α_1、β肾上腺素受体调控快激活延迟整流钾电流的机制
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摘要
背景室性心律失常往往继发于运动和情绪激动等交感神经兴奋的情况下,循环及组织局部儿茶酚胺浓度的增高改变了心肌细胞离子通道的特性,是导致恶性室性心律失常发生的重要原因。心肌细胞膜上分布着大量离子通道,作为参与心肌细胞动作电位的主要电流,快激活延迟整流钾电流I__kr是心肌细胞复极化的主要电流,它的抑制可使动作电位时程延长。编码人类快激活延迟整流钾电流α亚单位的基因为hERG基因,该通道的基因突变导致的I__kr电流减少是遗传性长QT综合征-2(LQTS-2)的发病因素。另外,hERG基因是临床广泛应用的I__I__I__类抗心律失常药物的作用靶点之一。许多抗心律失常药物及非抗心律失常药物对hERG通道的过度抑制是获得性长QT综合征的主要发病机制。由运动或情绪激动引起的交感神经兴奋激活心肌细胞的α和β肾上腺素受体。目前至少有9种肾上腺素受体已被明确:α1A、α1B、α1D、α2A、α2B、α2C、β1、β2及β3。人类心肌细胞上主要为α1及β肾上腺素受体,近期研究表明α1和β肾上腺素受体激活后可调控hERG/I__kr电流的大小,但α1及β肾上腺素受体通过何种亚型调控hERG/I__kr电流以及确切的调控机制尚需进一步的研究来阐明。
目的采用全细胞膜片钳技术研究α1和β肾上腺素受体及其亚型对豚鼠心室肌细胞快激活延迟整流钾电流的调控及可能的机制,探讨应激触发室性心律失常发生的机制。
内容与方法
1.成年豚鼠心室肌细胞的分离:雄性豚鼠,体重250-300g,采用Langendorff灌流装置逆行灌流心脏,酶解分离出单个心室肌细胞。
2.豚鼠心室肌细胞快激活延迟整流钾电流(I__kkr)的记录:分离出的细胞悬液置于细胞池中,采用全细胞方式膜片钳技术记录豚鼠心室肌细胞的快激活延迟整流钾电流。膜片钳参数为:钳制电压-40mv,预刺激从-40mv至+40mv,脉宽200ms,刺激从相应电压降至-40mv,脉宽600ms,记录I__kr尾电流。
3.α1肾上腺素受体激活对豚鼠心室肌细胞I__kkr电流的调控:
3.1.α1肾上腺素受体激活对I__kkr电流的影响:持续灌流含有选择性α1肾上腺素受体激动剂苯肾上腺素(0.0001μmol/L-100μmol/L)的细胞外液,记录苯肾上腺素灌流前后的I__kr电流。分别由灌流系统持续灌流含有哌唑嗪(α1肾上腺素受体阻断剂)或5-甲基乌拉地尔(α1A肾上腺素受体阻断剂)或chlorethylclonidine(α1B肾上腺素受体阻断剂)或BMY7378(α1D肾上腺素受体阻断剂)的细胞外液;再给予苯肾上腺素干预,记录苯肾上腺素灌流前后的I__kr电流。
3.2.蛋白激酶A和蛋白激酶C在α1肾上腺素受体激动剂影响I__kkr电流中的作用:分离出的单个心室肌细胞室温分别与特异性蛋白激酶A(PKA)抑制剂KT5720(2.5μmol/L)或特异性蛋白激酶C(PKC)抑制剂chelerythrine(1μmol/L)共同孵育1小时后灌流含有苯肾上腺素的细胞外液,记录苯肾上腺素灌流前后的I__kr电流。
4.β肾上腺素受体激活对豚鼠心室肌细胞I__kkr电流的调控:
4.1.β肾上腺素受体激活对I__kkr电流的影响:持续灌流含有非选择性β肾上腺素受体激动剂异丙肾上腺素(0.001μmol/L-100μmol/L)的细胞外液,记录异丙肾上腺素灌流前后的I__kr电流。分别由灌流系统持续灌流含有普萘洛尔(β肾上腺素受体阻断剂)或CGP20712A(β1肾上腺素受体阻断剂)或I__CI__118551(β2肾上腺素受体阻断剂)的细胞外液;再给予异丙肾上腺素干预,记录异丙肾上腺素灌流前后的I__kr电流。
4.2.β1肾上腺素受体激动剂对I__kkr电流的影响:持续灌流含有选择性β1肾上腺素受体激动剂扎莫特罗(0.01μmol/L-100μmol/L)的细胞外液,记录扎莫特罗灌流前后的I__kr电流。
4.3.蛋白激酶A、蛋白激酶C、磷脂酶C和钙/钙调蛋白依赖性蛋白激酶在β1肾上腺素受体激动剂影响I__kkr电流中的作用:分离出的单个心室肌细胞分别用特异性PKA抑制剂KT5720(2.5μmol/L)或特异性PKC抑制剂chelerythrine(1μmol/L)或特异性PLC抑制剂U73122(100nmmol/L)孵育1小时或特异性CaMKI__I__抑制剂KN93(10μmol/L)孵育30小时,灌流含有扎莫特罗的细胞外液,记录扎莫特罗灌流前后的I__kr电流。
5.α1和β肾上腺素受体在调控I__kr电流中的交互作用
5.1.急性激活α1肾上腺素受体对β肾上腺素受体激动剂调控I__kkr电流的影响:先灌流含有苯肾上腺素的细胞外液10min,记录苯肾上腺素灌流前后的I__kr电流;再灌流含有异丙肾上腺素的细胞外液10min,记录异丙肾上腺素作用后的I__kr电流。
5.2.急性激活β肾上腺素受体对α1肾上腺素受体激动剂调控I__kkr电流的影响:先灌流含有异丙肾上腺素的细胞外液10min,记录异丙肾上腺素灌流前后的I__kr电流。再灌流含有苯肾上腺素的细胞外液10min,记录苯肾上腺素作用后的I__kr电流。
结果
1.豚鼠心室肌细胞I__kkr电流的记录:用全细胞膜片钳技术可记录到豚鼠心室肌细胞的I__kr尾电流,该电流可被1μmol/L的多非立特完全阻断。I__kr电流受温度影响,当灌流槽温度由22℃逐渐升高至37℃,I__kr电流亦逐渐增大。当预刺激电压为+40mV时,I__kr电流电流密度由22℃时的0.28±0.07pA/pC增加到37℃时的0.62±0.07pA/pC。
2.α1肾上腺素受体激活对豚鼠心室肌细胞I__kkr电流的调控:
2.1.α1肾上腺素受体及其亚型对豚鼠心室肌细胞I__kr电流的影响:选择性α1上腺素对I__kr电流的减低作用;而β2肾上腺素受体阻断剂I__CI__118551不能减弱异丙肾上腺素对I__kr电流的减低作用。
3.2.β1肾上腺素受体对豚鼠心室肌细胞I__kkr电流的影响:选择性β1肾上腺素受体激动剂扎莫特罗也可剂量依赖性地降低I__kr电流。依次灌流含0.01、0.1、1、10、100μmol/L的扎莫特罗可使I__kr电流降为原来的基础电流大小的0.96±0.12、0.85±0.13、0.67±0.12、0.59±0.10、0.55±0.11。开始即灌流10μmol/L扎莫特罗可使I__kr电流减低到基础电流大小的0.56±0.04。
3.3.蛋白激酶A、磷脂酶C/蛋白激酶C和钙/钙调蛋白依赖性蛋白激酶在β1肾上腺素受体激动剂影响I__kkr电流中的作用:(1)正常对照组(细胞未用任何蛋白酶抑制剂预处理):10μmol/L扎莫特罗可使I__kr电流减低到原基础电流大小的0.56±0.04。(2)KT5720组(细胞先用特异性PKA抑制剂KT5720预孵育1小时):10μmol/L扎莫特罗能使I__kr电流减低到基础电流大小0.87±0.03,与正常对照组相比有明显统计学差异。(3)U73122组(细胞先用PLC抑制剂U73122预孵育1小时):10μmol/L扎莫特罗能使I__kr电流减低到基础电流大小的0.91±0.07,与正常对照组相比有明显统计学差异。(4)Chelerythrine组(细胞先用特异性PKC抑制剂chelerythrine预孵育1小时):10μmol/L扎莫特罗仅能使I__kr电流减低到基础电流大小的0.71±0.01,与正常对照组相比有明显统计学差异。(5)KN93组(细胞用特异性CaMKI__I__抑制剂KN93预孵育30分钟):10μmol/L扎莫特罗仍能使I__kr电流减低到原电流大小的0.68±0.07,与正常对照组相比相比无统计学差异。
4.α1和β肾上腺素受体在调控豚鼠心室肌细胞I__kkr电流中的交互作用:
4.1.急性激活α1肾上腺素受体对β肾上腺素受体激动剂调控I__kkr电流的影响:若细胞未先加用α1肾上腺素受体激动剂苯肾上腺素,β肾上腺素受体激动剂异丙肾上腺素能使I__kr电流降为基础电流大小的0.55±0.06。若细胞先加用苯肾上腺素,异丙肾上腺素则不能降低I__kr电流的大小,提示α1肾上上腺素对I_kr电流的减低作用;而β2肾上腺素受体阻断剂I_CI_118551不能减弱异丙肾上腺素对I_kr电流的减低作用。
3.2.β1肾上腺素受体对豚鼠心室肌细胞I_kkr电流的影响:选择性β1肾上腺素受体激动剂扎莫特罗也可剂量依赖性地降低I_kr电流。依次灌流含0.01、0.1、1、10、100μmol/L的扎莫特罗可使I_kr电流降为原来的基础电流大小的0.96±0.12、0.85±0.13、0.67±0.12、0.59±0.10、0.55±0.11。开始即灌流10μmol/L扎莫特罗可使I_kr电流减低到基础电流大小的0.56±0.04。
3.3.蛋白激酶A、磷脂酶C/蛋白激酶C和钙/钙调蛋白依赖性蛋白激酶在β1肾上腺素受体激动剂影响I_kkr电流中的作用:(1)正常对照组(细胞未用任何蛋白酶抑制剂预处理):10μmol/L扎莫特罗可使I_kr电流减低到原基础电流大小的0.56±0.04。(2)KT5720组(细胞先用特异性PKA抑制剂KT5720预孵育1小时):10μmol/L扎莫特罗能使I_kr电流减低到基础电流大小0.87±0.03,与正常对照组相比有明显统计学差异。(3)U73122组(细胞先用PLC抑制剂U73122预孵育1小时):10μmol/L扎莫特罗能使I_kr电流减低到基础电流大小的0.91±0.07,与正常对照组相比有明显统计学差异。(4)Chelerythrine组(细胞先用特异性PKC抑制剂chelerythrine预孵育1小时):10μmol/L扎莫特罗仅能使I_kr电流减低到基础电流大小的0.71±0.01,与正常对照组相比有明显统计学差异。(5)KN93组(细胞用特异性CaMKI_I_抑制剂KN93预孵育30分钟):10μmol/L扎莫特罗仍能使I_kr电流减低到原电流大小的0.68±0.07,与正常对照组相比相比无统计学差异。
4.α1和β肾上腺素受体在调控豚鼠心室肌细胞I_kkr电流中的交互作用:
4.1.急性激活α1肾上腺素受体对β肾上腺素受体激动剂调控I_kkr电流的影响:若细胞未先加用α1肾上腺素受体激动剂苯肾上腺素,β肾上腺素受体激动剂异丙肾上腺素能使I_kr电流降为基础电流大小的0.55±0.06。若细胞先加用苯肾上腺素,异丙肾上腺素则不能降低I_kr电流的大小,提示α1肾上腺素受体激活可抑制β肾上腺素受体激活对I_kr电流的降低作用。4.2.急性激活β肾上腺素受体对α1肾上腺素受体激动剂调控I_kkr电流的影响:细胞若未预先加用β肾上腺素受体激动剂异丙肾上腺素,α1肾上腺素受体激动剂苯肾上腺素能使I_kr电流降为基础电流大小的0.58±0.04。若细胞先加用了异丙肾上腺素,苯肾上腺素能使I_kr电流降为基础电流大小的0.80±0.02,提示β肾上腺素受体激活可减弱α1肾上腺素受体激活对I_kr电流的降低作用。
结论
1.α1肾上腺素受体激活可浓度依赖性地减弱豚鼠心肌细胞的I_kr电流,此作用主要通过α1A肾上腺素受体介导。
2.特异性PKA和PKC抑制剂均可减弱苯肾上腺素对I_kr电流的降低作用,提示α1A受体激活对I_kr电流的调控依赖于PKA以及PKC的激活。
3.β肾上腺素受体激活可剂量依赖性地减弱豚鼠心肌细胞的I_kr电流,此作用主要通过β1肾上腺素受体介导。
4.β1肾上腺素受体的瞬时激活对I_kr电流的调控作用依赖于PKA、PLC以及PKC的激活,而与CaMKI_I_的激活无关。
5.α1肾上腺素受体激活可抑制β肾上腺素受体激活对I_kr电流的降低作用,β肾上腺素受体激活亦可减弱α1肾上腺素受体激活对I_kr电流的降低作用;提示α1和β肾上腺素受体在对I_kr电流的调控上可能存在交互作用。
Background Ventricular arrhythmias are often precipitated by physical oremotional stress. An increased release of the endogenous catecholamines changes thecharacteristics of ionic currents in the cardiomyocytes, which is an important reasonfor ventricular arrhythmia. There are many ionic currents in the cardiomyocytemembrane. The rapid component of the delayed rectifier potassium current, Ikr, is themajor outward current involved in ventricular repolarization and inhibiton of Ikr maylead to action potential duration prolongation. The human ether-a-go-go-related gene(hERG) encodes the voltage-gated potassium channelα-subunit underlying Ikr.Reduction of hERG currents due to mutations in hERG produces congenital long QTsyndrome (LQTS-2). On the other hand, hERG channels are a primary target for thepharmacological management of cardiac arrhythmias with class III antiarrhythmicagents. Excessive blockade of hERG channels by antiarrhythmic or nonantiarrhythmicdrugs may lead to acquired long QT syndrome (aLQTS). Stimulationof the sympathetic nervous system (SNS) in response to exercise or emotional stresscauses stimulation of adrenergic receptors. At least nine adrenoceptor subtypes havebeen identified:α1A,α1B,α1D,α2A,α2B,α2C,β1,β2 andβ3. In human heart, the mainlypresence of adrenoceptor subtypes areα1 andβadrenoceptors. Recent investigationsrevealed that the rapid component of the delayed rectifier potassium current may beinhibited by eitherα1 orβadrenergic stimulation. However, the effects of adrenergicreceptor subtypes on the Ikr and the underlying mechanisms need further study.
Objectives 1. Whole-cell patch clamp techniques were used to investigate the regulation of Ikr in guinea pig cardiomyocytes byα1 andβadrenergic receptor andtheir subtypes. 2. Their underlying signal pathway involved in Ikr were studied,which may help us to study the mechanism that stress induced ventriculararrhythmias.
MaterialMaterials and Methods
1. Myocyte isolation: Single ventricular myocytes were isolated from male guineapig（weighted 250-300g）hearts using a standard enzymatic technique withLangendorff perfusion.
2. Patch clamp recording of Ikr tail currents in guinea pig ventricular myocytes:Isolated ventriular myocytes were placed in experimental chammber and wholecellpatch clamp recording technique was used to record Ikr. Ikr was elicited usingthe following test pulse protocol: after a holding potential of ?40 mV, test pulseswere applied at various voltages from ?40mV to +40mV (step width 20 mV, stepduration 200 ms) before returning to ?40mV for tail current recording.
3. Regulation of Ikr currents byα1-adrenergic stimulation.
3.1.α1-adrenergic effects on Ikr currents: Ikr currents were recorded before andafter application of specificα1-adrenergic receptor agonist phenylephrine(0.0001μmol/L－100μmol/L). The ventricular myocytes were applicatedprazosin (α1-adrenergic antagonist), 5-MU (α1A-adrenergic antagonist),chloroethylclonidine (α1B-adrenergic antagonist) or BMY7378 (α1Dadrenergicantagonist) respectively before phenylephrine application and Ikrcurrents were recorded before and after application of phenylephrine.
3.2. Role of protein kinase A (PKA) and protein kinase C (PKC) inα1-adrenergic effects on Ikr currents: The ventricular myocytes werepretreated with specific PKA inhibitor (KT5720, 2.5μmol/L) or specific PKC inhibitor (chelerythrine, 1μmol/L) for 1 hour. Then Ikr currents wererecorded before and after application of phenylephrine.
4. Regulation of Ikr currents byβ-adrenergic stimulation.
4.1.β-adrenergic effects on Ikr currents: Ikr currents were recorded before andafter application of unspecificβ-adrenergic receptor agonist isoproterenol(0.001μmol/L－100μmol/L). The ventricular myocytes were applicatedpropranolol (β-adrenergic antagonist), CGP20712A (β1-adrenergicantagonist) or ICI118551 (β2-adrenergic antagonist) before isoproterenolapplication and Ikr currents were recorded before and after application ofisoproterenol.
4.2.β1-adrenergic effects on Ikr currents: Ikr currents were recorded before andafter application of specificβ1-adrenergic receptor agonist xamotorol (0.01μmol/L－100μmol/L).
4.3. Role of protein kinase A (PKA), phospholipase C (PLC) protein kinase C(PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII) inβ1-adrenergic effects on Ikr currents: Cardiomyocytes were pretreated withspecific PKA inhibitor (KT5720, 2.5μmol/L), specific PLC inhibitior(U73122, 100nmol/L), specific PKC inhibitor (chelerythrine, 1μmol/L) for1 hour respectively, or specific CaMKII inbitor KN93 (10μmol/L) for 30minutes. Then, Ikr currents were recorded before and after application ofβ1-adrenergic receptor agonist xamotorol.
5. Cross talk betweenα1 andβadrenergic effects on Ikr currents.
5.1. Effects of isoproterenol on Ikr in the presence of phenylephrine: Theventricular myocytes were application of phenylephrine for 10 min beforeapplication of isoproterenol. Ikr currents were recorded before and afterapplication of phenylephrine and after application of isoproterenol.
5.2. EffectEffects of phenylephrine on Ikr in the presence of isoproterenol: Theventricular myocytes were application of isoproterenol for 10 min beforeapplication of phenylephrine. Ikr currents were recorded before and afterapplication of isoproterenol and after application of phenylephrine.
Results
1. Patch clamp recording of Ikr tail currents in guinea pig ventricular myocytes: Ikrtail current of guinea pig ventricular myocyte was recorded using whole cell patchclamp and it can be completely blocked by 1μmol/L dofetilide. Ikr tail currents aremarkedly sensitive to temperature changes. The Ikr tail current density at +40 mVincreased from 0.28±0.07 pA/pC at 22°C to 0.62±0.07 pA/pC at 37°C.
2. Regulation of Ikr currents byα1-adrenergic stimulation.
2.1.α1-adrenergic effects on Ikr currents: The dose-dependent effect ofphenylephrine, anα1-adrenoreceptor agonist, on Ikr was examined infreshly isolated guinea pig ventricular myocytes. The amplitude of Ikr wasreduced to 0.67±0.03 in response to 0.1μmol/L phenylephrine. This effect wasblocked by theα-adrenoreceptor antagonist prazosin and the selectiveα1Aadrenoreceptorantagonist 5-MU, but not by theα1B-adrenoreceptor antagonistchlorethylclonidine or theα1D-adrenoreceptor antagonist BMY7378.
2.2. Role of protein kinase A (PKA) and protein kinase C (PKC) inα1-adrenergic effects on Ikr currents: When cardiomyocytes were pretreatedwith chelerythrine or KT5720 for 1 hour, the amplitude of Ikr was reduced to0.98±0.02 and 0.77±0.03 respectively in response to 0.1μmol/L phenylephrine.By comparison, phenylephrine elicited a reduction to 0.67±0.03 on Ikr in theabsence of chelerythrine and KT5720.
3. Regulation of Ikr currents byβ-adrenergic stimulation.
3.1.β-adrenergi-adrenergic effects on Ikr currents: The dose-dependent effect ofisoproterenol, a nonspecificβ-adrenoreceptor agonist, on Ikr was alsoexamined in freshly isolated guinea pig ventricular myocytes. The amplitudeof Ikr was reduced to 0.62±0.03 in response to 10μmol/L isoproterenol. Thiseffect was blocked by theβ-adrenoreceptor antagonist propranolol and theselectiveβ1-adrenoreceptor antagonist CGP20712A, but not by theβ2-adrenoreceptor antagonist ICI118551.
3.2.β1-adrenergic effects on Ikr currents: Stimulation ofβ1-adrenergic receptorsusing xamotorol also reduced Ikr current in a dose-dependent manner. 10μmol/L xamotorol decreased Ikr current to 0.56±0.04.
3.3. Role of protein kinase A (PKA), phospholipase C (PLC) protein kinase C(PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII) inβ1-adrenergic effects on Ikr currents: When xamotorol was combined withKT5720 (2.5μmol/L), a specific inhibitor of PKA, the inhibitory effect wasdrastically reduced. The amplitude of Ikr relative current was reduced to0.87±0.03, it was significantly different from xamotorol elicited a reductionto 0.56±0.04 on Ikr in absence of KT5720. When cardiomyocytes were pretreatedwith PLC inhibitor, U73122 (100 nmol/L) or a general PKC inhibitor,chelerythrine (1μmol/L) for 1 hour prior to the recording the xamotoroleffect on Ikr. Xamotorol inhibited Ikr to 0.91±0.07 or 0.71±0.01, respectivelyin the presence of U73122 or chelerythrine. They were both significantlydifferent from xamotorol elicited a reduction to 0.56±0.04 on Ikr in theabsence of chelerythrine and U73122. When cardiomyocytes were pretreatedwith KN93 (10μmol/L for 30 minutes), a synthetic CaMKIIinhibitor, the inhibitory effect of xamotorol on Ikr was unaffected by KN93,xamotorol inhibited Ikr to 0.68±0.07 compared to 0.56±0.04 without KN93.
4. Cross talk betweenα1 andβadrenergic effects on Ikr currents.
4.1. Effects of isoproterenol on Ikr in the presence of phenylephrine: Whencardiomyocytes were firstly acute stimulated by phenylephrine, anα1-adrenoreceptor agonist, the Ikr tail currents were not decreased byisoproterenol, aβ-adrenoreceptor agonist. In an other word, isoproterenol cannot reduce Ikr tail currents in cardiomyocytes pretreated with phenylephrinebefore. It was significantly different from the cardiomyocytes not firstly acutestimulated by phenylephrine group.
4.2. Effects of phenylephrine on Ikr in the presence of isoproterenol: Whencardiomyocytes were firstly acute stimulated by isoproterenol, aβ-adrenoreceptor agonist, the Ikr tail currents were only deceased to 0.80±0.02by phenylephrine, anα1-adrenoreceptor agonist, which was significantlydifferent from the cardiomyocytes not firstly acute stimulated by isoproterenolgroup.
Conclusions
1. Phenylephrine, anα1-adrenoreceptor agonist, can reduce Ikr current in a dosedependentmanner. This effect is mediated by theα1A-adrenoreceptor subtyperather than otherα1-adrenoreceptor subtypes.
2. When cardiomyocytes were pre-treated with chelerythrine or KT5720 for 1 hour,both chelerythrine and KT5720 drastically reduced the phenylephrine-inducedeffects, indicating possible involvement of PKC and PKA in theα1-adrenergicinhibition of Ikr.
3. Isoproterenol reduced Ikr current in a dose-dependent manner. This effect ismediated byβ1-adrenoreceptor subtype rather than otherβ2-adrenoreceptorsubtype.
4. When xamotorol was combined with KT5720, a specific inhibitor of PKA, theinhibitory effect was drastically reduced. Both Chelerythrine, a specific inhibitorof PKC, and U73122, a inhibitor of phospholipase C (PLC) inhibited thecurrent decreasing induced by xamotorol. However, KN93, an inhibitorCaMKII, may not attenuate the inhibtory effects of xamotorol on Ikr. Our datasuggest a link between Ikr and theβ1-adrenergic receptor, involving activationPKA , PLC and PKC.
5. Signaling“cross talk”betweenα1- andβ-adrenergic cascades might be involvedin regulation of Ikr tail current in guinea pig ventricular myocyte.
目的采用全细胞膜片钳技术研究α1和β肾上腺素受体及其亚型对豚鼠心室肌细胞快激活延迟整流钾电流的调控及可能的机制,探讨应激触发室性心律失常发生的机制。
内容与方法
1.成年豚鼠心室肌细胞的分离:雄性豚鼠,体重250-300g,采用Langendorff灌流装置逆行灌流心脏,酶解分离出单个心室肌细胞。
2.豚鼠心室肌细胞快激活延迟整流钾电流(I__kkr)的记录:分离出的细胞悬液置于细胞池中,采用全细胞方式膜片钳技术记录豚鼠心室肌细胞的快激活延迟整流钾电流。膜片钳参数为:钳制电压-40mv,预刺激从-40mv至+40mv,脉宽200ms,刺激从相应电压降至-40mv,脉宽600ms,记录I__kr尾电流。
3.α1肾上腺素受体激活对豚鼠心室肌细胞I__kkr电流的调控:
3.1.α1肾上腺素受体激活对I__kkr电流的影响:持续灌流含有选择性α1肾上腺素受体激动剂苯肾上腺素(0.0001μmol/L-100μmol/L)的细胞外液,记录苯肾上腺素灌流前后的I__kr电流。分别由灌流系统持续灌流含有哌唑嗪(α1肾上腺素受体阻断剂)或5-甲基乌拉地尔(α1A肾上腺素受体阻断剂)或chlorethylclonidine(α1B肾上腺素受体阻断剂)或BMY7378(α1D肾上腺素受体阻断剂)的细胞外液;再给予苯肾上腺素干预,记录苯肾上腺素灌流前后的I__kr电流。
3.2.蛋白激酶A和蛋白激酶C在α1肾上腺素受体激动剂影响I__kkr电流中的作用:分离出的单个心室肌细胞室温分别与特异性蛋白激酶A(PKA)抑制剂KT5720(2.5μmol/L)或特异性蛋白激酶C(PKC)抑制剂chelerythrine(1μmol/L)共同孵育1小时后灌流含有苯肾上腺素的细胞外液,记录苯肾上腺素灌流前后的I__kr电流。
4.β肾上腺素受体激活对豚鼠心室肌细胞I__kkr电流的调控:
4.1.β肾上腺素受体激活对I__kkr电流的影响:持续灌流含有非选择性β肾上腺素受体激动剂异丙肾上腺素(0.001μmol/L-100μmol/L)的细胞外液,记录异丙肾上腺素灌流前后的I__kr电流。分别由灌流系统持续灌流含有普萘洛尔(β肾上腺素受体阻断剂)或CGP20712A(β1肾上腺素受体阻断剂)或I__CI__118551(β2肾上腺素受体阻断剂)的细胞外液;再给予异丙肾上腺素干预,记录异丙肾上腺素灌流前后的I__kr电流。
4.2.β1肾上腺素受体激动剂对I__kkr电流的影响:持续灌流含有选择性β1肾上腺素受体激动剂扎莫特罗(0.01μmol/L-100μmol/L)的细胞外液,记录扎莫特罗灌流前后的I__kr电流。
4.3.蛋白激酶A、蛋白激酶C、磷脂酶C和钙/钙调蛋白依赖性蛋白激酶在β1肾上腺素受体激动剂影响I__kkr电流中的作用:分离出的单个心室肌细胞分别用特异性PKA抑制剂KT5720(2.5μmol/L)或特异性PKC抑制剂chelerythrine(1μmol/L)或特异性PLC抑制剂U73122(100nmmol/L)孵育1小时或特异性CaMKI__I__抑制剂KN93(10μmol/L)孵育30小时,灌流含有扎莫特罗的细胞外液,记录扎莫特罗灌流前后的I__kr电流。
5.α1和β肾上腺素受体在调控I__kr电流中的交互作用
5.1.急性激活α1肾上腺素受体对β肾上腺素受体激动剂调控I__kkr电流的影响:先灌流含有苯肾上腺素的细胞外液10min,记录苯肾上腺素灌流前后的I__kr电流;再灌流含有异丙肾上腺素的细胞外液10min,记录异丙肾上腺素作用后的I__kr电流。
5.2.急性激活β肾上腺素受体对α1肾上腺素受体激动剂调控I__kkr电流的影响:先灌流含有异丙肾上腺素的细胞外液10min,记录异丙肾上腺素灌流前后的I__kr电流。再灌流含有苯肾上腺素的细胞外液10min,记录苯肾上腺素作用后的I__kr电流。
结果
1.豚鼠心室肌细胞I__kkr电流的记录:用全细胞膜片钳技术可记录到豚鼠心室肌细胞的I__kr尾电流,该电流可被1μmol/L的多非立特完全阻断。I__kr电流受温度影响,当灌流槽温度由22℃逐渐升高至37℃,I__kr电流亦逐渐增大。当预刺激电压为+40mV时,I__kr电流电流密度由22℃时的0.28±0.07pA/pC增加到37℃时的0.62±0.07pA/pC。
2.α1肾上腺素受体激活对豚鼠心室肌细胞I__kkr电流的调控:
2.1.α1肾上腺素受体及其亚型对豚鼠心室肌细胞I__kr电流的影响:选择性α1上腺素对I__kr电流的减低作用;而β2肾上腺素受体阻断剂I__CI__118551不能减弱异丙肾上腺素对I__kr电流的减低作用。
3.2.β1肾上腺素受体对豚鼠心室肌细胞I__kkr电流的影响:选择性β1肾上腺素受体激动剂扎莫特罗也可剂量依赖性地降低I__kr电流。依次灌流含0.01、0.1、1、10、100μmol/L的扎莫特罗可使I__kr电流降为原来的基础电流大小的0.96±0.12、0.85±0.13、0.67±0.12、0.59±0.10、0.55±0.11。开始即灌流10μmol/L扎莫特罗可使I__kr电流减低到基础电流大小的0.56±0.04。
3.3.蛋白激酶A、磷脂酶C/蛋白激酶C和钙/钙调蛋白依赖性蛋白激酶在β1肾上腺素受体激动剂影响I__kkr电流中的作用:(1)正常对照组(细胞未用任何蛋白酶抑制剂预处理):10μmol/L扎莫特罗可使I__kr电流减低到原基础电流大小的0.56±0.04。(2)KT5720组(细胞先用特异性PKA抑制剂KT5720预孵育1小时):10μmol/L扎莫特罗能使I__kr电流减低到基础电流大小0.87±0.03,与正常对照组相比有明显统计学差异。(3)U73122组(细胞先用PLC抑制剂U73122预孵育1小时):10μmol/L扎莫特罗能使I__kr电流减低到基础电流大小的0.91±0.07,与正常对照组相比有明显统计学差异。(4)Chelerythrine组(细胞先用特异性PKC抑制剂chelerythrine预孵育1小时):10μmol/L扎莫特罗仅能使I__kr电流减低到基础电流大小的0.71±0.01,与正常对照组相比有明显统计学差异。(5)KN93组(细胞用特异性CaMKI__I__抑制剂KN93预孵育30分钟):10μmol/L扎莫特罗仍能使I__kr电流减低到原电流大小的0.68±0.07,与正常对照组相比相比无统计学差异。
4.α1和β肾上腺素受体在调控豚鼠心室肌细胞I__kkr电流中的交互作用:
4.1.急性激活α1肾上腺素受体对β肾上腺素受体激动剂调控I__kkr电流的影响:若细胞未先加用α1肾上腺素受体激动剂苯肾上腺素,β肾上腺素受体激动剂异丙肾上腺素能使I__kr电流降为基础电流大小的0.55±0.06。若细胞先加用苯肾上腺素,异丙肾上腺素则不能降低I__kr电流的大小,提示α1肾上上腺素对I_kr电流的减低作用;而β2肾上腺素受体阻断剂I_CI_118551不能减弱异丙肾上腺素对I_kr电流的减低作用。
3.2.β1肾上腺素受体对豚鼠心室肌细胞I_kkr电流的影响:选择性β1肾上腺素受体激动剂扎莫特罗也可剂量依赖性地降低I_kr电流。依次灌流含0.01、0.1、1、10、100μmol/L的扎莫特罗可使I_kr电流降为原来的基础电流大小的0.96±0.12、0.85±0.13、0.67±0.12、0.59±0.10、0.55±0.11。开始即灌流10μmol/L扎莫特罗可使I_kr电流减低到基础电流大小的0.56±0.04。
3.3.蛋白激酶A、磷脂酶C/蛋白激酶C和钙/钙调蛋白依赖性蛋白激酶在β1肾上腺素受体激动剂影响I_kkr电流中的作用:(1)正常对照组(细胞未用任何蛋白酶抑制剂预处理):10μmol/L扎莫特罗可使I_kr电流减低到原基础电流大小的0.56±0.04。(2)KT5720组(细胞先用特异性PKA抑制剂KT5720预孵育1小时):10μmol/L扎莫特罗能使I_kr电流减低到基础电流大小0.87±0.03,与正常对照组相比有明显统计学差异。(3)U73122组(细胞先用PLC抑制剂U73122预孵育1小时):10μmol/L扎莫特罗能使I_kr电流减低到基础电流大小的0.91±0.07,与正常对照组相比有明显统计学差异。(4)Chelerythrine组(细胞先用特异性PKC抑制剂chelerythrine预孵育1小时):10μmol/L扎莫特罗仅能使I_kr电流减低到基础电流大小的0.71±0.01,与正常对照组相比有明显统计学差异。(5)KN93组(细胞用特异性CaMKI_I_抑制剂KN93预孵育30分钟):10μmol/L扎莫特罗仍能使I_kr电流减低到原电流大小的0.68±0.07,与正常对照组相比相比无统计学差异。
4.α1和β肾上腺素受体在调控豚鼠心室肌细胞I_kkr电流中的交互作用:
4.1.急性激活α1肾上腺素受体对β肾上腺素受体激动剂调控I_kkr电流的影响:若细胞未先加用α1肾上腺素受体激动剂苯肾上腺素,β肾上腺素受体激动剂异丙肾上腺素能使I_kr电流降为基础电流大小的0.55±0.06。若细胞先加用苯肾上腺素,异丙肾上腺素则不能降低I_kr电流的大小,提示α1肾上腺素受体激活可抑制β肾上腺素受体激活对I_kr电流的降低作用。4.2.急性激活β肾上腺素受体对α1肾上腺素受体激动剂调控I_kkr电流的影响:细胞若未预先加用β肾上腺素受体激动剂异丙肾上腺素,α1肾上腺素受体激动剂苯肾上腺素能使I_kr电流降为基础电流大小的0.58±0.04。若细胞先加用了异丙肾上腺素,苯肾上腺素能使I_kr电流降为基础电流大小的0.80±0.02,提示β肾上腺素受体激活可减弱α1肾上腺素受体激活对I_kr电流的降低作用。
结论
1.α1肾上腺素受体激活可浓度依赖性地减弱豚鼠心肌细胞的I_kr电流,此作用主要通过α1A肾上腺素受体介导。
2.特异性PKA和PKC抑制剂均可减弱苯肾上腺素对I_kr电流的降低作用,提示α1A受体激活对I_kr电流的调控依赖于PKA以及PKC的激活。
3.β肾上腺素受体激活可剂量依赖性地减弱豚鼠心肌细胞的I_kr电流,此作用主要通过β1肾上腺素受体介导。
4.β1肾上腺素受体的瞬时激活对I_kr电流的调控作用依赖于PKA、PLC以及PKC的激活,而与CaMKI_I_的激活无关。
5.α1肾上腺素受体激活可抑制β肾上腺素受体激活对I_kr电流的降低作用,β肾上腺素受体激活亦可减弱α1肾上腺素受体激活对I_kr电流的降低作用;提示α1和β肾上腺素受体在对I_kr电流的调控上可能存在交互作用。
Background Ventricular arrhythmias are often precipitated by physical oremotional stress. An increased release of the endogenous catecholamines changes thecharacteristics of ionic currents in the cardiomyocytes, which is an important reasonfor ventricular arrhythmia. There are many ionic currents in the cardiomyocytemembrane. The rapid component of the delayed rectifier potassium current, Ikr, is themajor outward current involved in ventricular repolarization and inhibiton of Ikr maylead to action potential duration prolongation. The human ether-a-go-go-related gene(hERG) encodes the voltage-gated potassium channelα-subunit underlying Ikr.Reduction of hERG currents due to mutations in hERG produces congenital long QTsyndrome (LQTS-2). On the other hand, hERG channels are a primary target for thepharmacological management of cardiac arrhythmias with class III antiarrhythmicagents. Excessive blockade of hERG channels by antiarrhythmic or nonantiarrhythmicdrugs may lead to acquired long QT syndrome (aLQTS). Stimulationof the sympathetic nervous system (SNS) in response to exercise or emotional stresscauses stimulation of adrenergic receptors. At least nine adrenoceptor subtypes havebeen identified:α1A,α1B,α1D,α2A,α2B,α2C,β1,β2 andβ3. In human heart, the mainlypresence of adrenoceptor subtypes areα1 andβadrenoceptors. Recent investigationsrevealed that the rapid component of the delayed rectifier potassium current may beinhibited by eitherα1 orβadrenergic stimulation. However, the effects of adrenergicreceptor subtypes on the Ikr and the underlying mechanisms need further study.
Objectives 1. Whole-cell patch clamp techniques were used to investigate the regulation of Ikr in guinea pig cardiomyocytes byα1 andβadrenergic receptor andtheir subtypes. 2. Their underlying signal pathway involved in Ikr were studied,which may help us to study the mechanism that stress induced ventriculararrhythmias.
MaterialMaterials and Methods
1. Myocyte isolation: Single ventricular myocytes were isolated from male guineapig（weighted 250-300g）hearts using a standard enzymatic technique withLangendorff perfusion.
2. Patch clamp recording of Ikr tail currents in guinea pig ventricular myocytes:Isolated ventriular myocytes were placed in experimental chammber and wholecellpatch clamp recording technique was used to record Ikr. Ikr was elicited usingthe following test pulse protocol: after a holding potential of ?40 mV, test pulseswere applied at various voltages from ?40mV to +40mV (step width 20 mV, stepduration 200 ms) before returning to ?40mV for tail current recording.
3. Regulation of Ikr currents byα1-adrenergic stimulation.
3.1.α1-adrenergic effects on Ikr currents: Ikr currents were recorded before andafter application of specificα1-adrenergic receptor agonist phenylephrine(0.0001μmol/L－100μmol/L). The ventricular myocytes were applicatedprazosin (α1-adrenergic antagonist), 5-MU (α1A-adrenergic antagonist),chloroethylclonidine (α1B-adrenergic antagonist) or BMY7378 (α1Dadrenergicantagonist) respectively before phenylephrine application and Ikrcurrents were recorded before and after application of phenylephrine.
3.2. Role of protein kinase A (PKA) and protein kinase C (PKC) inα1-adrenergic effects on Ikr currents: The ventricular myocytes werepretreated with specific PKA inhibitor (KT5720, 2.5μmol/L) or specific PKC inhibitor (chelerythrine, 1μmol/L) for 1 hour. Then Ikr currents wererecorded before and after application of phenylephrine.
4. Regulation of Ikr currents byβ-adrenergic stimulation.
4.1.β-adrenergic effects on Ikr currents: Ikr currents were recorded before andafter application of unspecificβ-adrenergic receptor agonist isoproterenol(0.001μmol/L－100μmol/L). The ventricular myocytes were applicatedpropranolol (β-adrenergic antagonist), CGP20712A (β1-adrenergicantagonist) or ICI118551 (β2-adrenergic antagonist) before isoproterenolapplication and Ikr currents were recorded before and after application ofisoproterenol.
4.2.β1-adrenergic effects on Ikr currents: Ikr currents were recorded before andafter application of specificβ1-adrenergic receptor agonist xamotorol (0.01μmol/L－100μmol/L).
4.3. Role of protein kinase A (PKA), phospholipase C (PLC) protein kinase C(PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII) inβ1-adrenergic effects on Ikr currents: Cardiomyocytes were pretreated withspecific PKA inhibitor (KT5720, 2.5μmol/L), specific PLC inhibitior(U73122, 100nmol/L), specific PKC inhibitor (chelerythrine, 1μmol/L) for1 hour respectively, or specific CaMKII inbitor KN93 (10μmol/L) for 30minutes. Then, Ikr currents were recorded before and after application ofβ1-adrenergic receptor agonist xamotorol.
5. Cross talk betweenα1 andβadrenergic effects on Ikr currents.
5.1. Effects of isoproterenol on Ikr in the presence of phenylephrine: Theventricular myocytes were application of phenylephrine for 10 min beforeapplication of isoproterenol. Ikr currents were recorded before and afterapplication of phenylephrine and after application of isoproterenol.
5.2. EffectEffects of phenylephrine on Ikr in the presence of isoproterenol: Theventricular myocytes were application of isoproterenol for 10 min beforeapplication of phenylephrine. Ikr currents were recorded before and afterapplication of isoproterenol and after application of phenylephrine.
Results
1. Patch clamp recording of Ikr tail currents in guinea pig ventricular myocytes: Ikrtail current of guinea pig ventricular myocyte was recorded using whole cell patchclamp and it can be completely blocked by 1μmol/L dofetilide. Ikr tail currents aremarkedly sensitive to temperature changes. The Ikr tail current density at +40 mVincreased from 0.28±0.07 pA/pC at 22°C to 0.62±0.07 pA/pC at 37°C.
2. Regulation of Ikr currents byα1-adrenergic stimulation.
2.1.α1-adrenergic effects on Ikr currents: The dose-dependent effect ofphenylephrine, anα1-adrenoreceptor agonist, on Ikr was examined infreshly isolated guinea pig ventricular myocytes. The amplitude of Ikr wasreduced to 0.67±0.03 in response to 0.1μmol/L phenylephrine. This effect wasblocked by theα-adrenoreceptor antagonist prazosin and the selectiveα1Aadrenoreceptorantagonist 5-MU, but not by theα1B-adrenoreceptor antagonistchlorethylclonidine or theα1D-adrenoreceptor antagonist BMY7378.
2.2. Role of protein kinase A (PKA) and protein kinase C (PKC) inα1-adrenergic effects on Ikr currents: When cardiomyocytes were pretreatedwith chelerythrine or KT5720 for 1 hour, the amplitude of Ikr was reduced to0.98±0.02 and 0.77±0.03 respectively in response to 0.1μmol/L phenylephrine.By comparison, phenylephrine elicited a reduction to 0.67±0.03 on Ikr in theabsence of chelerythrine and KT5720.
3. Regulation of Ikr currents byβ-adrenergic stimulation.
3.1.β-adrenergi-adrenergic effects on Ikr currents: The dose-dependent effect ofisoproterenol, a nonspecificβ-adrenoreceptor agonist, on Ikr was alsoexamined in freshly isolated guinea pig ventricular myocytes. The amplitudeof Ikr was reduced to 0.62±0.03 in response to 10μmol/L isoproterenol. Thiseffect was blocked by theβ-adrenoreceptor antagonist propranolol and theselectiveβ1-adrenoreceptor antagonist CGP20712A, but not by theβ2-adrenoreceptor antagonist ICI118551.
3.2.β1-adrenergic effects on Ikr currents: Stimulation ofβ1-adrenergic receptorsusing xamotorol also reduced Ikr current in a dose-dependent manner. 10μmol/L xamotorol decreased Ikr current to 0.56±0.04.
3.3. Role of protein kinase A (PKA), phospholipase C (PLC) protein kinase C(PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII) inβ1-adrenergic effects on Ikr currents: When xamotorol was combined withKT5720 (2.5μmol/L), a specific inhibitor of PKA, the inhibitory effect wasdrastically reduced. The amplitude of Ikr relative current was reduced to0.87±0.03, it was significantly different from xamotorol elicited a reductionto 0.56±0.04 on Ikr in absence of KT5720. When cardiomyocytes were pretreatedwith PLC inhibitor, U73122 (100 nmol/L) or a general PKC inhibitor,chelerythrine (1μmol/L) for 1 hour prior to the recording the xamotoroleffect on Ikr. Xamotorol inhibited Ikr to 0.91±0.07 or 0.71±0.01, respectivelyin the presence of U73122 or chelerythrine. They were both significantlydifferent from xamotorol elicited a reduction to 0.56±0.04 on Ikr in theabsence of chelerythrine and U73122. When cardiomyocytes were pretreatedwith KN93 (10μmol/L for 30 minutes), a synthetic CaMKIIinhibitor, the inhibitory effect of xamotorol on Ikr was unaffected by KN93,xamotorol inhibited Ikr to 0.68±0.07 compared to 0.56±0.04 without KN93.
4. Cross talk betweenα1 andβadrenergic effects on Ikr currents.
4.1. Effects of isoproterenol on Ikr in the presence of phenylephrine: Whencardiomyocytes were firstly acute stimulated by phenylephrine, anα1-adrenoreceptor agonist, the Ikr tail currents were not decreased byisoproterenol, aβ-adrenoreceptor agonist. In an other word, isoproterenol cannot reduce Ikr tail currents in cardiomyocytes pretreated with phenylephrinebefore. It was significantly different from the cardiomyocytes not firstly acutestimulated by phenylephrine group.
4.2. Effects of phenylephrine on Ikr in the presence of isoproterenol: Whencardiomyocytes were firstly acute stimulated by isoproterenol, aβ-adrenoreceptor agonist, the Ikr tail currents were only deceased to 0.80±0.02by phenylephrine, anα1-adrenoreceptor agonist, which was significantlydifferent from the cardiomyocytes not firstly acute stimulated by isoproterenolgroup.
Conclusions
1. Phenylephrine, anα1-adrenoreceptor agonist, can reduce Ikr current in a dosedependentmanner. This effect is mediated by theα1A-adrenoreceptor subtyperather than otherα1-adrenoreceptor subtypes.
2. When cardiomyocytes were pre-treated with chelerythrine or KT5720 for 1 hour,both chelerythrine and KT5720 drastically reduced the phenylephrine-inducedeffects, indicating possible involvement of PKC and PKA in theα1-adrenergicinhibition of Ikr.
3. Isoproterenol reduced Ikr current in a dose-dependent manner. This effect ismediated byβ1-adrenoreceptor subtype rather than otherβ2-adrenoreceptorsubtype.
4. When xamotorol was combined with KT5720, a specific inhibitor of PKA, theinhibitory effect was drastically reduced. Both Chelerythrine, a specific inhibitorof PKC, and U73122, a inhibitor of phospholipase C (PLC) inhibited thecurrent decreasing induced by xamotorol. However, KN93, an inhibitorCaMKII, may not attenuate the inhibtory effects of xamotorol on Ikr. Our datasuggest a link between Ikr and theβ1-adrenergic receptor, involving activationPKA , PLC and PKC.
5. Signaling“cross talk”betweenα1- andβ-adrenergic cascades might be involvedin regulation of Ikr tail current in guinea pig ventricular myocyte.
引文
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