严重烫伤延长大鼠心室肌细胞动作电位时程的机制

严重烫伤引起心肌细胞动作电位时程（action potential duration,APD）延长,通过加重烫伤心肌细胞钙紊乱和诱发室性心律失常,促进烫伤心功能障碍的发生,但APD延长的机制尚不清楚。通过制作约40％体表面积（total body surface area,TBSA）Ⅲ度烫伤大鼠模型,在伤后12h大鼠心功能明显减弱时分离其心肌细胞,采用膜片钳技术观察心肌细胞APD以及动作电位复极化相关的重要离子通道电流,包括瞬间外向钾电流（transient outward K^＋ current,Ito）,L-型钙电流（L-type Ca^2＋ current,ICa-L）和内向整流钾电流（inward rectifier K^＋ current,IK1）。结果显示,烫伤后12h单个心肌细胞APD明显延长,APD50和APD90在烫伤组分别为（46．02±3．78）ms、（123．24±12．48）ms（n=19）,明显长于对照组的（23．28±4．85）ms、（72．12±3．57）ms（n=17）（P〈0．01）。烫伤引起,Ito电流密度降低,＋60 mV下烫伤组的电流密度（20．39±1．98）pA／pF（n=25）明显低于对照组的（34．15±3．78）pA／pF（n=20,P〈0．01）;烫伤组在-120至-80mV电压刺激下所产生的IK1电流密度显著低于对照组：而两组之间ICa-L电流密度、电压依赖性的激活和失活无显著性差异。结果提示,烫伤引起心肌细胞APD延长的机制与瞬间外向钾通道和内向整流钾通道功能下调有关。     

Action potential characterization in intact mouse heart: steady-state cycle length dependence and electrical restitution

Transgenic mice have been increasingly utilized to investigate the molecular mechanisms of cardiac arrhythmias, yet the rate dependence of the murine action potential duration and the electrical restitution curve (ERC) remain undefined. In the present study, 21 isolated, Langendorff-perfused, and atrioventricular node-ablated mouse hearts were studied. Left ventricular and left atrial action potentials were recorded using a validated miniaturized monophasic action potential probe. Murine action potentials (AP) were measured at 30, 50, 70, and 90% repolarization (APD(30)-APD(90)) during steady-state pacing and varied coupling intervals to determine ERCs. Murine APD showed rate adaptation as well as restitution properties. The ERC time course differed dramatically between early and late repolarization: APD(30) shortened with increasing S1-S2 intervals, whereas APD(90) was prolonged. When fitted with a monoexponential function, APD(30) reached plateau values significantly faster than APD(90) (tau = 29 +/- 2 vs. 78 +/- 6 ms, P < 0.01, n = 12). The slope of early APD(90) restitution was significantly <1 (0.16 +/- 0.02). Atrial myocardium had shorter final repolarization and significantly faster ERCs that were shifted leftward compared with ventricular myocardium. Recovery kinetics of intracellular Ca(2+) transients recorded from isolated ventricular myocytes at 37 degrees C (tau = 93 +/- 4 ms, n = 18) resembled the APD(90) ERC kinetics. We conclude that mouse myocardium shows AP cycle length dependence and electrical restitution properties that are surprisingly similar to those of larger mammals and humans.     

Myocardial infarction in rat eliminates regional heterogeneity of AP profiles,I(to) K(+) currents,and [Ca(2+)](i) transients

Transient outward K(+) current density (I(to)) has been shown to vary between different regions of the normal myocardium and to be reduced in heart disease. In this study, we measured regional changes in action potential duration (APD), I(to), and intracellular Ca(2+) concentration ([Ca(2+)](i)) transients of ventricular myocytes derived from the right ventricular free wall (RVW) and interventricular septum (SEP) 8 wk after myocardial infarction (MI). At +40 mV, I(to) density in sham-operated hearts was significantly higher (P < 0.01) in the RVW (15.0 +/- 0.8 pA/pF, n = 47) compared with the SEP (7.0 +/- 1.1 pA/pF, n = 18). After MI, I(to) density was not reduced in SEP myocytes but was reduced (P < 0.01) in RVW myocytes (8.7 +/- 1.0 pA/pF, n = 26) to levels indistinguishable from post-MI SEP myocytes. These changes in I(to) density correlated with Kv4.2 (but not Kv4.3) protein expression. By contrast, Kv1.4 expression was significantly higher in the RVW compared with the SEP and increased significantly after MI in RVW. APD measured at 50% or 90% repolarization was prolonged, whereas peak [Ca(2+)](i) transients amplitude was higher in the SEP compared with the RVW in sham myocytes. These regional differences in APD and [Ca(2+)](i) transients were eliminated by MI. Our results demonstrate that the significant regional differences in I(to) density, APD, and [Ca(2+)](i) between RVW and SEP are linked to a variation in Kv4.2 expression, which largely disappears after MI.     

压力负荷性心衰小鼠左心室跨壁L-型钙电流的变化

为了观察正常和心衰时心内膜下和心外膜下心肌细胞L-型钙电流(ICa-L)的差别,我们采用主动脉弓狭窄的方法建立小鼠压力超负荷性心衰模型,采用全细胞膜片钳技术记录了正常、主动脉狭窄(band)及假手术对照(sham)组动物左心室游离壁内、外膜下心肌细胞的动作电位时程(action potential duration,APD)和ICa-L。结果显示:(1)与sham组同龄的正常小鼠左心室心内膜下细胞动作电位复极达90％的时程(APD90)为(38．2±6．44)ms,较心外膜下细胞的APD90(15.67±5.31)ms明显延长,二者的比值约为2．5:1;内膜下细胞和外膜下细胞ICa-L密度没有差异,峰电流密度分别为(-2.7±0.49)pA/pF和(-2.54±0．53)pA/pF;(2)Band组内、外膜下细胞的动作电位复极达50％的时程(APD50)、APD90均较sham组显著延长,尤以内膜下细胞延长突出,分别较sham组延长了400％和360％,内、外膜下细胞APD90的比值约为4.2:1;(3)与sham组相比, band组内膜下细胞ICa-L密度显著减小,在+10 mV～+40 mV的4个电压下分别降低了20．2％、21．4％、21.6％和25.7％(P< 0．01),但其激活电位、峰电位和翻转电位没有改变;band组外膜下细胞的ICa-L密度与同期sham组相比无明显变化;band组钙通道激活、失活及复活的动力学特征与sham组相比没有改变。以上结果提示,生理状态下小鼠左心室内、外膜下细胞ICa-L密度不存在明显差别,提示ICa-L与APD跨壁异质性的产生无关;心衰时左心室内、外膜下细胞APD明显延长,以内膜下细胞延长尤为突出,内膜下细胞ICa-L密度明显减少,而外膜下细胞ICa-L密度无明显改变,这种ICa-L的非同步变化在心衰时可能起到对抗APD延长、减少复极离散度的有益作用。     

The effect of adrenomedullin on the L-type calcium current in myocytes from septic shock rats: signaling pathway

Adrenomedullin (ADM) is upregulated in cardiac tissue under various pathophysiological conditions, particularly in septic shock. The intracellular mechanisms involved in the effect of ADM on adult rat ventricular myocytes are still to be elucidated. Ventricular myocytes were isolated from adult rats 4 h after an intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Membrane potential and L-type calcium current (I(Ca,L)) were determined using whole cell patch-clamp methods. APD in LPS group was significantly shorter than control values (time to 50% repolarization: LPS, 169 +/- 2 ms; control, 257 +/- 2 ms, P < 0.05; time to 90% repolarization: LPS, 220 +/- 2 ms; control, 305 +/- 2 ms, P < 0.05). I(Ca,L) density was significantly reduced in myocytes from the LPS group (-3.2 +/- 0.8 pA/pF) compared with that of control myocytes (-6.7 +/- 0.3 pA/pF, P < 0.05). The ADM antagonist ADM-(22-52) reversed the shortened APD and abolished the reduction of I(Ca,L) in shock myocytes. In myocytes from control rats, incubating with ADM for 1 h induced a marked decrease in peak I(Ca,L) density. This effect was reversed by ADM-(22-52). The G(i) protein inhibitor, pertussis toxin (PTX), the protein kinase A (PKA) inhibitor, KT-5720, and the specific cyclooxygenase 2 (COX-2) inhibitor, nimesulide, reversed the LPS-induced reduction in peak I(Ca,L). The results suggest a COX-2-involved PKA-dependent switch from G(s) coupled to PTX-sensitive G(i) coupling by ADM in adult rat ventricular myocytes. The present study delineates the intracellular pathways involved in ADM-mediated effects on I(Ca,L) in adult rat ventricular myocytes and also suggests a role of ADM in sepsis.     

Thyroid hormone regulates mRNA expression and currents of ion channels in rat atrium

Atrial fibrillation is one of the common arrhythmias associated with hyperthyroidism. This study examined the effects of thyroid hormone (T3) on mRNA expression and currents of major ionic channels determining the action potential duration (APD) in the rat atrium using the RNase protection assay and the whole-cell patch-clamp technique, respectively. T3 increased the Kv1.5 mRNA expression and decreased the L-type calcium channel mRNA expression, while the Kv4.2 mRNA expression did not change. APD was shorter in hyperthyroid than in euthyroid myocytes. The ultrarapid delayed rectifier potassium currents were remarkably increased in hyperthyroid than in euthyroid myocytes, whereas the transient outward potassium currents were unchanged. L-type calcium currents were decreased in hyperthyroid than in euthyroid myocytes. T3 shifted the current-voltage relationship for calcium currents negatively. In conclusion, T3 increased the outward currents and decreased the inward currents. The resultant changes of ionic currents shortened APD, providing a substrate for atrial fibrillation.     

Postnatal development has a marked effect on ventricular repolarization in mice

To better understand the mechanisms that underlie cardiac repolarization abnormalities in the immature heart, this study characterized and compared K(+) currents in mouse ventricular myocytes from day 1, day 7, day 20, and adult CD1 mice to determine the effects of postnatal development on ventricular repolarization. Current- and patch-clamp techniques were used to examine action potentials and the K(+) currents underlying repolarization in isolated myocytes. RT-PCR was used to quantify mRNA expression for the K(+) channels of interest. This study found that action potential duration (APD) decreased as age increased, with the shortest APDs observed in adult myocytes. This study also showed that K(+) currents and the mRNA relative abundance for the various K(+) channels were significantly greater in adult myocytes compared with day 1 myocytes. Examination of the individual components of total K(+) current revealed that the inward rectifier K(+) current (I(K1)) developed by day 7, both the Ca(2+)-independent transient outward current (I(to)) and the steady-state outward K(+) current (I(ss)) developed by day 20, and the ultrarapid delayed rectifier K(+) current (I(Kur)) did not fully develop until the mouse reached maturity. Interestingly, the increase in I(Kur) was not associated with a decrease in APD. Comparison of atrial and ventricular K(+) currents showed that I(to) and I(Kur) density were significantly greater in day 7, day 20, and adult myocytes compared with age-matched atrial cells. Overall, it appears that, in mouse ventricle, developmental changes in APD are likely attributable to increases in I(to), I(ss), and I(K1), whereas the role of I(Kur) during postnatal development appears to be less critical to APD.     

血小板活化因子对豚鼠心室肌细胞动作电位和钾通道的影响

应用全细胞膜片钳技术研究了血小板活化因子(platelet activatingfactor,PAF)对豚鼠心室肌细胞动作电位和钾电流的影响.结果发现,当电极内液ATP浓度为5 mmol/L(模拟正常条件)时,1 μmol/L PAF使APD90由对照的225.8±23.3 ms延长至352.8±29.8ms(n=5,P＜0.05);使IK尾电流在指令电压 30 mV由对照的173.5±16.7 pA降至152.1±11.5 pA(P＜0.05,n=4);使Ikl在指令电压为-120 mV时由对照组的-6.1±1.3 nA降至-5.6±1.1 nA(P＜0.05,n=5);但PAF在生理膜电位范围(-90mV～ 20mV)对IK1没有影响.当电极内液ATP浓度为0mmol/L时,IK·ATP开放(模拟缺血条件),1 μmol/LPAF却显著缩短APD90,由对照的153±24.6 ms缩短至88.2±19.4 ms(n=5,P＜0.01).而用1 μmol/L格列本脲(IK·ATP的特异阻断剂)预处理后,恢复了PAF可显著延长动作电位时程的作用.结果提示,PAF可能扩大缺血心肌和正常心肌细胞动作电位时程的不均一性,是缺血/再灌注性心律失常发生的重要原因.     

Sprint training shortens prolonged action potential duration in postinfarction rat myocyte: mechanisms.

Two electrophysiological manifestations of myocardial infarction (MI)-induced myocyte hypertrophy are prolongation of action potential duration (APD) and reduction of transient outward current (I(to)) density. Because high-intensity sprint training (HIST) ameliorated myocyte hypertrophy and improved myocyte Ca(2+) homeostasis and contractility after MI, the present study evaluated whether 6-8 wk of HIST would shorten the prolonged APD and improve the depressed I(to) in post-MI myocytes. There were no differences in resting membrane potential and action potential amplitude (APA) measured in myocytes isolated from sham-sedentary (Sed), MI-Sed, and MI-HIST groups. Times required for repolarization to 50 and 90% APA were significantly (P < 0.001) prolonged in MI-Sed myocytes. HIST reduced times required for repolarization to 50 and 90% APA to values observed in Sham-Sed myocytes. The fast and slow components of I(to) were significantly (P < 0.0001) reduced in MI-Sed myocytes. HIST significantly (P < 0.001) enhanced the fast and slow components of I(to) in MI myocytes, although not to levels observed in Sham-Sed myocytes. There were no significant differences in steady-state I(to) inactivation and activation parameters among Sham-Sed, MI-Sed, and MI-HIST myocytes. Likewise, recovery from time-dependent inactivation was also similar among the three groups. We suggest that normalization of APD after MI by HIST may be mediated by restoration of I(to) toward normal levels.     

Effect of simulated I(to) on guinea pig and canine ventricular action potential morphology

The transient outward current (I(to)) is a major repolarizing current in the heart. Marked reduction of I(to) density occurs in heart failure and is accompanied by significant action potential duration (APD) prolongation. To understand the species-dependent role of I(to) in regulating the ventricular action potential morphology and duration, we introduced simulated I(to) conductance in guinea pig and canine endocardial ventricular myocytes using the dynamic clamp technique and perforated patch-clamp recordings. The effects of simulated I(to) in both types of cells were complex and biphasic, separated by a clear density threshold of approximately 40 pA/pF. Below this threshold, simulated I(to) resulted in a distinct phase 1 notch and had little effect on or moderately prolonged the APD. I(to) above the threshold resulted in all-or-none repolarization and precipitously reduced the APD. Qualitatively, these results agreed with our previous studies in canine ventricular cells using whole cell recordings. We conclude that 1) contrary to previous gene transfer studies involving the Kv4.3 current, the response of guinea pig ventricular myocytes to a fully inactivating I(to) is similar to that of canine ventricular cells and 2) in animals such as dogs that have a broad cardiac action potential, I(to) does not play a major role in setting the APD.     

Aging-associated changes in whole cell K(+) and L-type Ca(2+) currents in rat ventricular myocytes

The effect of aging on cardiac membrane currents remains unclear. This study examined the inward rectifier K(+) current (I(K1)), the transient outward K(+) current (I(to)), and the L-type Ca(2+) channel current (I(Ca,L)) in ventricular myocytes isolated from young adult (6 mo) and aged (>27 mo) Fischer 344 rats using whole cell patch-clamp techniques. Along with an increase in the cell size and membrane capacitance, aged myocytes had the same magnitude of peak I(K1) with a greater slope conductance but displayed smaller steady-state I(K1). Aged myocytes also had a greater I(to) with an increased rate of activation, but the I(to) inactivation kinetics, steady-state inactivation, and responsiveness to L-phenylephrine, an alpha(1)-adrenergic agonist, were unaltered. The magnitude of peak I(Ca,L) in aged myocytes was decreased and accompanied by a slower inactivation, but the I(Ca,L) steady-state inactivation was unaltered. Action potential duration in aged myocytes was prolonged only at 90% of full repolarization (APD(90)) when compared with the action potential duration of young adult myocytes. Aged myocytes from Long-Evans rats showed similar changes in I(to) and I(Ca,L) but an increased I(K1). These results demonstrate aging-associated changes in action potential, in morphology, and in I(K1), I(to), and I(Ca,L) of rat ventricular myocytes that possibly contribute to the decreased cardiac function of aged hearts.     

Existence of a transient outward K(+) current in guinea pig cardiac myocytes

A novel transient outward K(+) current that exhibits inward-going rectification (I(to.ir)) was identified in guinea pig atrial and ventricular myocytes. I(to.ir) was insensitive to 4-aminopyridine (4-AP) but was blocked by 200 micromol/l Ba(2+) or removal of external K(+). The zero current potential shifted 51-53 mV/decade change in external K(+). I(to.ir) density was twofold greater in ventricular than in atrial myocytes, and biexponential inactivation occurs in both types of myocytes. At -20 mV, the fast inactivation time constants were 7.7 +/- 1.8 and 6.1 +/- 1.2 ms and the slow inactivation time constants were 85.1 +/- 14.8 and 77.3 +/- 10.4 ms in ventricular and atrial cells, respectively. The midpoints for steady-state inactivation were -36.4 +/- 0.3 and -51.6 +/- 0.4 mV, and recovery from inactivation was rapid near the resting potential (time constants = 7.9 +/- 1.9 and 8.8 +/- 2.1 ms, respectively). I(to.ir) was detected in Na(+)-containing and Na(+)-free solutions and was not blocked by 20 nmol/l saxitoxin. Action potential clamp revealed that I(to.ir) contributed an outward current that activated rapidly on depolarization and inactivated by early phase 2 in both tissues. Although it is well known that 4-AP-sensitive transient outward current is absent in guinea pig, this Ba(2+)-sensitive and 4-AP-insensitive K(+) current has been overlooked.     

兔心室肌细胞电生理异质性研究--缺血对动作电位和钾流的影响

实验用全细胞膜片箝技术,观察正常及缺血条件下,兔心内膜下心室肌细胞与心外膜下心室肌细胞的动作电位和稳态外向钾流及其变化。结果显示：（１）正常条件下,心外膜下心室肌细胞与心内膜下心室肌细胞动作电位形态有差异,心外膜下心室肌细胞动作电位时程（ＡＰＤ）较短,复极１期后有明显的初迹,动作电位形态是“锋和圆顶”,而心内膜下心室肌细胞ＡＰＤ较长,并且没有上述动作电位形态特征。这两类细胞静息电位无差异。（２）在     

氧自由基致豚鼠心室肌细胞跨膜电位变化的离子电流基础

目的：旨在提示氧自由基参与缺血／再灌注性心委失常发生的离子电流基础。方法：采用膜片钳全细胞式记录技术,观察Ｈ２Ｏ２（１ｍｍｏｌ／Ｌ）对豚鼠心室肌细胞跨膜电位和相关离子电流的影响。结果：Ｈ２Ｏ２使豚鼠心肌单细胞的静息电位（ＲＰ）降低,动作电位时程（ＡＳＤ）显著缩短,对动作电位幅度（ＡＰＡ）和超射（ＯＳ）及钠电流的峰值（ＩＮａ）均无明显影响;明显抑制内向整流钾电流（ＩＫ１）,尤其在超极化时;增强延迟外     

Modulation of membrane potential by an acetylcholine-activated potassium current in trout atrial myocytes

Application of the current-clamp technique in rainbow trout atrial myocytes has yielded resting membrane potentials that are incompatible with normal atrial function. To investigate this paradox, we recorded the whole membrane current (I(m)) and compared membrane potentials recorded in isolated cardiac myocytes and multicellular preparations. Atrial tissue and ventricular myocytes had stable resting potentials of -87 +/- 2 mV and -83.9 +/- 0.4 mV, respectively. In contrast, 50 out of 59 atrial myocytes had unstable depolarized membrane potentials that were sensitive to the holding current. We hypothesized that this is at least partly due to a small slope conductance of I(m) around the resting membrane potential in atrial myocytes. In accordance with this hypothesis, the slope conductance of I(m) was about sevenfold smaller in atrial than in ventricular myocytes. Interestingly, ACh increased I(m) at -120 mV from 4.3 pA/pF to 27 pA/pF with an EC(50) of 45 nM in atrial myocytes. Moreover, 3 nM ACh increased the slope conductance of I(m) fourfold, shifted its reversal potential from -78 +/- 3 to -84 +/- 3 mV, and stabilized the resting membrane potential at -92 +/- 4 mV. ACh also shortened the action potential in both atrial myocytes and tissue, and this effect was antagonized by atropine. When applied alone, atropine prolonged the action potential in atrial tissue but had no effect on membrane potential, action potential, or I(m) in isolated atrial myocytes. This suggests that ACh-mediated activation of an inwardly rectifying K(+) current can modulate the membrane potential in the trout atrial myocytes and stabilize the resting membrane potential.     

Involvement of veratridine-induced increase of reverse Na(+)/Ca(2+) exchange current in intracellular Ca(2+) overload and extension of action potential duration in rabbit ventricular myocytes

The objectives of this study were to investigate the effects of veratridine (VER) on persistent sodium current (I(Na.P)), Na(+)/Ca(2+) exchange current (I(NCX)), calcium transients and the action potential (AP) in rabbit ventricular myocytes, and to explore the mechanism in intracellular calcium overload and myocardial contraction enhancement by using whole-cell patch clamp recording technique, visual motion edge detection system, intracellular calcium measurement system and multi-channel physiological signal acquisition and processing system. The results showed that I(Na.P) and reverse I(NCX) in ventricular myocytes were obviously increased after giving 10, 20 μmol/L VER, with the current density of I(Na.P) increasing from (-0.22 ± 0.12) to (-0.61 ± 0.13) and (-2.15 ± 0.14) pA/pF (P < 0.01, n = 10) at -20 mV, and that of reverse I(NCX) increasing from (1.62 ± 0.12) to (2.19 ± 0.09) and (2.58 ± 0.11) pA/pF (P < 0.05, n = 10) at +50 mV. After adding 4 μmol/L tetrodotoxin (TTX), current density of I(Na.P) and reverse I(NCX) returned to (-0.07 ± 0.14) and (1.69 ± 0.15) pA/pF (P < 0.05, n = 10). Another specific blocker of I(Na.P), ranolazine (RAN), could obviously inhibit VER-increased I(Na.P) and reverse I(NCX). After giving 2.5 μmol/L VER, the maximal contraction rate of ventricular myocytes increased from (-0.91 ± 0.29) to (-1.53 ± 0.29) μm/s (P < 0.01, n = 7), the amplitude of contraction increased from (0.10 ± 0.04) to (0.16 ± 0.04) μm (P < 0.05, n = 7), and the baseline of calcium transients (diastolic calcium concentration) increased from (1.21 ± 0.08) to (1.37 ± 0.12) (P < 0.05, n = 7). After adding 2 μmol/L TTX, the maximal contraction rate and amplitude of ventricular myocytes decreased to (-0.86 ± 0.24) μm/s and (0.09 ± 0.03) μm (P < 0.01, n = 7) respectively. And the baseline of calcium transients reduced to (1.17 ± 0.09) (P < 0.05, n = 7). VER (20 μmol/L) could extend action potential duration at 50% repolarization (APD(50)) and at 90% repolarization (APD(90)) in ventricular myocytes from (123.18 ± 23.70) to (271.90 ± 32.81) and from (146.94 ± 24.15) to (429.79 ± 32.04) ms (P < 0.01, n = 6) respectively. Early afterdepolarizations (EADs) appeared in 3 out of the 6 cases. After adding 4 μmol/L TTX, APD(50) and APD(90) were reduced to (99.07 ± 22.81) and (163.84 ± 26.06) ms (P < 0.01, n = 6) respectively, and EADs disappeared accordingly in 3 cases. It could be suggested that: (1) As a specific agonist of the I(Na.P), VER could result in I(Na.P) increase and intracellular Na(+) overload, and subsequently intracellular Ca(2+) overload with the increase of reverse I(NCX). (2) The VER-increased I(Na.P) could further extend the action potential duration (APD) and induce EADs. (3) TTX could restrain the abnormal VER-induced changes of the above-mentioned indexes, indicating that these abnormal changes were caused by the increase of I(Na.P). Based on this study, it is concluded that as the I(Na.P) agonist, VER can enhance reverse I(NCX) by increasing I(Na.P), leading to intracellular Ca(2+) overload and APD abnormal extension.     

铬对大鼠心电图及心肌细胞的电生理影响

应用心电图及细胞内微电极技术观察铬对心肌电生理的影响。大鼠腹腔内注射铬,９周后心电图显示各剂量组ＱＴ间期均缩短,细胞内微电极检查显示动作电位时程（ＡＰＤ５０、ＡＰＤ９０）于２周后随剂量增加而逐渐缩短,０．４ｍｇ组显著缩短,９周后各剂量组ＡＰＤ５０、ＡＰＤ９０均缩短。心率、静息电位（ＲＰ）与动作电位（ＡＰＡ）幅度及动作电位最大上升速率（Ｖｍａｘ）无变化。铬影响了心肌复极引起ＱＴ间期缩短,而ＡＰＤ５０、ＡＰＤ９０缩短可能是铬影响了钙内流及钾外流的结果。     

DITPA restores the repolarizing potassium currents Itof and Iss in cardiac ventricular myocytes of diabetic rats

Diabetes Mellitus (DM) can produce an increase in the cardiac action potential duration and QT interval that can be associated with sudden death. These cardiac effects are due to a region-specific decrease in repolarizing outward K(+) currents. Some authors have suggested that the proarrhythmic effects of diabetes can be due to diabetes-induced hypothyroidism. Thus, we have examined the effect of the thyroid hormone analog diiodothyropropionic acid (DITPA) on calcium-independent outward potassium currents in ventricular myocytes from diabetic rats. Sustained (I(ss)) and fast transient outward (I(tof)) K(+) currents were recorded using the whole-cell configuration of the patch-clamp technique. Myocytes were enzymatically isolated from the free wall of the right ventricle, and the epicardial and endocardial layers of the left ventricle of healthy, diabetic and DITPA-treated diabetic rats. Circulating thyroid hormones were measured by electrochemiluminescence. DITPA-treatment of diabetic rats restored I(tof) and I(ss) current densities in cardiac myocytes from the three regions studied, but did not alter current densities in myocytes of control rats. T(3) and T(4) levels were reduced by diabetes, and DITPA-treatment increased circulating T(3) levels. T(3)-treatment of diabetic rats also restored current densities to control values. However, direct incubation of diabetic myocytes with DITPA did not restore current densities. In summary, DITPA-treatment of diabetic rats restored the potassium current (I(tof) and I(ss)) densities in myocytes from all ventricular regions.     

Heterogeneous ventricular chamber response to hypokalemia and inward rectifier potassium channel blockade underlies bifurcated T wave in guinea pig

It was previously demonstrated that transmural electrophysiological heterogeneities can inscribe the ECG T wave. However, the bifurcated T wave caused by loss of inward rectifier potassium current (I(K1)) function is not fully explained by transmural heterogeneities. Since right ventricular (RV) guinea pig myocytes have significantly lower I(K1) than left ventricular (LV) myocytes, we hypothesized that the complex ECG can be inscribed by heterogeneous chamber-specific responses to hypokalemia and partial I(K1) blockade. Ratiometric optical action potentials were recorded from the epicardial surface of the RV and LV. BaCl(2) (10 micromol/l) was perfused to partially block I(K1) in isolated guinea pig whole heart preparations. BaCl(2) or hypokalemia alone significantly increased RV basal (RV(B)) action potential duration (APD) by approximately 30% above control compared with LV apical (LV(A)) APD (14%, P<0.05). In the presence of BaCl(2), 2 mmol/l extracellular potassium (hypokalemia) further increased RV(B) APD to a greater extent (31%) than LV(A) APD (19%, P<0.05) compared with BaCl(2) perfusion alone. Maximal dispersion between RV(B) and LV(A) APD increased by 105% (P<0.05), and the QT interval prolonged by 55% (P<0.05) during hypokalemia and BaCl(2). Hypokalemia and BaCl(2) produced an ECG with a double repolarization wave. The first wave (QT1) corresponded to selective depression of apical LV plateau potentials, while the second wave (QT2) corresponded to the latest repolarizing RV(B) myocytes. These data suggest that final repolarization is more sensitive to extracellular potassium changes in regions with reduced I(K1), particularly when I(K1) availability is reduced. Furthermore, underlying I(K1) heterogeneities can potentially contribute to the complex ECG during I(K1) loss of function and hypokalemia.