糖尿病大鼠心肌电学的改变及环维黄杨星D对其电生理的影响

目的：观察糖尿病大鼠心肌电学变化特点，探讨环维黄杨星D(CVB-D)对糖尿病心肌电生理的影响。 方法： 以SD雄性大鼠尾静脉注射四氧嘧啶(alloxan,50 mg·kg^-1)复制糖尿病模型，选择以年龄相匹配的SD雄性大鼠作为对照组。2周后，记录大鼠体表心电图和右心室乳头肌跨膜电位，观察CVB-D对跨膜电位的影响。 结果： 糖尿病造模后第2周时，心率明显减慢于对照组，体表心电图QT间期和右室乳头肌动作电位时程（APD）各水平均明显长于对照组大鼠（P<0.01）,而静息膜电位（RP）、动作电位幅度(APA)和 超射值（OS）以及0期去极化最大速率（Vmax）均无明显变化。CVB-D具有剂量依赖效应，在13.3-63.3 μmol·L^-1范围内呈剂量依赖性地延长糖尿病大鼠和对照组大鼠APD30、APD50、APD70和APD90，对糖尿病大鼠APD延长作用更大。在33.3-63.3 μmol·L^-1浓度范围内，CVB-D呈剂量依赖性抑制糖尿病大鼠和对照组大鼠的静息电位(RP)、动作电位幅值（APA）和0期最大去极化速度（Vmax），但对糖尿病组抑制更大。研究结果还显示，CVB-D还具有时间依赖效应，当20 μmol·L^-1灌流心室肌10 min后开始出现作用，对照组到40 min左右作用达高峰，而糖尿病组40 min后仍继续延长。 结论： 糖尿病大鼠右室乳头肌动作电位时程和QT间期明显延长。CVB-D可进一步延长糖尿病大鼠的APD，抑制其RP、APA、OS以及Vmax，作用较对照组明显。     

糖尿病大鼠不同阶段心肌电学的改变

目的:探讨糖尿病(DM)易出现心律失常的可能机制。方法:SD雄性大鼠尾静脉注射四氧嘧啶(alloxan,50mg·kg^-1以生理盐水稀释)复制糖尿病模型,选择以年龄相匹配健康成年SD雄性大鼠尾静脉注射相同剂量的生理盐水作为对照组。分别观察2、4、6和8周4个不同时段。记录大鼠右心室乳头肌跨膜电位。结果:在糖尿病成模后第2周起,右室乳头肌动作电位时程(APD)复极化各水平均不同程度地长于正常大鼠(P<0.01),8周时较2周时更明显(P<0.05)。而去极化最大速率(V_max)超射值(OS)和动作电位幅度(APA)以及静息膜电位(RP)水平均无明显变化。结论:糖尿病大鼠右室乳头肌动作电位时程明显延长,而动作电位的过度延长可能是糖尿病易导致心律失常以及心源性猝死的主要原因,尤其是糖尿病晚期阶段。     

Transfection by eukaryotic expression vector pcDNA3-HERG inhibits the cultured neonatal rabbit ventricular myocyte hypertrophy induced by phenylephrine

ObjectiveProlonged action potential and decreased outward K⁺ currents are consistent findings in hypertrophic myocardium. The relation between action potential prolongation and myocyte hypertrophy has remained unclear. The present study investigated the temporal relation between action potential prolongation and myocyte hypertrophy, and the effect of enhancing repolarization on myocyte hypertrophy induced by phenylephrine.MethodsNeonatal rabbit ventricular myocytes were cultured and treated with 10 μmol/l phenylephrine. At 6 and 48 h after phenylephrine stimulation, myocyte hypertrophic parameters (including myocyte volume, total protein content, and membrane capacitance), action potential duration (APD), and calcineurin activity were measured; meanwhile, the effect of human-ether-a-go-go–related gene (HERG; encoding the αsubunit of rapidly activating delayed rectifier potassium channel) transfection on the above parameters at 48 h of phenylephrine stimulation was also measured.ResultsAt 6 h after phenylephrine treatment, APD at 90% repolarization of neonatal rabbit ventricular myocytes was prolonged by 14.3% (P<.05), but myocyte hypertrophy was not found. At 48 h after phenylephrine stimulation, APD at 90% repolarization of neonatal rabbit ventricular myocytes was furthermore prolonged by 18.8% (P<.05); at the same time, myocyte volume, total protein content, membrane capacitance, and calcineurin activity were increased by 40.0%, 41.8%, 36.4%, and 124.1%, respectively (P<.01). Neonatal rabbit ventricular myocytes transfected by pcDNA3-HERG overexpressed I_HERG,tail current, which was about fourfold higher than I_Kr (rapidly activating delayed rectifier K⁺ current) of neonatal rabbit ventricular myocytes without transfection of HERG. HERG overexpression could accelerate repolarization and shorten APD at 90% repolarization prolonged by phenylephrine and partially inhibit myocyte hypertrophy and calcineurin activation.ConclusionsDuring the myocyte hypertrophy induced by phenylephrine, prolongation of APD at 90% repolarization is not secondary to but precedes myocyte hypertrophy. HERG overexpression could enhance the repolarization and inhibit the calcineurin activation and myocyte hypertrophy induced by phenylephrine.     

Intracellular calcium and electrical restitution in mammalian cardiac cells

The role of calcium current and changes in intracellular calcium concentration ([Ca²⁺]_i) in regulation of action potential duration (APD) during electrical restitution process was studied in mammalian ventricular preparations. Properly timed action potentials were recorded from multicellular preparations and isolated cardiomyocytes using conventional microelectrodes and EGTA-containing patch pipettes. APD increased monotonically in canine and guinea pig ventricular preparations with increasing diastolic interval (DI), while in rabbit papillary muscles the restitution process was biphasic: APD first lengthened, then shortened as the DI increased. When the restitution process was studied in single cardiomyocytes using EGTA-containing patch pipettes, the restitution pattern was similar in the three species studied. Similarly, no difference was observed in the recovery time constant of calcium current (I_Ca-L) measured under these conditions in voltage clamped myocytes. Loading the myocytes with the [Ca²⁺]_i-chelator BAPTA-AM had adverse effects in rabbit and canine cells. In rabbit myocytes steady-state APD lengthened and the late shortening component of restitution was abolished in BAPTA-loaded cells. In canine myocytes BAPTA-load shortened steady-state APD markedly, and during restitution, APD decreased with increasing DI. The late shortening component of restitution, observed in untreated rabbit preparations, was greatly reduced after nifedipine treatment, but remained preserved in the presence of 4-aminopyridine or nicorandil. Beat to beat changes in APD, peak I_Ca-L and [Ca²⁺]_i, measured using the fluorescent dye, Fura-2, were monitored in rabbit ventricular myocytes after a 1-min period of rest. In these cells, the shortening of APD was accompanied by a gradual reduction of the peak I_Ca-L and elevation of diastolic [Ca²⁺]_i during the initial eight post-rest action potentials. It is concluded that elevation of [Ca²⁺]_i shortens, while reduction of [Ca²⁺]_i lengthens APD in rabbit, but not in canine ventricular myocytes. These differences may probably be related to different distributions of [Ca²⁺]_i-dependent ion currents and/or to differences in calcium handling between the two species.     

Arrhythmogenic mechanisms in the isolated perfused hypokalaemic murine heart

Aim: Hypokalaemia is associated with a lethal form of ventricular tachycardia (VT), torsade de pointes, through pathophysiological mechanisms requiring clarification. Methods: Left ventricular endocardial and epicardial monophasic action potentials were compared in isolated mouse hearts paced from the right ventricular epicardium perfused with hypokalaemic (3 and 4 mm [K⁺]_o) solutions. Corresponding K⁺ currents were compared in whole‐cell patch‐clamped epicardial and endocardial myocytes. Results: Hypokalaemia prolonged epicardial action potential durations (APD) from mean APD₉₀s of 37.2 ± 1.7 ms (n = 7) to 58.4 ± 4.1 ms (n =7) and 66.7 ± 2.1 ms (n = 11) at 5.2, 4 and 3 mm [K⁺]_o respectively. Endocardial APD₉₀s correspondingly increased from 51.6 ± 1.9 ms (n = 7) to 62.8 ± 2.8 ms (n = 7) and 62.9 ± 5.9 ms (n = 11) giving reductions in endocardial–epicardial differences, ΔAPD₉₀, from 14.4 ± 2.6 to 4.4 ± 5.0 and ?3.4 ± 6.0 ms respectively. Early afterdepolarizations (EADs) occurred in epicardia in three of seven spontaneously beating hearts at 4 mm [K⁺]_o with triggered beats followed by episodes of non‐sustained VT in nine of 11 preparations at 3 mm . Programmed electrical stimulation never induced arrhythmic events in preparations perfused with normokalemic solutions yet induced VT in two of seven and nine of 11 preparations at 4 and 3 mm [K⁺]_o respectively. Early outward K⁺ current correspondingly fell from 73.46 ± 8.45 to 61.16±6.14 pA/pF in isolated epicardial but not endocardial myocytes (n = 9) (3 mm [K⁺]_o). Conclusions: Hypokalaemic mouse hearts recapitulate the clinical arrhythmogenic phenotype, demonstrating EADs and triggered beats that might initiate VT on the one hand and reduced transmural dispersion of repolarization reflected in ΔAPD₉₀ suggesting arrhythmogenic substrate on the other.     

Atrial arrhythmogenesis in wild-type and Scn5a+/Δ murine hearts modelling LQT3 syndrome

Long QT(3) (LQT3) syndrome is associated with abnormal repolarisation kinetics, prolonged action potential durations (APD) and QT intervals and may lead to life-threatening ventricular arrhythmias. However, there have been few physiological studies of its effects on atrial electrophysiology. Programmed electrical stimulation and burst pacing induced atrial arrhythmic episodes in 16 out of 16 (16/16) wild-type (WT) and 7/16 genetically modified Scn5a+/Δ (KPQ) Langendorff-perfused murine hearts modelling LQT3 (P < 0.001 for both), and in 14/16 WT and 1/16 KPQ hearts (P < 0.001 for both; Fisher’s exact test), respectively. The arrhythmogenic WT hearts had significantly larger positive critical intervals (CI), given by the difference between atrial effective refractory periods (AERPs) and action potential durations at 90% recovery (APD₉₀), compared to KPQ hearts (8.1 and 3.2 ms, respectively, P < 0.001). Flecainide prevented atrial arrhythmias in all arrhythmogenic WT (P < 0.001) and KPQ hearts (P < 0.05). It prolonged the AERP to a larger extent than it did the APD₉₀ in both WT and KPQ groups, giving negative CIs. Quinidine similarly exerted anti-arrhythmic effects, prolonged AERP over corresponding APD₉₀ in both WT and KPQ groups. These findings, thus, demonstrate, for the first time, inhibitory effects of the KPQ mutation on atrial arrhythmogenesis and its modification by flecainide and quinidine. They attribute these findings to differences in the CI between WT and mutant hearts, in the presence or absence of these drugs. Thus, prolongation of APD₉₀ over AERP gave positive CI values and increased atrial arrhythmogenicity whereas lengthening of AERP over APD₉₀ reduced such CI values and produced the opposite effect.     

QT离散度与心自主神经的关系

ＱＴ离散度 (ＱＴｄｉｓｐｅｒｓｉｏｎ ,ＱＴｄ)定义为同步记录 1 2导联心电图中测量的最大ＱＴ间期 (ＱＴｍａｘ)与最小ＱＴ间期 (ＱＴｍｉｎ)之差[1 ] ,反映了心室肌复极不同步性和电不稳定性[2 - 4 ] 。这一概念已得到了心内膜和心外膜单相动作电位与体表心电图的对照研究[4,5] 及动物实验[6] 证实 ,大量临床研究也证明了ＱＴｄ与心室肌复极不同步性的高度相关[7- 9] 。近年来 ,对于ＱＴｄ的电生理基础及其本质引起广泛关注 ,人们认识到自主神经系统与心性猝死密切相关 ,交感过度激活可导致致命性心律失常发作 ,而迷走激活却有保护和抗…     

Effects of potassium channel openers in the isolated perfused hypokalaemic murine heart

Aim: We explored the anti‐arrhythmic efficacy of K⁺ channel activation in the hypokalaemic murine heart using NS1643 and nicorandil, compounds which augment I_Kr and I_KATP respectively. Methods: Left ventricular epicardial and endocardial monophasic action potentials were compared in normokalaemic and hypokalaemic preparations in the absence and presence of NS1643 (30 μm ) and nicorandil (20 μm ). Results: Spontaneously beating hypokalaemic hearts (3 mm K⁺) all elicited early afterdepolarizations (EADs) and episodes of ventricular tachycardia (VT). Perfusion with NS1643 and nicorandil suppressed EADs and VT in 7 of 13 and five of six hypokalaemic hearts. Provoked arrhythmia studies using programmed electrical stimulation induced VT in all hypokalaemic hearts, but failed to do so in 7 of 13 and five of six hearts perfused with NS1643 and nicorandil respectively. These anti‐arrhythmic effects were accompanied by reductions in action potential duration at 90% repolarization (APD₉₀) and changes in the transmural gradient of repolarization, reflected in ΔAPD₉₀. NS1643 and nicorandil reduced epicardial APD₉₀ from 68.3 ± 1.1 to 56.5 ± 4.1 and 51.5 ± 1.5 ms, respectively, but preserved endocardial APD₉₀ in hypokalaemic hearts. NS1643 and nicorandil thus restored ΔAPD₉₀ from ?9.6 ± 4.3 ms under baseline hypokalaemic conditions to 3.9 ± 4.1 and 9.9 ± 2.1 ms, respectively, close to normokalaemic values. Conclusion: These findings demonstrate, for the first time, the anti‐arrhythmic efficacy of K⁺ channel activation in the setting of hypokalaemia. NS1643 and nicorandil are anti‐arrhythmic through the suppression of EADs, reductions in APD₉₀ and restorations of ΔAPD₉₀.     

胺碘酮对低O_2、酸中毒及肾上腺素条件下豚鼠左心室流出道自律细胞电活动的影响

目的:研究胺碘酮对豚鼠左心室流出道自律细胞电活动的影响以及胺碘酮对低O2、酸中毒和肾上腺素(EPI)所致该部位自律性改变的影响。方法:采用标准玻璃微电极细胞内电位记录技术,分别观测胺碘酮对豚鼠左心室流出道自发慢反应电位的影响,以及胺碘酮对无糖低氧、pH6.8和EPI导致的该电位改变的影响。结果:(1)0.1μmol/L胺碘酮可使左心室流出道自发慢反应电位自发放电频率(RPF)减慢,最大舒张电位(MDP)绝对值减小,复极80%时间(APD80)延长(P0.05);1μmol/L胺碘酮可引起4相自动除极速度(VDD)和0相最大除极速度(Vmax)减慢,动作电位幅度(APA)减小,复极50%时间(APD50)延长(P0.05),RPF减慢,MDP减小和APD80延长(P0.01);10μmol/L胺碘酮可使VDD进一步减慢,APA进一步减小(P0.01),其它指标的改变维持1μmol/L胺碘酮灌流时的水平。(2)低O2可使VDD、RPF和Vmax减慢,MDP和APA减小,APD50缩短(P0.05);和低O2组相比,1μmol/L胺碘酮+低O2可使RPF和Vmax进一步减慢,MDP增大,APD80延长(P0.05),VDD进一步减慢,APD50延长(P0.01)。(3)pH6.8的灌流液可使VDD和RPF减慢,APD80缩短(P0.05),Vmax减慢,APA减小(P0.01);与pH6.8组相比,pH6.8的1μmol/L胺碘酮可使RPF进一步减慢,MDP和APA进一步减小,APD80延长(P0.05),VDD进一步减慢,APD50延长(P0.01)。(4)10μmol/LEPI可使VDD、RPF和Vmax加快,MDP增大,APD50和APD80缩短(P0.05),APA增大(P0.01);1μmol/L胺碘酮+10μmol/LEPI可使VDD和RPF减慢,MDP和APA减小,Vmax减慢,APD50和APD80延长(P0.05,P0.01)。结论:胺碘酮可降低豚鼠左心室流出道的自律性,同时对低O2、酸中毒和EPI所致的该部位自律性改变有一定的影响。     

Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in DeltaKPQ Scn5a murine hearts modelling human long QT 3 syndrome

Aim: To perform an empirical, pharmacological, separation of early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in a genetically modified mouse heart modelling human long QT syndrome (LQT) 3. Methods: Left ventricular endocardial and epicardial monophasic action potentials and arrhythmogenic tendency were compared in isolated wild type (WT) and Scn5a+/Δ hearts perfused with 0.1 and 1 μm propranolol and paced from the right ventricular epicardium. Results: All spontaneously beating bradycardic Scn5a+/Δ hearts displayed EADs, triggered beats and ventricular tachycardia (VT; n = 7), events never seen in WT hearts (n = 5). Perfusion with 0.1 and 1 μm propranolol suppressed all EADs, triggered beats and episodes of VT. In contrast, triggering of VT persisted following programmed electrical stimulation in 6 of 12 (50%), one of eight (12.5%), but six of eight (75%) Scn5a+/Δ hearts perfused with 0, 0.1 and 1 μm propranolol respectively in parallel with corresponding alterations in repolarization gradients, reflected in action potential duration (ΔAPD₉₀) values. Thus 0.1 μm propranolol reduced epicardial but not endocardial APD₉₀ from 54.7 ± 1.6 to 44.0 ± 2.0 ms, restoring ΔAPD₉₀ from ?3.8 ± 1.6 to 3.5 ± 2.5 ms (all n = 5), close to WT values. However, 1 μm propranolol increased epicardial APD₉₀ to 72.5 ± 1.2 ms and decreased endocardial APD₉₀ from 50.9 ± 1.0 to 24.5 ± 0.3 ms, increasing ΔAPD₉₀ to ?48.0 ± 1.2 ms. Conclusion: These findings empirically implicate EADs in potentially initiating spontaneous arrhythmogenic phenomena and transmural repolarization gradients in the re‐entrant substrate that would sustain such activity when provoked by extrasystolic activity in murine hearts modelling human LQT3 syndrome.     

Mechanisms responsible for the altered cardiac repolarization dispersion in experimental hypothyroidism

Aims: To identify the causes for the inhomogeneity of ventricular repolarization and increased QT dispersion in hypothyroid mice. Methods: We studied the effects of 5‐propyl‐2‐thiouracil‐induced hypothyroidism on the ECG, action potential (AP) and current density of the repolarizing potassium currents I_to,fast, I_to,slow, I_K,slow and I_ss in enzymatically isolated myocytes from three different regions of mouse heart: right ventricle (RV), epicardium of the left ventricle (Epi‐LV) and interventricular septum. K⁺ currents were recorded with the patch‐clamp technique. Membranes from isolated ventricular myocytes were extracted by centrifugation. Kv4.2, Kv4.3, KChIP and Na/Ca exchanger proteins were visualized by Western blot. Results: The frequency or conduction velocity was not changed by hypothyroidism, but QTc was prolonged. Neither resting membrane potential nor AP amplitude was modified. The action potential duration (APD)₉₀ increased in the RV and Epi‐LV, but not in the septum. Hypothyroid status has no effect either on I_to,slow, I_k,slow or I_ss in any of the regions analysed. However, I_to,fast was significantly reduced in the Epi‐LV and in the RV, whereas it was not altered in cells from the septum. Western blot analysis reveals a reduction in Kv4.2 and Kv4.3 protein levels in both the Epi‐LV and the RV and an increase in Na/Ca exchanger. Conclusion: From these results we suggest that the regional differences in APD lengthening, and thus in repolarization inhomogeneity, induced by experimental hypothyroidism are at least partially explained by the uneven decrease in I_to,fast and the differences in the relative contribution of the depolarization‐activated outward currents to the repolarization process.     

Ventricular arrhythmogenesis following slowed conduction in heptanol-treated, Langendorff-perfused mouse hearts

Arrhythmogenic effects of slowed action potential conduction produced by the gap junction and sodium-channel inhibitor heptanol (0.1–2 mM) were explored in Langendorff-perfused mouse hearts. Monophasic action potential recordings showed that 2 mM heptanol induced ventricular tachycardia in the absence of triggered activity arising from early or after-depolarizations during regular 8 Hz pacing and programmed electrical stimulation (PES). It also increased activation latencies and ventricular effective refractory periods (VERPs), but did not alter action potential duration (APD), thereby reducing local critical intervals for re-excitation given by APD₉₀ − VERP. Bipolar electrogram recordings showed that 2 mM heptanol increased electrogram duration (EGD) and ratios of EGDs obtained at the longest to those obtained at the shortest S1S2 intervals studied during PES, suggesting increased dispersion of conduction velocities. These findings show, for the first time in the mouse heart, that slowed conduction induces reversible arrhythmogenic effects despite repolarization abnormalities expected to reduce arrhythmogenicity.     

兔左室肥厚心肌跨室壁复极不均一性及其膜离子流变化的实验研究

目的:探讨兔左心室肥厚心肌心外膜下、中层、心内膜下3层心肌细胞动作电位及膜离子流变化的不均一性。方法: 心肌肥厚组以腹主动脉缩窄术复制兔压力超负荷心肌肥厚模型,并设正常对照组以作比较。胶原酶两步消化法分离获取兔单个心室肌细胞,其中用植皮刀分离左室游离壁内膜下、中层、外膜下3层心肌。以全细胞膜片钳记录单细胞跨膜动作电位和离子电流。结果: 肥厚组3层心肌细胞动作电位时程(APD₉₀)较对照组3层心肌细胞APD₉₀均分别有明显延长,而以中层心肌细胞APD₉₀延长最为明显(延长比例:中层26.0%±2.7%,外膜14.0%±1.6%,内膜10.0%±1.1%),使肥厚心肌跨室壁复极不均一性明显大于对照组。肥厚组各层心肌细胞瞬时外向钾电流(I_to)和缓慢激活的延迟整流钾电流(I_Ks)密度均低于对照组,且均以中层细胞下降的幅度最大。肥厚组各层心肌细胞L型钙电流(I_Ca,L)与快速激活的延迟整流钾电流(I_Kr) 密度与对照组均无明显差异。肥厚组各层心肌细胞内向整流钾电流(I_K1) 均明显低于对照组,但各层变低的幅度无明显差异。 结论:兔肥厚心肌跨室壁复极不均一性明显增大,I_to及I_Ks的跨室壁不均一性下降可能是其主要原因。     

Electrophysiological actions of histamien and H1-,H 2-receptor antagonists in cardiac tissue

Electrophysiological investigations of histamine in different cardiac tissues have led to the following results:

1. Histamine and the H₂-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium (especially a decrease in action potential duration), which are completely blocked by cimetidine and enhanced by the phosphodiesterase inhibitor 1-methyl,3-isobutylxanthine (IBMX). These effects may be explained by an increase in cellular cAMP leading to an increase in slow inward current and outward currents as shown by voltage clamp experiments.
2. Histamine in contrast to IBMX increases action potential duration at 90% repolarization (APD₉₀) in atria. Histamine effects in atrial myocardium are completely reversed by the H₁-antagonist dimetindene. Stimulation of atrial H₁-receptors is suggested to directly cause an increase in Ca-channel conductance independent of intracellular cAMP content.
3. Histamine reduces AH-interval, increases \(\dot V_{max} \) of NH — cells and may induce AV — node arrhythmias (at concentrations ≥ 3 μmol/l). These effects remain unchanged by dimetindene, but are reversed by cimetidine. The results indicate that histamine increases AV — nodal conduction via H₂-receptors.
4. Unspecific membrane actions of cimetidine are not observed up to 100 μmol/l. Dimetindene increases action potential duration (APD) in left atria and decreases \(\dot V_{max} \) at concentrations ≥ 10 μmol/l. However, H₁-antagonistic actions of dimetindene are already observed at concentrations 1,000 to 10,000 times lower (pA₂—values 8.39–9.12) so that unspecific membrane actions are suggested not to occur on a therapeutic dose level.

     

家兔陈旧性心肌梗死心室肌细胞钾离子电流的变化

目的:探讨陈旧性心肌梗死(HMI)心律失常的发生机制,观察HMI非梗死区心肌细胞动作电位时程(APD)、瞬时外向钾电流(I_to)、延迟整流钾电流(I_K)和内向整流钾电流(I_K1)的变化。方法: 12只家兔随机分为2组,陈旧性心肌梗死组(HMI)开胸结扎冠状动脉左回旋支,假手术组开胸但不结扎冠状动脉。3个月后应用全细胞膜片钳技术记录非梗死区心肌细胞的APD、I_to、 I_K和I_K1。 结果: (1)HMI组心肌细胞的膜电容明显高于假手术组;(2)HMI组心肌细胞的APD显著延长,并有早期后除极(EAD)出现;(3)HMI组心肌细胞I_to 、I_K,tail和I_K1的电流密度分别为(4.03±0.33)pA/pF、(1.14±0.11)pA/pF和(17.6±2.3)pA/pF,显著低于假手术组的(6.72±0.42)pA/pF、(1.54±0.13)pA/pF和(25.6±2.6)pA/pF(P<0.01)。结论: HMI非梗死区心室肌细胞I_to 、I_K,tail、和I_K1的电流密度的降低是其APD延长和EAD出现的离子流基础,而APD延长和EAD的出现,可能在HMI恶性心律失常的发生中起着重要作用。     

利多卡因对低氧、酸中毒及肾上腺素条件下豚鼠左心室流出道心肌组织电活动的影响

 目的：研究利多卡因对豚鼠左心室流出道心肌组织电活动的影响及其对该部位自律性异常的干预作用。方法：采用标准玻璃微电极细胞内电位记录技术,观测利多卡因对豚鼠左心室流出道自发慢反应电位的影响,以及利多卡因对无糖低O2、pH 6.8 和肾上腺素 （EPI） 导致的该电位改变的影响。结果：（1）0.1、1、10 μmol/L 利多卡因可呈剂量依赖性地导致左心室流出道自发慢反应电位4相自动除极速度（VDD）、自发放电频率(RPF) 和0相最大除极速度(Vmax) 减慢,最大舒张电位（MDP）绝对值和动作电位幅度（APA）减小,复极50%和80%时间（APD50和APD80）缩短。（2）低O2可使 VDD、RPF和Vmax减慢,MDP绝对值和APA减小,APD50缩短;和低O2灌流组相比,1 μmol/L利多卡因+低O2可使VDD、RPF和Vmax进一步减慢,MDP绝对值增大,APA进一步降低。（3）pH 6.8的灌流液可使VDD、RPF和Vmax明显减慢,MDP绝对值增大,APA减小,APD50和APD80缩短;与pH 6.8灌流组相比,pH 6.8的1 μmol/L利多卡因可使 VDD、RPF和Vmax进一步减慢,MDP绝对值进一步增大,APD50和APD80延长。（4）10 μmol/L 肾上腺素可使VDD、RPF和Vmax明显加快,MDP绝对值和APA增大,APD50和APD80缩短;1 μmol/L利多卡因+10 μmol/L EPI可使VDD和RPF减慢,MDP绝对值和APA减小,APD50和APD80延长。结论：利多卡因可降低豚鼠左心室流出道的自律性,同时对低 O2、酸中毒和 EPI 所致的该部位自律性改变有一定的影响。     

Cellular basis of sex disparities in human cardiac electrophysiology

Aim: Sex disparities in electrocardiogram variables and dysrhythmia susceptibility exist, notably in long QT syndrome (LQTS) and Brugada syndrome, but the underlying mechanisms in man are unknown. We studied the cellular basis of sex distinctions in human cardiac electrophysiology and dysrhythmia susceptibility using mathematical models of human ventricular myocytes. Methods: We implemented sex differences in the Priebe–Beuckelmann and ten Tusscher–Noble–Noble–Panfilov human ventricular cell models by modifying densities of the L‐type Ca²⁺ current (I_Ca,L), transient outward K⁺ current (I_to), and rapid delayed rectifier K⁺ current (I_Kr), according to experimental data from male and female hearts of various species. Sex disparities in transmural repolarization were studied in transmural strands of cells with ion current densities based on canine experimental data. Results: Female cells have longer action potential duration (APD), steeper APD‐heart rate relationship, larger transmural APD heterogeneity, and a greater susceptibility to pro‐dysrhythmogenic early afterdepolarizations (EADs) than male cells. Conversely, male cells have more prominent phase‐1 repolarization and are more susceptible to all‐or‐none repolarization. Conclusion: Sex differences in I_Ca,L, I_to and I_Kr densities may explain sex disparities in human cardiac electrophysiology. Female cells exhibit a limited ‘repolarization reserve’ as demonstrated by their larger susceptibility to EADs, which, combined with their larger transmural electrical heterogeneity, renders them more vulnerable to tachydysrhythmias in LQTS. Conversely, male cells have a limited ‘depolarization reserve’, as shown by their larger susceptibility to all‐or‐none repolarization, which facilitates tachydysrhythmias in Brugada syndrome. These general principles may also apply to dysrhythmia susceptibility in common disease.     

实验性糖尿病大鼠心肌细胞膜完整性的改变

应用电生理和辣根过氧化物酶示踪技术观察链脲佐菌素引起的实验性糖尿病大鼠心肌细胞膜完整性的变化。实验结果表明,糖尿病大鼠心肌细胞动作电位波幅、最大舒张电位,阈电位和最大除极速度均比对照动物明显减低(P<0.001),而复极不同水平的动作电位时程比对照动物显著延长(P<0.001),糖尿病大鼠心肌中辣根过氧化物酶阳性的肌细胞数明显多于对照动物(P<0.05)。这些结果说明,糖尿病大鼠心肌细胞膜存在损伤的电位变化,并有肌膜通透性增大。提示心肌细胞膜完整性的损害在糖尿病性心肌病的发生机理中可能起一定作用。     

Post-partum prolongation of the atrial repolarization in rabbit

Female sexual steroids are known to modify the expression of various K⁺ channels and thus they can alter cardiac repolarization. In the present work, using conventional microelectrode techniques, action potential characteristics were studied in atrial myocardium isolated from virgin, late pregnant, early (1–3 days) post-partum and late (2–3 weeks) post-partum rabbits. No changes in action potential configuration were observed during pregnancy. However, the duration, overshoot and amplitude of action potentials were significantly increased in the early (1–3 days) post-partum period. Resting potential and maximum rate of depolarization remained unchanged. The observed changes were transient, normal action potential characteristics were obtained at weeks 2–3 post-partum. 4-aminopyridine (1 mmol L^–1). caused a marked lengthening of action potential duration in all preparations obtained from non-pregnant and pregnant rabbits, whereas this 4-aminopyridine-induced prolongation was moderate in those preparations excised from the hearts of early post-partum animals. Action potential configuration was not affected by pinacidil (10 μmol L^–1) or glibenclamide (5 μmol L^–1) in non-pregnant or pregnant animals. In preparations obtained from early post-partum rabbits, pinacidil significantly shortened action potential duration, which was reverted by glibenclamide. The lengthening of action potential duration together with the decreased sensitivity to 4-aminopyridine observed in early post-partum animals may probably be caused by reduction of the transient outward K⁺ current at this stage. The results also suggest that electrophysiological alterations in the early post-partum period may probably be more pronounced than those associated with pregnancy itself.     

Electrophysiological determinants of hypokalaemia‐induced arrhythmogenicity in the guinea‐pig heart

Aim: Hypokalaemia is an independent risk factor contributing to arrhythmic death in cardiac patients. In the present study, we explored the mechanisms of hypokalaemia‐induced tachyarrhythmias by measuring ventricular refractoriness, spatial repolarization gradients, and ventricular conduction time in isolated, perfused guinea‐pig heart preparations. Methods: Epicardial and endocardial monophasic action potentials from distinct left ventricular (LV) and right ventricular (RV) recording sites were monitored simultaneously with volume‐conducted electrocardiogram (ECG) during steady‐state pacing and following a premature extrastimulus application at progressively reducing coupling stimulation intervals in normokalaemic and hypokalaemic conditions. Results: Hypokalaemic perfusion (2.5 mm K⁺ for 30 min) markedly increased the inducibility of tachyarrhythmias by programmed ventricular stimulation and rapid pacing, prolonged ventricular repolarization and shortened LV epicardial and endocardial effective refractory periods, thereby increasing the critical interval for LV re‐excitation. Hypokalaemia increased the RV‐to‐LV transepicardial repolarization gradients but had no effect on transmural dispersion of APD₉₀ and refractoriness across the LV wall. As determined by local activation time recordings, the LV‐to‐RV transepicardial conduction and the LV transmural (epicardial‐to‐endocardial) conduction were slowed in hypokalaemic heart preparations. This change was attributed to depressed diastolic excitability as evidenced by increased ventricular pacing thresholds. Conclusion: These findings suggest that hypokalaemia‐induced arrhythmogenicity is attributed to shortened LV refractoriness, increased critical intervals for LV re‐excitation, amplified RV‐to‐LV transepicardial repolarization gradients and slowed ventricular conduction in the guinea‐pig heart.