心肌梗死后大鼠钾通道Kv9.X基因表达变化及药物干预机制的研究
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摘要
第一部分心肌梗死后钾通道Kv9.Ⅹ基因表达水平变化及意义
目的研究大鼠心肌梗死后钾通道Kv9.Ⅹ(Kv9.1、Kv9.2、Kv9.3)基因表达水平的改变，并初步探讨此种变化的意义。
方法通过结扎大鼠左前降支近端建立心肌梗死大鼠模型，手术后存活大鼠进入心肌梗死组(MI组)(7天组；30天组)。同时，设立相应的假手术组(SH组)。应用半定量RT-PCR方法检测左室心肌(心肌梗死者取非梗死区左室心肌)钾通道Kv9.1、Kv9.2、Kv9.3m RNA量。
结果7天组：与假手术组比较，MI组Kv9.1、Kv9.2、Kv9.3m RNA量明显下降(P＜0.05)。30天组：与假手术组比较，MI组Kv9.1、Kv9.2、Kv9.3mRNA的量均极显著下降(P＜0.01)。MI组：30天组与7天组比较，Kv9.1、Kv9.2、Kv9.3mRNA的量显著下降(P＜0.05)。
结论心肌梗死后钾通道Kv9.1、Kv9.2、Kv9.3mRNA表达呈时间依赖性下调。
第二部分缬沙坦对大鼠心肌梗死后钾通道Kv9.Ⅹ表达变化的影响
目的研究缬沙坦对大鼠心肌梗死后钾通道Kv9.Ⅹ(Kv9.1、Kv9.2、Kv9.3)变化的影响。
方法通过结扎大鼠左前降支近端建立心肌梗死大鼠模型，手术后存活大鼠随机分入心肌梗死(MI)组(7天组，30天组)和缬沙坦(VAS)组(7天组，30天组：缬沙坦30mg／kg，1次／日)，同时设立相应假手术(SH)组。心肌梗死组和假手术组对应给予等量盐水。应用半定量RT-PCR方法检测非梗死左室心肌钾通道Kv9.1、Kv9.2、Kv9.3 m RNA量。
结果与心肌梗死组比较，无论7天或是30天，缬沙坦组钾通道Kv9.1、Kv9.2、Kv9.3m RNA量均明显升高(分别为：P＜0.05；P<0.01)。与假手术组比较，缬沙坦组钾通道Kv9.1、Kv9.2、Kv9.3m RNA量无差异。与假手术组比较，无论7天或是30天，心肌梗死组钾通道Kv9.1、Kv9.2、Kv9.3m RNA量均明显降低(分别为：P＜0.05；P＜0.01)。心肌梗死30天时与7天时比较钾通道Kv9.1、Kv9.2、Kv9.3mRNA量下降(P＜0.05)。
结论缬沙坦可以显著逆转心肌梗死后钾通道Kv9.1、Kv9.2、Kv9.3mRNA表达的下调，且这一作用迅速而完全。
第三部分美托洛尔对大鼠心肌梗死后钾通道Kv9.Ⅹ基因表达的影响
目的研究美托洛尔对心肌梗死后大鼠心室肌钾通道Kv9.Ⅹ(Kv9.1、Kv9.2、Kv9.3)表达的影响。
方法通过结扎大鼠左前降支近端建立心肌梗死大鼠模型，手术后存活大鼠随机分入心肌梗死(MI)组(7天、30天)、美托洛尔(Meto)组(7天、30天；美托洛尔8mg／kg／日，2次／日)，同时设立相应假手术(SH)组。应用半定量RT-PCR方法检测左室心肌(梗死者取非梗死心肌)钾通道Kv9.1、Kv9.2、Kv9.3mRNA量。
结果与心肌梗死组比较，30天时美托洛尔组钾通道Kv9.1、Kv9.2、Kv9.3mRNA明显升高(P＜0.05)，7天时无差异。与假手术组比较，无论7天或30天，美托洛尔组钾通道Kv9.1、Kv9.2、Kv9.3mRNA均明显降低(均为P＜0.05)。与假手术组比较，无论7天或30天，心肌梗死组钾通道Kv9.1、Kv9.2、Kv9.3mRNA均显著降低(分别为：P＜0.05；P＜0.01)。心肌梗死30天时与7天时比较钾通道Kv9.1、Kv9.2、Kv9.3m RNA量下降(P＜0.05)。美托洛尔组7天与30天比较无差别。
结论美托洛尔能够逆转钾通道Kv9.1、Kv9.2、Kv9.3表达的下调，且这一逆转作用是缓慢的。
Part I
The changes and its signification of gene expression of potassium channels Kv9.X in post-MI rat heart
Objective To study the changes and signification of the expression of potassium channels Kv9.X( Kv9.1、 Kv9.2、 Kv9.3) mRNA in post-MI rat heart. Methods Using a rat model of MI, induced by the left anterior descending coronary artery (LAD) ligation in female Sprague-Dawley rats, the living rats divided into post-MI group( 7 days group[n=10]; 30 days group[n=11]). Accordingly, the sham-operation group (sham-group) was established. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we measured Kv9.1、 Kv9.2、
Kv9.3mRNA in each group.
Results 7 days group: Compared to the sham-group, Kv9.1、 Kv9.2、 Kv9.3mRNA in
the post-MI group remarkably decreases (P<0.05); 30 days group: compared to the
sham-group, Kv9.1、 Kv9.2、 Kv9.3 mRNA in the post-MI group prominently reduces
(P<0.01); post-MI group: compared to the 7 days group, Kv9.1、 Kv9.2、 Kv9.3 mRNA in
the 30 days group remarkably reduces (P<0.05).
Conclusion The expression of potassium channels Kv9.1、 Kv9.2、 Kv9.3 mRNA after
myocardial infarction exhibits the time-dependent downregulation. Part II
Effects of valsartan on the changes of expression of potassium channels Kv9.X in post-myocardial infarction rat
Objective: To study the effects of valsartan on the changes of the expression of potassium channels Kv9.X (Kv9.1、 Kv9.2、 Kv9.3) of left ventricular non-infarcted myocardiums in post-myocardial infarction (post-MI) rats.
Methods: Using a rat model of MI, induced by the left anterior descending coronary artery (LAD) ligation in female Sprague-Dawley rats, the living rats randomly divided into post-MI group ( 7 days group[n=10]; 30 days group[n=11]) or valsartan group(7 days group[n=10]; 30 days group[n=10]; valsartan 30mg.kg~(-1).day~(-1)). Accordingly, the sham-operation group (sham-group) was established. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we measured Kv9.1、 Kv9.2、 Kv9.3 mRNA in each group.
Results: Compared to MI groups, potassium channels Kv9.1、 KV9.2、 Kv9.3 mRNA in the valsartan groups remarkably increases regardless of on 7 days or 30 days (respectively, P<0.05; P<0.01). There is no difference between the valsartan groups and the sham-groups. Compared to the sham-groups, potassium channels Kv9.1、 Kv9.2、 Kv9.3 mRNA in the MI groups remarkably decreases regardless of on 7 days or 30 days (respectively, P<0.05; P<0.01). Compared to on 7 days after myocardial infarction,
potassium channels Kv9.1、 Kv9.2、 Kv9.3 mRNA remarkably decreases on 30 days
(P<0.05).
Conclusion: Valsartan may reverse the downregulation of expression of potassium
channels Kv9.1、Kv9.2、Kv9.3 mRNA in post-myocardial infarction rat markedly, which
is quick and absolute. Part III
Effects of metoprolol on the changes of expression of potassium channels Kv9.X in post-myocardial infarction rat
Objective: To study the effects of metoprolol on the changes of the expression of potassium channels Kv9.X (Kv9.1、 Kv9.2、 Kv9.3) of left ventricular non-infarcted myocardiums in post-myocardial infarction (post-MI) rats.
Methods: Using a rat model of MI, induced by the left anterior descending coronary artery (LAD) ligation in female Sprague-Dawley rats, the living rats randomly divided into post-MI group (7 days group[n=10]; 30 days group[n=11]) or metoprolol group(7 days group[n=10]; 30 days group[n=9]; 8mg.kg~(-1).day~(-1)). Accordingly, the sham-operation group (sham-group) was established. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we measured Kv9.1、 Kv9.2、 Kv9.3 mRNA in each group.
Results: Compared to MI groups, potassium channels Kv9.1、 Kv9.2、 Kv9.3 mRNA in the metoprolol group remarkably increases on 30 days (P<0.05). Compared to the sham-groups, potassium channels Kv9.1、 Kv9.2、Kv9.3 mRNA in the metoprolol groups remarkably decreases regardless of on 7 days or 30 days (P<0.05). Compared to the sham-groups, potassium channels Kv9.1、 Kv9.2、 Kv9.3 mRNA in the MI groups remarkably decreases regardless of on 7 days or 30 days (respectively, P<0.05; P<0.01).
Compared to on 7 days after myocardial infarction, potassium channels Kv9.1 、 Kv9.2、
Kv9.3 mRNA remarkably decreases on 30 days (P<0.05).
Conclusion: Metoprolol may reverse the downregulation of expression of potassium
channels Kv9.1 、 Kv9.2、 Kv9.3mRNA in post-myocardial infarction rats and this reverse
effect is tardo.
目的研究大鼠心肌梗死后钾通道Kv9.Ⅹ(Kv9.1、Kv9.2、Kv9.3)基因表达水平的改变，并初步探讨此种变化的意义。
方法通过结扎大鼠左前降支近端建立心肌梗死大鼠模型，手术后存活大鼠进入心肌梗死组(MI组)(7天组；30天组)。同时，设立相应的假手术组(SH组)。应用半定量RT-PCR方法检测左室心肌(心肌梗死者取非梗死区左室心肌)钾通道Kv9.1、Kv9.2、Kv9.3m RNA量。
结果7天组：与假手术组比较，MI组Kv9.1、Kv9.2、Kv9.3m RNA量明显下降(P＜0.05)。30天组：与假手术组比较，MI组Kv9.1、Kv9.2、Kv9.3mRNA的量均极显著下降(P＜0.01)。MI组：30天组与7天组比较，Kv9.1、Kv9.2、Kv9.3mRNA的量显著下降(P＜0.05)。
结论心肌梗死后钾通道Kv9.1、Kv9.2、Kv9.3mRNA表达呈时间依赖性下调。
第二部分缬沙坦对大鼠心肌梗死后钾通道Kv9.Ⅹ表达变化的影响
目的研究缬沙坦对大鼠心肌梗死后钾通道Kv9.Ⅹ(Kv9.1、Kv9.2、Kv9.3)变化的影响。
方法通过结扎大鼠左前降支近端建立心肌梗死大鼠模型，手术后存活大鼠随机分入心肌梗死(MI)组(7天组，30天组)和缬沙坦(VAS)组(7天组，30天组：缬沙坦30mg／kg，1次／日)，同时设立相应假手术(SH)组。心肌梗死组和假手术组对应给予等量盐水。应用半定量RT-PCR方法检测非梗死左室心肌钾通道Kv9.1、Kv9.2、Kv9.3 m RNA量。
结果与心肌梗死组比较，无论7天或是30天，缬沙坦组钾通道Kv9.1、Kv9.2、Kv9.3m RNA量均明显升高(分别为：P＜0.05；P<0.01)。与假手术组比较，缬沙坦组钾通道Kv9.1、Kv9.2、Kv9.3m RNA量无差异。与假手术组比较，无论7天或是30天，心肌梗死组钾通道Kv9.1、Kv9.2、Kv9.3m RNA量均明显降低(分别为：P＜0.05；P＜0.01)。心肌梗死30天时与7天时比较钾通道Kv9.1、Kv9.2、Kv9.3mRNA量下降(P＜0.05)。
结论缬沙坦可以显著逆转心肌梗死后钾通道Kv9.1、Kv9.2、Kv9.3mRNA表达的下调，且这一作用迅速而完全。
第三部分美托洛尔对大鼠心肌梗死后钾通道Kv9.Ⅹ基因表达的影响
目的研究美托洛尔对心肌梗死后大鼠心室肌钾通道Kv9.Ⅹ(Kv9.1、Kv9.2、Kv9.3)表达的影响。
方法通过结扎大鼠左前降支近端建立心肌梗死大鼠模型，手术后存活大鼠随机分入心肌梗死(MI)组(7天、30天)、美托洛尔(Meto)组(7天、30天；美托洛尔8mg／kg／日，2次／日)，同时设立相应假手术(SH)组。应用半定量RT-PCR方法检测左室心肌(梗死者取非梗死心肌)钾通道Kv9.1、Kv9.2、Kv9.3mRNA量。
结果与心肌梗死组比较，30天时美托洛尔组钾通道Kv9.1、Kv9.2、Kv9.3mRNA明显升高(P＜0.05)，7天时无差异。与假手术组比较，无论7天或30天，美托洛尔组钾通道Kv9.1、Kv9.2、Kv9.3mRNA均明显降低(均为P＜0.05)。与假手术组比较，无论7天或30天，心肌梗死组钾通道Kv9.1、Kv9.2、Kv9.3mRNA均显著降低(分别为：P＜0.05；P＜0.01)。心肌梗死30天时与7天时比较钾通道Kv9.1、Kv9.2、Kv9.3m RNA量下降(P＜0.05)。美托洛尔组7天与30天比较无差别。
结论美托洛尔能够逆转钾通道Kv9.1、Kv9.2、Kv9.3表达的下调，且这一逆转作用是缓慢的。
Part I
The changes and its signification of gene expression of potassium channels Kv9.X in post-MI rat heart
Objective To study the changes and signification of the expression of potassium channels Kv9.X( Kv9.1、 Kv9.2、 Kv9.3) mRNA in post-MI rat heart. Methods Using a rat model of MI, induced by the left anterior descending coronary artery (LAD) ligation in female Sprague-Dawley rats, the living rats divided into post-MI group( 7 days group[n=10]; 30 days group[n=11]). Accordingly, the sham-operation group (sham-group) was established. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we measured Kv9.1、 Kv9.2、
Kv9.3mRNA in each group.
Results 7 days group: Compared to the sham-group, Kv9.1、 Kv9.2、 Kv9.3mRNA in
the post-MI group remarkably decreases (P<0.05); 30 days group: compared to the
sham-group, Kv9.1、 Kv9.2、 Kv9.3 mRNA in the post-MI group prominently reduces
(P<0.01); post-MI group: compared to the 7 days group, Kv9.1、 Kv9.2、 Kv9.3 mRNA in
the 30 days group remarkably reduces (P<0.05).
Conclusion The expression of potassium channels Kv9.1、 Kv9.2、 Kv9.3 mRNA after
myocardial infarction exhibits the time-dependent downregulation. Part II
Effects of valsartan on the changes of expression of potassium channels Kv9.X in post-myocardial infarction rat
Objective: To study the effects of valsartan on the changes of the expression of potassium channels Kv9.X (Kv9.1、 Kv9.2、 Kv9.3) of left ventricular non-infarcted myocardiums in post-myocardial infarction (post-MI) rats.
Methods: Using a rat model of MI, induced by the left anterior descending coronary artery (LAD) ligation in female Sprague-Dawley rats, the living rats randomly divided into post-MI group ( 7 days group[n=10]; 30 days group[n=11]) or valsartan group(7 days group[n=10]; 30 days group[n=10]; valsartan 30mg.kg~(-1).day~(-1)). Accordingly, the sham-operation group (sham-group) was established. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we measured Kv9.1、 Kv9.2、 Kv9.3 mRNA in each group.
Results: Compared to MI groups, potassium channels Kv9.1、 KV9.2、 Kv9.3 mRNA in the valsartan groups remarkably increases regardless of on 7 days or 30 days (respectively, P<0.05; P<0.01). There is no difference between the valsartan groups and the sham-groups. Compared to the sham-groups, potassium channels Kv9.1、 Kv9.2、 Kv9.3 mRNA in the MI groups remarkably decreases regardless of on 7 days or 30 days (respectively, P<0.05; P<0.01). Compared to on 7 days after myocardial infarction,
potassium channels Kv9.1、 Kv9.2、 Kv9.3 mRNA remarkably decreases on 30 days
(P<0.05).
Conclusion: Valsartan may reverse the downregulation of expression of potassium
channels Kv9.1、Kv9.2、Kv9.3 mRNA in post-myocardial infarction rat markedly, which
is quick and absolute. Part III
Effects of metoprolol on the changes of expression of potassium channels Kv9.X in post-myocardial infarction rat
Objective: To study the effects of metoprolol on the changes of the expression of potassium channels Kv9.X (Kv9.1、 Kv9.2、 Kv9.3) of left ventricular non-infarcted myocardiums in post-myocardial infarction (post-MI) rats.
Methods: Using a rat model of MI, induced by the left anterior descending coronary artery (LAD) ligation in female Sprague-Dawley rats, the living rats randomly divided into post-MI group (7 days group[n=10]; 30 days group[n=11]) or metoprolol group(7 days group[n=10]; 30 days group[n=9]; 8mg.kg~(-1).day~(-1)). Accordingly, the sham-operation group (sham-group) was established. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we measured Kv9.1、 Kv9.2、 Kv9.3 mRNA in each group.
Results: Compared to MI groups, potassium channels Kv9.1、 Kv9.2、 Kv9.3 mRNA in the metoprolol group remarkably increases on 30 days (P<0.05). Compared to the sham-groups, potassium channels Kv9.1、 Kv9.2、Kv9.3 mRNA in the metoprolol groups remarkably decreases regardless of on 7 days or 30 days (P<0.05). Compared to the sham-groups, potassium channels Kv9.1、 Kv9.2、 Kv9.3 mRNA in the MI groups remarkably decreases regardless of on 7 days or 30 days (respectively, P<0.05; P<0.01).
Compared to on 7 days after myocardial infarction, potassium channels Kv9.1 、 Kv9.2、
Kv9.3 mRNA remarkably decreases on 30 days (P<0.05).
Conclusion: Metoprolol may reverse the downregulation of expression of potassium
channels Kv9.1 、 Kv9.2、 Kv9.3mRNA in post-myocardial infarction rats and this reverse
effect is tardo.
引文
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2. Xu H, Barry DM, Li H, et al. Attenuation of the slow component of delayed rectification, action potential prolongation, and triggered activity in mice expressing a dominant-negative Kv2 α subunit [J]. Circ Res, 1999, 85: 623-633.
3. Wang W, Hino N, Yamasaki H, et al. Kv2.1 K~+ channels underlie major voltage-gated K~+ outward current in H9c2 myoblasts [J]. Jpn J Physiol, 2001, 52:507-514.
4. Salinas M, Duprat F, Heurteaux C, et al. New modulatory α subunits for mammalian Shab K~+ channels [J]. J Biol Chem, 1997, 271(39): 24371-24379.
5. Kerschensteiner D, Stocker M. Heteromeric assembly of Kv2.1 with Kv9.3: Effect on the state dependence of inactivation [J]. Biophys J, 1999, 77(1): 248-257.
6. Surawicz B. Ventricular fibrillation and dispersion of repolarization [J]. J Cardiovasc Electrophysiol, 1997, 8:1009-1012.
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12. El-Adawi H, Deng LL, Tramontano A, et al. The functional role of the JAK-STAT pathway in post-infarction remodeling [J]. Cardiovasc Res, 2003, 57: 129-138.
1. Alinas M, Duprat F, Heurteaux C, et al. New modulatory a subunits for mammalian Shab K+ channels [J]. J Biol Chem, 1997, 271(39): 24371-24379.
2. Kerschensteiner D, Stocker M. Heteromeric assembly of Kv2.1 with Kv9.3: Effect on the state dependence of inactivation [J]. Biophys J, 1999, 77(1): 248-257.
3. Stocker M, Kerschensteiner D. Cloning and tissue distribution of two new potassium channels α-subunits from rat brain [J]. Biochem Biophys Res Commun,1998, 248:927-934.
4. Xiao RP. β-adrenergic signaling in the heart: dual coupling of the β_(2~-) adrenergic receptor to G_s and G_i proteins [J]. Sci. STKE. 104: RE15.
5. Dohlman HG，Thorner J, Caron MG, et al. Model systems for the study of seven-transmembrane-segment receptors [J]. Annu Rev Biochem, 1991, 60:653-688.
6. Wilson GG，O'Neill CA, Sivaprasadarao A, et al. Modulation by protein kinase A of a cloned rat brain potassium channel expressed in Xenopus Oocytes [J]. Pflugers Archiv European Journal of Physiology, 1994, 428:186-193.
7. Aiello EA, Walsh MP, Cole WC. Phosphorylation by protein kinase A enhances delayed rectifier K+ current in rabbit vascular smooth muscle cells [J]. Am J Physiol,1995, 268: H926-H934.
8. Bristow MR, Ginsburg R, Minobe W, et al. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts [J]. N Engl J Med, 1982,307(4):205-211.
9. Maurice JP, Shan AS, Kypson AP, et al. Molecular β-adrenergic signaling abnormalities in failing rabbit hearts after infarction [J]. Am J Physiol Heart Circ Physiol, 1999, 276: H1853-H1860.
10. Heilbrunn SM, Shah P, Bristow MR, et al. Increased β-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy [J]. Circulation,1989, 79: 483-490.
1. Shibasaki T. Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart[J]. J Physiol(Lond), 1987, 387:227-250
2. Anyukhovsky EP, Sosunov EA, Gainullin RZ, et al.The controversial M cell[J]. J Cardiovasc Electrophysiol, 1 999, 10: 244- 260.
3. Virag L, lost N, Opincariu M, et al. The slow compoment of the delayed rectifier potassium current in undiseased human ventricular myocytes [J]. Cardiovasc Res, 2001,49:790-797.
4. Pereon YI, De molombe SI, Bano II, et al. Differential expression of Kv LQT I isoforms across the human ventricular wall [J]. Am J Physiol, Heart Circ Physiol, 2000,276:HI908-H1915.
5. Zygmunt AC, Gibbons WR. Calcium-activated chloride current in rabbit ventricular myocytes [J]. Circ Res, 1991, 68:424-437
6. Wett wer EI, Amos GJI, Posival HI, et al. Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin [J]. Circ Res, 1 994, 75:473-482.
7. Drouin E, Charpentier F, Gauthier C, et al. Electrophysiological characteristics of cells spanning the left ventricular wall of human hearts , evidence for presence of M cells [J]. J Am Coll Cardiol, 1995, 26: 185- 192.
8. Nabauer M, Beuckelmann DJ, Ubenfuhr P, et al. Regional differences in current density and rate dependent properties of the transient out ward current in subepicardial alld subendocardial myocytes of human left ventricle [J]. Circulation,1996, 93: 168-177.
9. Li GR, Feng JI, Yue L, et al. Transmural heterogeneity of action potentials and Ito in myocytes isolated from the human right ventricle [J]. Am J Physiol, 1998, 275(Heart Circ Physiol 44):H369-H377
10. An WF, Bowlby MR, Beuy M, et al. Modulation of A type potassium channels by a family of calcium sensors[J]. Nature, 2000, 403: 553-556.
11. Rasati B, Pan Z, Lypen S, et al. Regulation of KCh I P2 potassiu m channel D subunit gene expression underlies the gradient of transient outward current in canine and human ventricle [J]. J Physiol, 2001, 533: Ⅰ19-Ⅰ25.
12. Noma A. ATP-regulated K+ channels in cardiac muscle [J]. Nature(Lond), 1983,305:147-148.
13. Nichols CG, Lederer WJ. The mechanism of KATP channel inhibition by ATP [J]. J Gen Physiol, 1991, 97:1095-1098.
14. TakanoM, Qin DY, Noma A. ATP-dependent decay and recovery of K+ channels in guinea pig cardiac myocytes [J]. Am J Physiol Heart Circ Physiol ,1990,258:H45-H50.
15. Boyden PA, Jeck CD. Ion channel function in disease [J]. Cardiovasc Res, 1995,29:312-318.
16. Hart G. Cellular electrophysiology in cardiac hypertrophy and failure [J]. Cardiovasc Res, 1994, 28:933-946.
17. Tomita F, Bassett AL,Myerburg RJ, et al. Diminished transient outward currents in rat hypertrophied ventricular myocytes [J]. Circ Res, 1994, 75:296-303.
18. Li Q, Keung EC. Effects of myocardial hypertrophy on transient outward current [J]. Am J Physiol Heart Circ Physiol, 1994, 266: H1738 -H1745
19. Lee JK, Kodama I, Honjo H, et al. Stage-dependent changes of membrane currents in rat ventricular myocytes associated with myocardial hypertrophy [J]. Circulation, 1995, 92(Suppl I): I-574.
20. Wettwer E, Amos GJ, Posival H, et al. Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin [J]. Circ Res, 1994, 75: 473-482.
21.Kleiman RB, Houser SR. Outward currents in normal and hypertrophied feline ventricular myocytes [J]. Am J Physiol Heart Circ Physiol, 1989, 256:H1450-H1461.
22. Furukawa T, Myerburg RJ, Furukawa N, et al. Metabolic inhibition of Ica, L and IK differs in feline left ventricular hypertrophy [J]. Am J Physiol Heart Circ Physiol, 1994, 266: H1121-H1131.
23. Qin D, Zhang Z-H, Jain P, et al. Potassium and calcium currents in remodeled rat ventricular myocytes following experimental myocardial infarction [J]. Biophys J, 1996, 70:A275.
24. Lue WM, Boyden PA. Abnormal electrical properties of myocytes from chronically infracted canine heart. Alterations in Vmax and the transient outward current [J]. Circulation, 1992, 85:1175-1188
25. Matsubara H, Suzuki J, Inada M. Shaker-related potassium channel, Kv1.4 mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and Kv1.5 genes in myocardial development and hypertrophy [J]. J Clin Invest, 1993, 92(4): 1659-1666
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59. Du XJ, Dart AM, Riemersma RA Sympathetic activation and increased extracellular potassium:Synergistic effects on cardiac potassium uptake andarrhythmlas [J]. J Cardiovasc pharmacol, 1999, 21(6):977-982.
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64. Kpperstuck M Mark wardt F. The new antiarrhythmiac substance AWD23-111 inhibits the delaged rectifier potassium current in guinea pig ventricular myocytes[J].Pharmazie, 1999, 54(1):61-68.
65. Wang JC, KlyosueT, Klriyama K,et al.Bepridil differentially inhibits two delayed rectifier K~+ currents, IKr and IKs, inguinea-pig entricularmyocytes[J]. Br J pharmacol, 1999, 128(8):1733-1738.
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68. Sieglp B. Blockers of ATP sensitive potassium current are of potential benefit in ischaemic heart disease [J].Cardiovasc Res, 1994,28:31-32.
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2. Surawicz B. Ventricular fibrillation and dispersion of repolarization [J]. J Cardiovasc Electrophysiol, 1997, 8:1009-1012.
3. Xu H, Barry DM, Li H, et al. Attenuation of the slow component of delayed rectification, action potential prolongation, and triggered activity in mice expressing a dominant-negative Kv2 a subunit [J]. Circ Res, 1999, 85: 623-633.
4. Wang W, Hino N, Yamasaki H, et al. Kv2.1 K+ channels underlie major voltage-gated K+ outward current in H9c2 myoblasts [J]. Jpn J Physiol, 2001, 52:507-514.
5. Salinas M, Duprat F, Heurteaux C, et al. New modulatory α subunits for mammalian Shab K+ channels [J]. J Biol Chem, 1997,271(39): 24371-24379.
6. Kerschensteiner D, Stocker M. Heteromeric assembly of Kv2.1 with Kv9.3: Effect on the state dependence of inactivation [J]. Biophys J, 1999,77(1): 248-257.
1. Roden DM, Balser JR, George Jr AL, et al. Cardiac ion channels [J]. Annu Rev Physiol, 2002,64: 431-75.
2. Xu H, Barry DM, Li H, et al. Attenuation of the slow component of delayed rectification, action potential prolongation, and triggered activity in mice expressing a dominant-negative Kv2 α subunit [J]. Circ Res, 1999, 85: 623-633.
3. Wang W, Hino N, Yamasaki H, et al. Kv2.1 K~+ channels underlie major voltage-gated K~+ outward current in H9c2 myoblasts [J]. Jpn J Physiol, 2001, 52:507-514.
4. Salinas M, Duprat F, Heurteaux C, et al. New modulatory α subunits for mammalian Shab K~+ channels [J]. J Biol Chem, 1997, 271(39): 24371-24379.
5. Kerschensteiner D, Stocker M. Heteromeric assembly of Kv2.1 with Kv9.3: Effect on the state dependence of inactivation [J]. Biophys J, 1999, 77(1): 248-257.
6. Surawicz B. Ventricular fibrillation and dispersion of repolarization [J]. J Cardiovasc Electrophysiol, 1997, 8:1009-1012.
7. Jiang M, Cabo C, Yao JA, et al. Delayed rectifier K currents have reduced amplitudes and altered kinetics in myocytes from infracted canine ventricle [J]. Cardiovasc Res, 2000,48: 34-43.
8. Huang B, Qin D, El-Sherif N. Early down-regulation of K+ channel genes and currents in the postinfarction heart [J]. J Cardiovasc Electrophysiol, 2000 ,11(11):1252-61.
9. Stocker M, Kerschensteiner D. Cloning and tissue distribution of two new potassium channels α-subunits from rat brain [J]. Biochem Biophys Res Commun,1998, 248:927-934.
10. Stocker M, Hellwig M, Kerschensteiner D. Subunit assembly and domain analysis of electrically silent K+ channel α-subunits of the rat Kv9 subfamily [J]. J Neurochem, 1999, 72:1725-1734.
1. Roden DM, Balser JR, George Jr AL, et al. Cardiac ion channels [J]. Annu Rev Physiol, 2002, 64:431-75.
2. Jiang M, Cabo C, Yao JA, et al. Delayed rectifier K currents have reduced amplitudes and altered kinetics in myocytes from infracted canine ventricle [J]. Cardiovasc Res, 2000, 48: 34-43.
3. Salinas M, Duprat F, Heurteaux C, et al. New modulatory α subunits for mammalian Shab K+ channels [J]. J Biol Chem, 1997, 271(39): 24371-24379.
4. Kerschensteiner D, Stocker M. Heteromeric assembly of Kv2.1 with Kv9.3: Effect on the state dependence of inactivation [J]. Biophys J, 1999, 77(1): 248-257.
5. Pan SJ, Zhu MY, Raizada MK, et al. ANG Ⅱ-mediated inhibition of neuronal delayed rectifier K+ current: role of protein kinase C-α[J]. Am J Physiol Cell Physiol, 2001, 281(1): C17-C23.
6. Clement-Chomienne O, Walsh MP, Cole WC. Angiotensin Ⅱactivation of protein kinase C decreases delayed rectifier K+ current in rabbit vascular myocytes [J]. J Physiol, 1996, 495(3):689-700.
7. Hayabuchi Y, Standen NB, Davies NW. Angiotensin Ⅱinhibits and alters kinetics of voltage-gated K+ channels of rat arterial smooth muscle [J]. Am J Physiol Heart Circ Physiol, 2001, 281(6): H2480-H2489.
8. Aiello EA, Malcolm AT, Walsh MP, et al. β-adrenoceptor activation and PKA regulate delayed rectifier K+ channels of vascular smooth muscle cells [J]. Am J physiol, 1998, 275:H448-H459.
9. Anand-Srivastava, MB. Angiotensin Ⅱreceptors negatively coupled to adenylate cyclase in rat aorta [J]. Biochem Biophys Res Commun, 1983, 117: 420-428.
10. Zhu MY, Gelband CH, Posner P, et al. Angiotensin ⅡDecreases Neuronal Delayed Rectifier Potassium Current: Role of Calcium/Calmodulin-Dependent Protein Kinase Ⅱ[J]. J Neurophysiol, 1999, 82(3): 1560-1568.
11. Mascareno E, Dhar EM, Siddiqui MAQ. Signal transduction and activator of transcription (STAT) protein-dependent activation of ANG promoter. A cellular signal for hypertrophy in cardiac muscle [J]. Proc Natl Acad Sci USA, 1998,95:5590-5594.
12. El-Adawi H, Deng LL, Tramontano A, et al. The functional role of the JAK-STAT pathway in post-infarction remodeling [J]. Cardiovasc Res, 2003, 57: 129-138.
1. Alinas M, Duprat F, Heurteaux C, et al. New modulatory a subunits for mammalian Shab K+ channels [J]. J Biol Chem, 1997, 271(39): 24371-24379.
2. Kerschensteiner D, Stocker M. Heteromeric assembly of Kv2.1 with Kv9.3: Effect on the state dependence of inactivation [J]. Biophys J, 1999, 77(1): 248-257.
3. Stocker M, Kerschensteiner D. Cloning and tissue distribution of two new potassium channels α-subunits from rat brain [J]. Biochem Biophys Res Commun,1998, 248:927-934.
4. Xiao RP. β-adrenergic signaling in the heart: dual coupling of the β_(2~-) adrenergic receptor to G_s and G_i proteins [J]. Sci. STKE. 104: RE15.
5. Dohlman HG，Thorner J, Caron MG, et al. Model systems for the study of seven-transmembrane-segment receptors [J]. Annu Rev Biochem, 1991, 60:653-688.
6. Wilson GG，O'Neill CA, Sivaprasadarao A, et al. Modulation by protein kinase A of a cloned rat brain potassium channel expressed in Xenopus Oocytes [J]. Pflugers Archiv European Journal of Physiology, 1994, 428:186-193.
7. Aiello EA, Walsh MP, Cole WC. Phosphorylation by protein kinase A enhances delayed rectifier K+ current in rabbit vascular smooth muscle cells [J]. Am J Physiol,1995, 268: H926-H934.
8. Bristow MR, Ginsburg R, Minobe W, et al. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts [J]. N Engl J Med, 1982,307(4):205-211.
9. Maurice JP, Shan AS, Kypson AP, et al. Molecular β-adrenergic signaling abnormalities in failing rabbit hearts after infarction [J]. Am J Physiol Heart Circ Physiol, 1999, 276: H1853-H1860.
10. Heilbrunn SM, Shah P, Bristow MR, et al. Increased β-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy [J]. Circulation,1989, 79: 483-490.
1. Shibasaki T. Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart[J]. J Physiol(Lond), 1987, 387:227-250
2. Anyukhovsky EP, Sosunov EA, Gainullin RZ, et al.The controversial M cell[J]. J Cardiovasc Electrophysiol, 1 999, 10: 244- 260.
3. Virag L, lost N, Opincariu M, et al. The slow compoment of the delayed rectifier potassium current in undiseased human ventricular myocytes [J]. Cardiovasc Res, 2001,49:790-797.
4. Pereon YI, De molombe SI, Bano II, et al. Differential expression of Kv LQT I isoforms across the human ventricular wall [J]. Am J Physiol, Heart Circ Physiol, 2000,276:HI908-H1915.
5. Zygmunt AC, Gibbons WR. Calcium-activated chloride current in rabbit ventricular myocytes [J]. Circ Res, 1991, 68:424-437
6. Wett wer EI, Amos GJI, Posival HI, et al. Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin [J]. Circ Res, 1 994, 75:473-482.
7. Drouin E, Charpentier F, Gauthier C, et al. Electrophysiological characteristics of cells spanning the left ventricular wall of human hearts , evidence for presence of M cells [J]. J Am Coll Cardiol, 1995, 26: 185- 192.
8. Nabauer M, Beuckelmann DJ, Ubenfuhr P, et al. Regional differences in current density and rate dependent properties of the transient out ward current in subepicardial alld subendocardial myocytes of human left ventricle [J]. Circulation,1996, 93: 168-177.
9. Li GR, Feng JI, Yue L, et al. Transmural heterogeneity of action potentials and Ito in myocytes isolated from the human right ventricle [J]. Am J Physiol, 1998, 275(Heart Circ Physiol 44):H369-H377
10. An WF, Bowlby MR, Beuy M, et al. Modulation of A type potassium channels by a family of calcium sensors[J]. Nature, 2000, 403: 553-556.
11. Rasati B, Pan Z, Lypen S, et al. Regulation of KCh I P2 potassiu m channel D subunit gene expression underlies the gradient of transient outward current in canine and human ventricle [J]. J Physiol, 2001, 533: Ⅰ19-Ⅰ25.
12. Noma A. ATP-regulated K+ channels in cardiac muscle [J]. Nature(Lond), 1983,305:147-148.
13. Nichols CG, Lederer WJ. The mechanism of KATP channel inhibition by ATP [J]. J Gen Physiol, 1991, 97:1095-1098.
14. TakanoM, Qin DY, Noma A. ATP-dependent decay and recovery of K+ channels in guinea pig cardiac myocytes [J]. Am J Physiol Heart Circ Physiol ,1990,258:H45-H50.
15. Boyden PA, Jeck CD. Ion channel function in disease [J]. Cardiovasc Res, 1995,29:312-318.
16. Hart G. Cellular electrophysiology in cardiac hypertrophy and failure [J]. Cardiovasc Res, 1994, 28:933-946.
17. Tomita F, Bassett AL,Myerburg RJ, et al. Diminished transient outward currents in rat hypertrophied ventricular myocytes [J]. Circ Res, 1994, 75:296-303.
18. Li Q, Keung EC. Effects of myocardial hypertrophy on transient outward current [J]. Am J Physiol Heart Circ Physiol, 1994, 266: H1738 -H1745
19. Lee JK, Kodama I, Honjo H, et al. Stage-dependent changes of membrane currents in rat ventricular myocytes associated with myocardial hypertrophy [J]. Circulation, 1995, 92(Suppl I): I-574.
20. Wettwer E, Amos GJ, Posival H, et al. Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin [J]. Circ Res, 1994, 75: 473-482.
21.Kleiman RB, Houser SR. Outward currents in normal and hypertrophied feline ventricular myocytes [J]. Am J Physiol Heart Circ Physiol, 1989, 256:H1450-H1461.
22. Furukawa T, Myerburg RJ, Furukawa N, et al. Metabolic inhibition of Ica, L and IK differs in feline left ventricular hypertrophy [J]. Am J Physiol Heart Circ Physiol, 1994, 266: H1121-H1131.
23. Qin D, Zhang Z-H, Jain P, et al. Potassium and calcium currents in remodeled rat ventricular myocytes following experimental myocardial infarction [J]. Biophys J, 1996, 70:A275.
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