 90.8% (−36.4%, 218.0%), 25.8% (11.9%, 39.7%), and 22.0% (14.9%, 29.1%) for APD 30%, 50%, and 90% repolarization, respectively. Reverse rate dependence was not observed, suggesting inhibition of ion channels other than those contributing to QT interval prolongation.     

胍丁胺对大鼠心室肌细胞L—钙通道电流的影响

目的:观察胍丁胺(Agm)对大鼠心室肌细胞L-型钙通道电流(I_(Ca-L))的影响.方法:以酶解法制备单个心室肌细胞.应用全细胞膜片箝技术记录大鼠单个心室肌细胞钙通道电流.结果:(1)Agm(0.5,1,2mmol/L)可浓度依赖性地降低电压依赖性激活I_(Ca-L)(pA)峰值,其值从1451±236 (对照组)到937±105(n=8,P<0.05),585±74(n=8,P<0.01),和301±156(n=8,P<0.01).(2)Agm 1 mmol/L使用依赖性地阻滞I_(Ca-L)·1 Hz时抑制率为53％±12％(P<0.05),3Hz时为69％±11％(P<0.01).(3)Agm使I-V曲线上移,但对I_(Ca-L)的电压依赖特征、最大激活电压以及I_(Ca-L)稳态激活无明显影响.在Agm 1 mmol/L作用下,半数激活电压(V_(0.5)和斜率参数(k)与对照组相比均无显著性差异.V_(0.5)分别为(-20.2±2.5)mV和(-20.5±2.7)mV,k分别为(3.2±0.4)mV和(3.0±0.5)mV.(4)Agm 1 mmol/L可明显使钙电流稳态失活曲线左移,加速钙通道电压依赖性稳态失活.V_(0.5)分别为(-32±6)mV和(-40±5)mV,k分别为(7.6±O.9)mV和(12.5±1.1)mV(P<0.05).(5)Agm 1mmol/L还使I_(Ca)从失活状态下恢复明显减慢.结论:Agm抑制I_(Ca-L),并主要作用于L-型钙通道的失活状态,表现为钙通道失活加速和从失活状态下恢复减慢.     

Atrial-selective prolongation of refractory period with AVE0118 is due principally to inhibition of sodium channel activity

The action of AVE0118 to prolong effective refractory period (ERP) in atria but not in ventricles is thought to be due to its inhibition of IKur. However, in nonremodeled atria, AVE0118 prolongs ERP but not action potential duration (APD70-90), which can be explained with the inhibition of sodium but not potassium channel current. ERP, APD, and the maximum rate of increase of the AP upstroke (Vmax) were measured in the canine-isolated coronary-perfused right atrial and in superfused ventricular tissue preparations. Whole-cell patch-clamp techniques were used to measure sodium channel current in HEK293 cells stably expressing SCN5A. AVE0118 (5-10 μM) prolonged ERP (P < 0.001) but not APD70 and decreased Vmax (by 15%, 10 μM, P < 0.05; n = 10 for each). Ventricular ERP, APD90, and Vmax were not changed significantly by 10 μM AVE0118 (all P = ns; n = 7). AVE0118 effectively suppressed acetylcholine-mediated persistent atrial fibrillation. AVE0118 (10 μM) reduced peak current amplitude of SCN5A-WT current by 36.5% ± 6.6% (P < 0.01; n = 7) and shifted half-inactivation voltage (V0.5) of the steady-state inactivation curve from -89.9 ± 0.5 to -96.0 ± 0.9 mV (P < 0.01; n = 7). Our data suggest that AVE0118-induced prolongation of atrial, but not ventricular ERP, is due largely to atrial-selective depression of sodium channel current, which likely contributes to the effectiveness of AVE0118 to suppress atrial fibrillation.     

植物性雌激素金雀异黄素对人心房肌的电生理效应

目的:研究植物性雌激素金雀异黄素(genistein,GST)对人心房肌的电生理效应及其作用机制.方法:应用经典玻璃微电极方法.结果:GST(10-100μmol/L)抑制人心房肌纤维的舒张期(4相)除极化速率(VDD)和起搏细胞放电频(RPF),此外,GST(100 μmol/L)缩短APD_(90).应用L型钙通道开放剂BayK8644(0.5 μmol/L)可拮抗GST对人心房肌纤维的上述电生理效应,但NO合酶阻断剂L-NAME(1 mmol/L)对GST的效应并无影响.结论:GST对人心房肌具有负性变时作用,并可缩短复极化时程.这些效应可能与其抑制钙离子内流有关.     

小檗碱对心肌细胞I_(K1)、I_K及HERG通道的抑制作用(英文)

目的:研究小檗碱(Ber)对豚鼠心室肌细胞钾通道和动作电位作用,以及在蛙卵中表达的人的HERG通道的作用。方法:酶解方法分离单个心肌细胞,采用全细胞膜片箝方法记录钾离子电流及动作电位,基因箝技术研究HERG通道电流。结果:Ber可显著延长动作电位时程,并呈剂量依赖性。Ber 100μmol/L使APD_(90)由对照的(450±48)ms延长至(888±90)ms(n=6,P<0.01)。Ber对I_(Kl)及I_K呈剂量依赖性抑制作用。Ber 100μmol/L对I_(Kl)的抑制率达65％±7％(n=6,P<0.01)。Ber 50μmol/L对I_K的抑制率达57％±6％;对I_(Ktail)的抑制率达53％±6％。Ber对I_K作用呈现电压依赖性。Ber对在蛙卵中表达的HERG通道具有很强的阻断作用,IC_(50)为75μmol/L,此阻断作用也呈电压依赖性。结论:Ber可使动作电位时程明显延长,对I_(Kl)及I_K具有阻断作用。Ber可显著抑制HERG通道。Ber抗心律失常的机制与其抑制I_(Kl)、I_K及HERG通道密切相关。