豚鼠心室肌细胞膜延迟整流钾通道电流（I_k）及L型钙通道电流（I_（Ca,L））在缺血预适应过程中的变化的实验研究
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摘要
目前冠心病的防治重点在于减少不可逆的心肌缺血损伤所造成的心肌梗死、猝死等急性事件的发生。心肌缺血预适应(IP)现象是已知的心肌缺血时最强的生理性保护机制，且内在机理不完全明了，而成为研究的重点。近几年对IP的研究从心脏整体水平转向细胞水平的生理、生化等研究。在IP机理的研究中，有关离子通道的研究集中在被认为是“终末效应器”的ATP敏感性钾通道(K_(ATP))，通道电流的分析也基本限于K_(ATP)，且直接报导不多。除缺血缺氧等病理情况下开放的K_(ATP)外，关于IP条件下心肌细胞膜其它生理性离子通道电流的研究尚未见直接报导。本研究应用膜片钳全细胞记录技术，在模拟缺血及早期缺血预适应条件下对豚鼠心室肌单细胞的延迟整流钾电流I_k(分为快速激活成分I_(kr)和缓慢激活成分I_(ks))和L型钙通道电流(I_(Ca,L))进行分析。
方法：用胶原酶Ⅰ分离出豚鼠心室肌单细胞。实验条件设定为：(1)无预适应的缺血模型：细胞经正常细胞外液灌流5min，记录正常状态离子通道电流为对照，再予模拟缺血细胞外液灌流10min，记录缺血状态离子通道电流。(2)缺血预适应模型：细胞经正常细胞外液灌流5min，记录正常状态离子通道电流为对照后，先予缺血细胞外液灌流3min，再予正常细胞外液灌流(再灌注)3min，如此重复操作2次作为缺血预适应刺激并记录离子通道电流，再予模拟缺血细胞外液灌流10min，记录预适应后的缺血状态离子通道电流。本实验共观察记录四组细胞：单纯缺血I_k组(n=14)、缺血预适应I_k组(n=10)、单纯缺血I_(Ca,L)组(n=12)和缺血预适应I_(Ca,L)组(n=11)。
结果：(1)急性缺血时I_k的变化：缺血后I_(kr)电流密度均大于缺血前正常状态，且自指令电压-20mV至最大+60mV有统计学显著性(P＜0.05)，将指令电压+40mV时的尾电流I_(kr,tail)也于缺血前后比较(n=9)，显示缺血后的I_(kr,tail)电流密度也显著大于缺血前(P＜0.05)；自指令电压-20mV至最大+60mV，缺血后I_(ks)的电流密度数值有增大趋势(P=0.069～0.088)，将其+40mV时的尾电流I_(ks,tail)于缺血前后比较(n=9)，显示缺血后的I_(ks,tail)电流密度与缺血前无显著性差异。(2)缺血预适应过程中I_k的变化：各指令电压下，正常状态、预适应后缺血前
天津医科大学博卜研究生学位论文
和预适应后缺血10分钟这三个IP时相的Ikr电流密度无显著差异，Ik，的电流
密度也无显著差异，Ik，和I。的+40mV尾电流分析未见显著差异。Ikr和Ik、峰
值变化趋势表现出预适应后略低于正常，缺血后又升高而接近正常。(3)缺血
IOmin后，预适应组细胞个体Ikr受抑制的概率大于单纯缺血组(7/10vs3/14，
确切概率P二0.035);预适应组细胞个体玩，受抑制的概率虽大于单纯缺血组，
但差异无统计学显著性(7/10 vS4八4，确切概率P=0.095)。(4)急性缺血时xe、L
的变化:持续缺血10min后内向Ica，:峰值电流密度由正常时的一5.72士2.ooPA·PF
明显减小至一2.54士1 .19PA.PF(P<0 .001)，外向稳态电流155电流密度由正常时一6.40
士4.04pA. pF增大至一3.15士2.85pA.pF(P<0.05)，缺血对最大激活电压(0 mV)和
反转电压(巧OmV)无影响，缺血使稳态激活曲线略右移(VI/2正常状态平均
一21.80mv，缺血后平均一17.35mV)。(5)缺血预适应过程中Ic。，L的变化:在IP
三个时相中，IC次L峰值电流密度于IP刺激后(一2.22士l.00PA·PF)和缺血后(一1.84
士乃OPA·PF)无显著差异，二者均小于正常状态的一5.60士1.90PA·pF(均为
P<0.001);三个时相的稳态电流155无显著性差异(分别为一4.35士2.90、一4.18士
2.18和一4.31士2.巧pA .PF)。三个时相最大激活电压和反转电压无变化。预适应
刺激和之后的缺血均使IC比L的稳态激活曲线略右移(V，/:在正常状态平均为
一17.IOmV，经预适应刺激后一11.57mV，缺血后一13.45mV)。
结论:(1)急性持续心肌缺血使Ik增大，且以Ikr的增大为主。(2)缺血预适
应的刺激抑制了持续缺血.时Ik的开放，对Ikr的抑制更为显著。(3)急性持续缺
血使内向Ica，L峰值电流减小，相应外向稳态电流155增大，稳态激活曲线略右
移，不影响最大激活电位和反转电位。(4)缺血预适应刺激仍使Ica，L峰值电流
减小，即短暂缺血后的再灌注不能使减小的Ica，L峰值恢复，但限制了IP之后
的持续缺血时Ica，!峰值进一步减低;IP刺激和之后缺血时的155均保持正常，
稳态激活曲线均比正常略右移，均不影响最大激活电位和反转电位。(5)缺血
预适应对Ik和IC、L的抑制可限制细胞过度的钾外流和钙内流，IP使I、s正常化
有助于稳定静息膜电位，可能与持续缺血时对心肌的保护作用有关。
Objective: Ischemic preconditioning (IP) is known by now to be the most physiologically effective protection against myocardial ischemia , the mechanism of which is not thoroughly clear and becomes an important investigative question. Most studies on ionic currents in the course of IP focus on ATP-sensitive potassium channel (Katp) which is regarded as terminal effector, and direct reports on other ionic currents opening in physiological condition has not yet been available. In this study by developing a cellular mode of acute ischemia and IP, analyses of delayed rectifier potassium current (Ik) that is divided into rapidly activated component (Ikr) and slowly activated component (Iks) and of L-type calcium current were performed in guinea pig ventricular myocytes with whole-cell configuration of patch clamp technique.
Methods: Single myocytes were isolated from the ventricles of adult guinea pigs. Experimental conditions for myocytes were set as (1) merely ischemia without preconditioning: ionic currents were recorded after 5min of equilibration with normal extracellular solution for control data, and then recorded following 10 min of perfusion with mimic ischemic solution; (2) ischemic preconditioning: after control data were recorded as above, two cycles of ischemic perfusion for 3min followed by normal reperfusion for 3 min were given as IP stimulation, after which currents were recorded, finally data of 10 min of mimic ischemia were collected. Thus altogether 4 experimental groups of cells were observed: Ik of merely ischemia(n=14), Ik of IP(n=10), Ica,L of merely ischemia(n=12) and Icax of
Results: (1) Compared with normal state, after 10 min of ischemia without IP , the current density of Ikr increased(from -20 to +60 mV differences were of statistical significance, P<0.05) and the density of corresponding tail current Ikr,tail at +40mV was also significantly increased(n=9, P<0.05), the density of Iks trended to increase from -20mV to +60mV(P=0.069~0.088) and the density of tail current Iks.tail at +40mV did not markedly change(n=9); (2)in the course of IP, the density of Ikr and Iks in the 3 phases(control, IP stimulation, persistent ischemia) showed no statistical difference, and Ikr,tail and IkS,tail did not differ; (3)the probability of
inhibition of Ikr in ischemia following IP was greater than in merely ischemia(7/10 vs 3/14, exact P=0.035), but that of Iks in preconditioned ischemia was greater than in merely ischemia without statistical significance(7/10 vs 4/14, exact P=0.095); (4)Compared with normal state, after 10 min of ischemia without IP , the inward current density of the peak value of Ica,L greatly reduced from -5.72+2.00pA pF to -2.54+ 1.19pA pF(P<0.001), and the outward density of corresponding steady-state current(Iss) increased from -6.40 + 4.04pA pF to -3.15 + 2.85pA pF (P<0.05), steady-state activation curve slightly moved to the right(V1/2 was -21.80mV on average in normal state, -17.35mV in ischemia), but the most activation voltage(0mV) and reversal voltage(+50mV) was unchanged; (5) in the 3 phases of IP, there was no difference between the density of the peak value of Ica,L in IP state(-2.22+ 1.00 pA-pF) and in following ischemia(-1.84 +7.50 pA-pF), both of which were significantly less than normal state(-5.60+1.90 pA
-pF, both P<0.001). Iss was also unchanged(-4.35 + 2.90, -4.18+2.18 and -4.31+2.15 pA.pF in time order), the most activation voltage and reversal voltage was still unchanged, steady-state activation curve in IP and in following ischemia consistently slightly moved to the right(on average V1/2 were -17.10mV, -11.57mV, -13.45mV in time order).
Conclusions: (1) Acute persistent myocardial ischemia could increase Ik, mainly by increasing Ikr; (2)Ischemic preconditioning could inhibit Ik opening during subsequent persistent ischemia, mainly by inhibiting Ikr; (3)Acute ischemia can decrease inward peak value of Ica,L and increase outward steady-state current(Iss); (4)IP stimulation still makes peak value of Ica,L decrease without affecting ISs, and may restrict further
方法：用胶原酶Ⅰ分离出豚鼠心室肌单细胞。实验条件设定为：(1)无预适应的缺血模型：细胞经正常细胞外液灌流5min，记录正常状态离子通道电流为对照，再予模拟缺血细胞外液灌流10min，记录缺血状态离子通道电流。(2)缺血预适应模型：细胞经正常细胞外液灌流5min，记录正常状态离子通道电流为对照后，先予缺血细胞外液灌流3min，再予正常细胞外液灌流(再灌注)3min，如此重复操作2次作为缺血预适应刺激并记录离子通道电流，再予模拟缺血细胞外液灌流10min，记录预适应后的缺血状态离子通道电流。本实验共观察记录四组细胞：单纯缺血I_k组(n=14)、缺血预适应I_k组(n=10)、单纯缺血I_(Ca,L)组(n=12)和缺血预适应I_(Ca,L)组(n=11)。
结果：(1)急性缺血时I_k的变化：缺血后I_(kr)电流密度均大于缺血前正常状态，且自指令电压-20mV至最大+60mV有统计学显著性(P＜0.05)，将指令电压+40mV时的尾电流I_(kr,tail)也于缺血前后比较(n=9)，显示缺血后的I_(kr,tail)电流密度也显著大于缺血前(P＜0.05)；自指令电压-20mV至最大+60mV，缺血后I_(ks)的电流密度数值有增大趋势(P=0.069～0.088)，将其+40mV时的尾电流I_(ks,tail)于缺血前后比较(n=9)，显示缺血后的I_(ks,tail)电流密度与缺血前无显著性差异。(2)缺血预适应过程中I_k的变化：各指令电压下，正常状态、预适应后缺血前
天津医科大学博卜研究生学位论文
和预适应后缺血10分钟这三个IP时相的Ikr电流密度无显著差异，Ik，的电流
密度也无显著差异，Ik，和I。的+40mV尾电流分析未见显著差异。Ikr和Ik、峰
值变化趋势表现出预适应后略低于正常，缺血后又升高而接近正常。(3)缺血
IOmin后，预适应组细胞个体Ikr受抑制的概率大于单纯缺血组(7/10vs3/14，
确切概率P二0.035);预适应组细胞个体玩，受抑制的概率虽大于单纯缺血组，
但差异无统计学显著性(7/10 vS4八4，确切概率P=0.095)。(4)急性缺血时xe、L
的变化:持续缺血10min后内向Ica，:峰值电流密度由正常时的一5.72士2.ooPA·PF
明显减小至一2.54士1 .19PA.PF(P<0 .001)，外向稳态电流155电流密度由正常时一6.40
士4.04pA. pF增大至一3.15士2.85pA.pF(P<0.05)，缺血对最大激活电压(0 mV)和
反转电压(巧OmV)无影响，缺血使稳态激活曲线略右移(VI/2正常状态平均
一21.80mv，缺血后平均一17.35mV)。(5)缺血预适应过程中Ic。，L的变化:在IP
三个时相中，IC次L峰值电流密度于IP刺激后(一2.22士l.00PA·PF)和缺血后(一1.84
士乃OPA·PF)无显著差异，二者均小于正常状态的一5.60士1.90PA·pF(均为
P<0.001);三个时相的稳态电流155无显著性差异(分别为一4.35士2.90、一4.18士
2.18和一4.31士2.巧pA .PF)。三个时相最大激活电压和反转电压无变化。预适应
刺激和之后的缺血均使IC比L的稳态激活曲线略右移(V，/:在正常状态平均为
一17.IOmV，经预适应刺激后一11.57mV，缺血后一13.45mV)。
结论:(1)急性持续心肌缺血使Ik增大，且以Ikr的增大为主。(2)缺血预适
应的刺激抑制了持续缺血.时Ik的开放，对Ikr的抑制更为显著。(3)急性持续缺
血使内向Ica，L峰值电流减小，相应外向稳态电流155增大，稳态激活曲线略右
移，不影响最大激活电位和反转电位。(4)缺血预适应刺激仍使Ica，L峰值电流
减小，即短暂缺血后的再灌注不能使减小的Ica，L峰值恢复，但限制了IP之后
的持续缺血时Ica，!峰值进一步减低;IP刺激和之后缺血时的155均保持正常，
稳态激活曲线均比正常略右移，均不影响最大激活电位和反转电位。(5)缺血
预适应对Ik和IC、L的抑制可限制细胞过度的钾外流和钙内流，IP使I、s正常化
有助于稳定静息膜电位，可能与持续缺血时对心肌的保护作用有关。
Objective: Ischemic preconditioning (IP) is known by now to be the most physiologically effective protection against myocardial ischemia , the mechanism of which is not thoroughly clear and becomes an important investigative question. Most studies on ionic currents in the course of IP focus on ATP-sensitive potassium channel (Katp) which is regarded as terminal effector, and direct reports on other ionic currents opening in physiological condition has not yet been available. In this study by developing a cellular mode of acute ischemia and IP, analyses of delayed rectifier potassium current (Ik) that is divided into rapidly activated component (Ikr) and slowly activated component (Iks) and of L-type calcium current were performed in guinea pig ventricular myocytes with whole-cell configuration of patch clamp technique.
Methods: Single myocytes were isolated from the ventricles of adult guinea pigs. Experimental conditions for myocytes were set as (1) merely ischemia without preconditioning: ionic currents were recorded after 5min of equilibration with normal extracellular solution for control data, and then recorded following 10 min of perfusion with mimic ischemic solution; (2) ischemic preconditioning: after control data were recorded as above, two cycles of ischemic perfusion for 3min followed by normal reperfusion for 3 min were given as IP stimulation, after which currents were recorded, finally data of 10 min of mimic ischemia were collected. Thus altogether 4 experimental groups of cells were observed: Ik of merely ischemia(n=14), Ik of IP(n=10), Ica,L of merely ischemia(n=12) and Icax of
Results: (1) Compared with normal state, after 10 min of ischemia without IP , the current density of Ikr increased(from -20 to +60 mV differences were of statistical significance, P<0.05) and the density of corresponding tail current Ikr,tail at +40mV was also significantly increased(n=9, P<0.05), the density of Iks trended to increase from -20mV to +60mV(P=0.069~0.088) and the density of tail current Iks.tail at +40mV did not markedly change(n=9); (2)in the course of IP, the density of Ikr and Iks in the 3 phases(control, IP stimulation, persistent ischemia) showed no statistical difference, and Ikr,tail and IkS,tail did not differ; (3)the probability of
inhibition of Ikr in ischemia following IP was greater than in merely ischemia(7/10 vs 3/14, exact P=0.035), but that of Iks in preconditioned ischemia was greater than in merely ischemia without statistical significance(7/10 vs 4/14, exact P=0.095); (4)Compared with normal state, after 10 min of ischemia without IP , the inward current density of the peak value of Ica,L greatly reduced from -5.72+2.00pA pF to -2.54+ 1.19pA pF(P<0.001), and the outward density of corresponding steady-state current(Iss) increased from -6.40 + 4.04pA pF to -3.15 + 2.85pA pF (P<0.05), steady-state activation curve slightly moved to the right(V1/2 was -21.80mV on average in normal state, -17.35mV in ischemia), but the most activation voltage(0mV) and reversal voltage(+50mV) was unchanged; (5) in the 3 phases of IP, there was no difference between the density of the peak value of Ica,L in IP state(-2.22+ 1.00 pA-pF) and in following ischemia(-1.84 +7.50 pA-pF), both of which were significantly less than normal state(-5.60+1.90 pA
-pF, both P<0.001). Iss was also unchanged(-4.35 + 2.90, -4.18+2.18 and -4.31+2.15 pA.pF in time order), the most activation voltage and reversal voltage was still unchanged, steady-state activation curve in IP and in following ischemia consistently slightly moved to the right(on average V1/2 were -17.10mV, -11.57mV, -13.45mV in time order).
Conclusions: (1) Acute persistent myocardial ischemia could increase Ik, mainly by increasing Ikr; (2)Ischemic preconditioning could inhibit Ik opening during subsequent persistent ischemia, mainly by inhibiting Ikr; (3)Acute ischemia can decrease inward peak value of Ica,L and increase outward steady-state current(Iss); (4)IP stimulation still makes peak value of Ica,L decrease without affecting ISs, and may restrict further
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