吡那地尔及二氮嗪对慢性低氧大鼠肺动脉平滑肌K_（ATP）通道蛋白表达的影响
|
摘要
目的:低氧性肺动脉高压(CHAPH)是慢性阻塞性肺疾病(COPD)发展为慢性肺源性心脏病的关键环节,基于经典的ATP敏感性钾通道(KATP)开放剂吡那地尔(Pin)能预防和抑制CHPAH的形成,线粒体膜ATP敏感性钾通道(MitoKATP)开放剂二氮嗪(DZ)能促使肺动脉高压的发生,本实验目的在于探讨慢性低氧对肺动脉平滑肌KATP通道蛋白表达的影响,及预先灌服过Pin和DZ对大鼠在慢性低氧刺激时该通道表达发生的变化。
方法:SD大鼠置于常压低氧环境下(氧浓度为10±0.5%),每天6小时,每周6天,持续4周,制备CHAPH模型。35只雄性实验动物随机分为阴性对照组(生理盐水5 ml/kg·d灌胃)、阳性对照组-低氧组(常压低氧环境+生理盐水5 ml/kg·d灌胃)、吡那地尔治疗组(预先30 min Pin 2.0 mg/kg·d灌胃+常压低氧环境)、二氮嗪治疗组(预先30 min DZ 1.5 mg/kg·d灌胃+常压低氧环境),二氮嗪+5-羟癸酸(5-HD)治疗组(预先60 min 5-HD 3.0 mg/kg·d灌胃,30 min后DZ 1.5 mg/kg·d灌胃+常压低氧环境)。每组7只。四周后,测定平均肺动脉压(mPAP)后处死大鼠,取出肺动脉主干,无菌条件下去除血管外膜和内膜后提取蛋白,用Western-Blot方法检测各组KATP通道蛋白的表达状况,并用光密度扫描仪半定量分析。
结果:(1)低氧组大鼠的mPAP(36.41+2.08 mmHg)显著高于正常对照组(18.47+1.99 mmHg,P＜0.05);吡那地尔治疗组mPAP(24.69+2.37 mmHg)较低氧组显著下降;二氮嗪治疗组加重慢性低氧所致的肺动脉压力升高(44.11±4.36 mmHg);5-HD+二氮嗪治疗组的mPAP(34.30±2.82 mmHg)显著低于二氮嗪治疗组。(2)大鼠肺动脉平滑肌上存在KATP通道,低氧组大鼠K_(ATP)通道SUR2B亚型蛋白表达水平明显低于对照组(0.04+0.004 vs 0.12±0.01,P＜0.05),吡那地尔治疗组明显高于低氧组(0.10±0.012 vs 0.04±0.004,P＜0.05),二氮嗪治疗组显著低于低氧组(0.01±0.004 vs 0.04±0.004,P＜0.05),5-HD+二氮嗪治疗组显著高于二氮嗪治疗组(0.07±0.008 vs0.01±0.004,P＜0.05),并亦高于低氧组(0.07±0.008 vs 0.04+0.004,P＜0.05)。5组Kir6.1蛋白表达没有显著差异。
结论:本研究结果提示肺动脉平滑肌KATP和MitoKATP功能紊乱可能参与形成CHPAH;Pin能拮抗慢性低氧所致的肺动脉平滑肌KATP通道蛋白表达下调,而二氮嗪能抑制肺动脉平滑肌KATP通道蛋白的表达。
Objective: Chronic hypoxic pulmonary hypertension(CHPH) has been demonstrated to been the key event in the process chronic obstructive pulmonary disease(COPD) to chronic cor pulmonale. Previous study had found that the ATP-sensitive potassium channel opener Pinacidil(Pin) could prevent pulmonary hypertension in chronic hypoxic rats, and the mitochondrial ATP-sensitive potassium channel (MitoK_(ATP)) opener Diazoxide (DZ) could aggravate pulmonary hypertension, so the aim of this study was to investigate if any difference exists in protein levels of ATP-sensitive potassium channel (K_(ATP)) in pulmonary smooth muscles between chronic hypoxic and normal rats, and to examine if any changes of K_(ATP) channel protein level occurred after long-term Pinacidil and Diazoxide treatment.
Methods: Sprague-Dawley rats were fed in hypoxic and normobaric environment (10±0.5% O_2, 6h·day~(-1) and 6day·week~(-1)) to establish CHPAH model. Thirty-five male SD rats were randomly divided into control group (NS 5 ml/kg·d), hypoxic group (hypoxia + NS 5 ml/kg·d), Pin treated group (Pin 2.0 mg/kg·d via oral gavage + hypoxia), DZ treated group (DZ 1.5 mg/kg·d via oral gavage + hypoxia) and 5-HD+DZ treated group (5-HD 3.0 mg/kg·d, then DZ 1.5 mg/kg·d via oral gavage + hypoxia). 7 rats are included in each group. Four weeks later, the mean pulmonary arterial pressure (mPAP) was measured, then the rats were executed, and the stems of pulmonary artery were immediately dissected. Western-blot were performed to analyze the protein level of K_(ATP) channels in pulmonary main artery smooth muscles.
Results: (1) The level of mPAP was significantly higher in the hypoxic group (36.41±2.08 mmHg) than those in control group (18.47±1.99 mmHg, P<0.05). Pinacidil treated group decreased the level of mPAP significantly (24.69±2.37 mmHg). While Diazoxide treated group increased the level of mPAP significantly (44.11±4.36 mmHg). The level of mPAP was significantly lower in the 5-HD + Diazoxide treated group (34.30±2.82 mmHg) than those in Diazoxide treated group. (2) The K_(ATP) channels were expressed in pulmonary main artery of rats. The protein level of SUR2B in the hypoxic group were significant lower than the control group (0.04±0.004 vs 0.12±0.01, P<0.05), Pinacidil treated group rats had higher expression levels than the hypoxic group (0.10±0.012 vs 0.04±0.004, P<0.05), Diazoxide treated group rats had lower expression levels than the hypoxic group (0.01±0.004 vs 0.04±0.004, P<0.05), and 5-HD + Diazoxide treated group rats had higher expression levels than the Diazoxide treated group (0.07±0.008 vs 0.01±0.004, P<0.05), and they also had higher expression levels than the hypoxic group (0.07±0.008 vs 0.04±0.004, P<0.05). Kir6.1 protein level did not show statically significant changes across the five groups.
Conclusion: The expression of K_(ATP) channel was down-regulated in pulmonary artery of CHPAH rats, and this down-regulation was prevented by Pin in chronic hypoxic rats. While DZ could fartherly down-regulate the K_(ATP) channel expression. The results indicate that dysfunction of K_(ATP) channel and MitoK_(ATP) channel of pulmonary artery maybe contribute to the pathogenesis of chronic hypoxia pulmonary hypertension.
方法:SD大鼠置于常压低氧环境下(氧浓度为10±0.5%),每天6小时,每周6天,持续4周,制备CHAPH模型。35只雄性实验动物随机分为阴性对照组(生理盐水5 ml/kg·d灌胃)、阳性对照组-低氧组(常压低氧环境+生理盐水5 ml/kg·d灌胃)、吡那地尔治疗组(预先30 min Pin 2.0 mg/kg·d灌胃+常压低氧环境)、二氮嗪治疗组(预先30 min DZ 1.5 mg/kg·d灌胃+常压低氧环境),二氮嗪+5-羟癸酸(5-HD)治疗组(预先60 min 5-HD 3.0 mg/kg·d灌胃,30 min后DZ 1.5 mg/kg·d灌胃+常压低氧环境)。每组7只。四周后,测定平均肺动脉压(mPAP)后处死大鼠,取出肺动脉主干,无菌条件下去除血管外膜和内膜后提取蛋白,用Western-Blot方法检测各组KATP通道蛋白的表达状况,并用光密度扫描仪半定量分析。
结果:(1)低氧组大鼠的mPAP(36.41+2.08 mmHg)显著高于正常对照组(18.47+1.99 mmHg,P＜0.05);吡那地尔治疗组mPAP(24.69+2.37 mmHg)较低氧组显著下降;二氮嗪治疗组加重慢性低氧所致的肺动脉压力升高(44.11±4.36 mmHg);5-HD+二氮嗪治疗组的mPAP(34.30±2.82 mmHg)显著低于二氮嗪治疗组。(2)大鼠肺动脉平滑肌上存在KATP通道,低氧组大鼠K_(ATP)通道SUR2B亚型蛋白表达水平明显低于对照组(0.04+0.004 vs 0.12±0.01,P＜0.05),吡那地尔治疗组明显高于低氧组(0.10±0.012 vs 0.04±0.004,P＜0.05),二氮嗪治疗组显著低于低氧组(0.01±0.004 vs 0.04±0.004,P＜0.05),5-HD+二氮嗪治疗组显著高于二氮嗪治疗组(0.07±0.008 vs0.01±0.004,P＜0.05),并亦高于低氧组(0.07±0.008 vs 0.04+0.004,P＜0.05)。5组Kir6.1蛋白表达没有显著差异。
结论:本研究结果提示肺动脉平滑肌KATP和MitoKATP功能紊乱可能参与形成CHPAH;Pin能拮抗慢性低氧所致的肺动脉平滑肌KATP通道蛋白表达下调,而二氮嗪能抑制肺动脉平滑肌KATP通道蛋白的表达。
Objective: Chronic hypoxic pulmonary hypertension(CHPH) has been demonstrated to been the key event in the process chronic obstructive pulmonary disease(COPD) to chronic cor pulmonale. Previous study had found that the ATP-sensitive potassium channel opener Pinacidil(Pin) could prevent pulmonary hypertension in chronic hypoxic rats, and the mitochondrial ATP-sensitive potassium channel (MitoK_(ATP)) opener Diazoxide (DZ) could aggravate pulmonary hypertension, so the aim of this study was to investigate if any difference exists in protein levels of ATP-sensitive potassium channel (K_(ATP)) in pulmonary smooth muscles between chronic hypoxic and normal rats, and to examine if any changes of K_(ATP) channel protein level occurred after long-term Pinacidil and Diazoxide treatment.
Methods: Sprague-Dawley rats were fed in hypoxic and normobaric environment (10±0.5% O_2, 6h·day~(-1) and 6day·week~(-1)) to establish CHPAH model. Thirty-five male SD rats were randomly divided into control group (NS 5 ml/kg·d), hypoxic group (hypoxia + NS 5 ml/kg·d), Pin treated group (Pin 2.0 mg/kg·d via oral gavage + hypoxia), DZ treated group (DZ 1.5 mg/kg·d via oral gavage + hypoxia) and 5-HD+DZ treated group (5-HD 3.0 mg/kg·d, then DZ 1.5 mg/kg·d via oral gavage + hypoxia). 7 rats are included in each group. Four weeks later, the mean pulmonary arterial pressure (mPAP) was measured, then the rats were executed, and the stems of pulmonary artery were immediately dissected. Western-blot were performed to analyze the protein level of K_(ATP) channels in pulmonary main artery smooth muscles.
Results: (1) The level of mPAP was significantly higher in the hypoxic group (36.41±2.08 mmHg) than those in control group (18.47±1.99 mmHg, P<0.05). Pinacidil treated group decreased the level of mPAP significantly (24.69±2.37 mmHg). While Diazoxide treated group increased the level of mPAP significantly (44.11±4.36 mmHg). The level of mPAP was significantly lower in the 5-HD + Diazoxide treated group (34.30±2.82 mmHg) than those in Diazoxide treated group. (2) The K_(ATP) channels were expressed in pulmonary main artery of rats. The protein level of SUR2B in the hypoxic group were significant lower than the control group (0.04±0.004 vs 0.12±0.01, P<0.05), Pinacidil treated group rats had higher expression levels than the hypoxic group (0.10±0.012 vs 0.04±0.004, P<0.05), Diazoxide treated group rats had lower expression levels than the hypoxic group (0.01±0.004 vs 0.04±0.004, P<0.05), and 5-HD + Diazoxide treated group rats had higher expression levels than the Diazoxide treated group (0.07±0.008 vs 0.01±0.004, P<0.05), and they also had higher expression levels than the hypoxic group (0.07±0.008 vs 0.04±0.004, P<0.05). Kir6.1 protein level did not show statically significant changes across the five groups.
Conclusion: The expression of K_(ATP) channel was down-regulated in pulmonary artery of CHPAH rats, and this down-regulation was prevented by Pin in chronic hypoxic rats. While DZ could fartherly down-regulate the K_(ATP) channel expression. The results indicate that dysfunction of K_(ATP) channel and MitoK_(ATP) channel of pulmonary artery maybe contribute to the pathogenesis of chronic hypoxia pulmonary hypertension.
引文
1.Barnes PJ.Chronic obstructive pulmonary disease.N Engl J Med,2000,343:269-279.
2.Barnes PJ.Therapy of chronic obstructive pulmonary disease.Pharmacology&Therapeutics,2003,97:87-94.
3.Champion H C,Bivalacqua T J,D.Souza F M,et al.Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo,Effect on agonist- induced and flow-mediated vascular.Circ Res,1999,84:1422-1432.
4.Budts W,Pokreisz P,Nong Z,et al.Aerosol genetransfer with inducible nitric oxide synthase reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats.Circulation,2000,102:2880-2885.
5.解卫平,王虹,胡刚等.肺动脉高压治疗现状.国外医学呼吸分册,2000.28:8-12.
6.费允云,徐凯峰,蔡柏蔷.肺动脉高压治疗进展.国外医学呼吸分册,2003,23:169-172.
7.解卫平,丁建花,王虹等.K_(ATP)通道开放剂吡那地尔对兔肺动脉平滑肌细胞增殖的影响.中国临床药理学与治疗学,2005,10:20-23。
8.Xu M,Wang Y,Ayub A,et al.Mitochondrial K_(ATP)channel activation reduces anoxic injury by restoring mitochondrial membrane potential. Am J Physiol Heart Circ Physiol, 2001, 281: H1295-H1303.
9. Coghlan MJ, Carroll WA, Gopalakrishnan M. Recent developments in the biology and medicinal chemistry of potassium channel modulators: update from a decade of progress. Med Chem, 2001, 44: 1627-1653.
10. Lawson K. Potassium chaeel openers as potential therapeutic weapons in ion channel disease. Kidney Int, 2000, 57: 838-845.
11. Ye D, Zhou W, Lee HC. Activation of rat mesenteric arterial K_(Atp) channels by 11, 12-epoxyeicosatrienoic acid. Am. J. Physiol. Heart. Circ. Physiol, 2005, 288: H358-H364.
12. Wang J, Juhaszova M, Rubin LJ, et al. Hypoxia inhibits gene expression of voltage-gated K~+ channel asubunits in pulmonary artery smooth muscle cells. J Clin Invest, 1997, 100: 2347-53.
13. Sweeney M, Yuan JXJ. Hypoxic pulmonary vasoconstriction: role of voltage-gated potassium channels. Respir Res, 2000, 1: 40-48.
14. Presberg KW, Dincer HE. Pathophysiology of pulmonary hypertension due to lung disease. Curr Opin Pulm Med, 2003, 9: 131-138.
15. Jeffery T K, Wanstall J C. Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension. Pharmacol Thera Peutics, 2001, 92: 1-20.
16. Qi JG, Tang XY, Du JB, et al. Influence of high pulmonary blood flow on ultrastructure of intra-acinar pulmonary arteries in rats.Journal of Chinese Electron Microscopy Society,2002,21:380- 382.
17.Jeffery TK,Morrell NW.Molecular and celluar basis of pulmonary vascular remodeling in pulmonary hypertension.Prog Cardiovasc Dis,2002,45:173-202.
18.Strange JW,Wharton J,Phillips PG,et al.Recent insights into the pathogenesis and therapeutics of pulmonary hypertension.Clin Sci,2002,102:253-268.
19.Tang XY,Du JB,Qi JG,et al.Ultrastructure observation intra-acinar pulmonary arteries on experimental hypoxic pulmonary hypertension.Journal of Chinese Electron Microscopy Society,2004,23:522-525.
20.王虹,王祥,解卫平.埃他卡林对低氧性肺动脉高压肺组织增殖细胞核抗原表达的抑制作用.医药导报,2005,24:7-9.
21.Du JB,Yan H,Wei B,et al.Effect of L-arginine on collagen of high flow-induced pulmonary arterial remodeling.Cirl J,2005,69:603-608.
22.Shi Y,Du JB,Tang XY,et al.Pulmonary vascular microstructure in chronic pulmonary hypertension.Journal of Applied Clinical Pediatrics,2005,20:628-629.
23.Cowan KN,Jones PL,Rabinovitch M.Elastase and matrix metalloproteinase inhibitors induce regression and tenascin-C antisense prevents progression of vascular disease.J Clin Inves, 2000,105:21-34.
24.Kanazawa F,Nakanishi K,Osada H,et al.Expression of endothelin-1 in the brain and lung of rats exposed to permanent hypobaric hypoxia.Brain Res,2005,1036:145-54.
25.Ambalavanan N,Bulger A,Murphy-Ullrich J,et al.Endothelin-A receptor blockade prevents and partially reverses neonatal hypoxic pulmonary vascular remodeling.Pediatr Res,2005,57:631-6.
26.Ivy DD,Yanagisawa M,Gariepy CE,et al.Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats.Am J Physiol Lung Cell Mol Physiol,2002,282:L703-12.
27.Li KX,Fouty B,Mcmurtry IF,et al.Enhanced ET_A-receptor-mediated inhibition of Kv channels in hypoxic hypertensive rat pulmonary artery myocytes.Am J Physiol,1999,277:H363-H370.
28.Peng W,Michael JR,Hoidal JR.ET-1 modulates Kca-channels activity and arterial tension in normoxic and hypoxic human pulmonary vasculature.Am J Physiol,1998,275:L729-L739.
29.Sato K,Morio Y,Morris KG,et al.Mechanism of hypoxic pulmonary vasoconstriction involves ET_A receptor-mediated inhibition of K_(ATP)channels.Am J Physiol,2000,278:L434-L442.
30.李志斌,邹霞英,赖晃文.一氧化氮在慢性缺氧性肺动脉高压中的作用.中华结核和呼吸杂志,1999,22:367-8。
31. Hampl V, Bibova J, Banasova A, et al. Pulmonary vascular iNOS induction participates in the onset of chronic hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol, 2006, 290: L11-20.
32. Qi JG, Du JB, Jia JF. Endogenous nitric oxide regulates hypoxic pulmonary vascular remodeling in rats. Chinese Journal of Pediatrics. 1999,37: 104-106.
33. Park MH. Advances in diagnosis and treatment in patients with pulmonary arterial hypertension. Catheter Cardiovasc Interv, 2008, 71:205-13.
34. Wright JL, Levy RD, Churg A. Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment. Thorax , 2005, 60: 605-9.
35. Geraci MW, Gao B, Shepherd DC, et al. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. Clin Invest, 1999, 103: 1509-1515.
36. Yuan XJ, Goldman WF, Tod ML. Hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes. Am J Physiol (Lung Cell Mol Physiol), 1993, 264: L116-L123.
37. Mandegar M, Yuan JXJ. Role of K~+ channels in pulmonary hypertension. Vascular Pharmocol, 2002, 38: 25-33.
38. Michelakis ED, Weir EK. The pathobiology of pulmonary hypertension. In:Rich S, McLaughlin VV. Pulmonary Hypertension. Philadelphia: W.B.Saunders Company, 2001:419-32.
39. Platoshyn O, Yu Y, Golovina VA, et al. Chronic hypoxia decreases Kv channel expression and function in pulmonary artery myocytes. Am J Physiol (Lung Cell Mol Physiol), 2001, 280: L801-L812.
40. Yuan XJ, Wang J, Juhaszova M, et al. Attenuated K~+ channel gene transcription in primary pulmonary hypertension. Lancet, 1998, 351: 726-727.
41. Yuan JXJ, Aldinger AM, Juhaszova M, et al. Dysfunction voltage-gated K~+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation, 1998, 98: 1400-1406.
42. Peng W, Hoidal JR, Karwande HS, et al. Effect of chronic hypoxianon K~+ channels: regulation in human pulmonary vascular smooth muscle cells. Am J Physiol (Cell Physiol 41), 272: C1271-C1278.
43. Muraki S, Tohse N, Seki S, et al. Decrease in the Ca~(2+)-activated K~+ current of pulmonary arterial smooth muscle in pulmonary hypertension rats. Naunyn-Schmiedeberg's Arch Pharmacol, 2001, 364: 183-192.
44. Cornfield D, Resnik ER, Herron JM, et al. Chronic intrauterine pulmonary hypertension decreases calcium-sensitive potassium channel mRNA expression.Am J Physiol Lung Cell Mol Physiol,2000,279:L857-L862.
45.Platoshyn O,Golovina VA,Bailey C,et al.Sustained membrane depolarization and pulmonary artery smooth muscles cell proliferation.Am J Physiol,2000,279:C1540-9.
46.Berridge MJ.Inositol trisphosphate and calcium signalling.Nature,1993,361:315 - 325.
47.Somlyo AP.Somlyo AV.Signal transduction and regulation in smooth muscle.Nature,2002,372:231- 236.
48.Brayden JE.Functional roles of K_(ATP)channels in vascular smooth muscles.Clin Exp Pharmacol Physiol,2002,29:312-6.
49.Murphy ME,Brayden JE.Nitric oxide hyperpolarizes rabbit mesenteric arteries via ATP-sensitive potassium channels.Journal of Physiology,1995,486:47-58.
50.肖欣荣,程德云,陈文彬.ATP敏感性钾通道开放剂对大鼠慢性低氧性肺动脉高压的作用.中华结核和呼吸杂志,2003,26:97-100。
51.Smirnov S,Robertson TP,Ward JPT,et al.Chronic hypoxia is associated with reduced delayed rectifier K~+ current in rat pulmonary artery muscle cells.Am J Physiol,1994,266:H365-H370.
52.钟小宁,梁国容,何志义等.吡那地尔防治大鼠低氧性肺动脉高 压肺血管重建的实验研究.中华结核和呼吸杂志,2000,23:727-9.
53.Michelakis E,Mcmurtry S,Wu XC,et al.Dichloroacetate,a metabolic modulator,prevents and reverses chronic hypoxic pulmonary hypertension in rats:role of increased expression and activity of voltage-gated potassium channels.Circulation,2002,105:244-250.
54.Wang Hong,Xie Weiping,Qi xu,et al.Effects of Pinacidil on proliferation of cultured rabbit airway smooth muscle cells induced by endthelin-1.Chin Med J(Engl),2005,118:587-590.
55.Das B,Sarkar C.Cardiomrocyte mitochondrial K_(ATP)channels participate in the antiarrhythmic and antiirfarct effect of K_(ATP)activators during ischemia and reperfusion in an intact anesthetized rabbit model.Pol J Pharmacol,2003,55:771-786.
56.WANG Tao,ZHANG Zhen xiang,XU Yong jian.Effect of mitochondrial K_(ATP)channel on voltage-gated K~+ channel in 24hour-hypoxic human pulmonary artery smooth muscle cells.Chin Med J(Engl),2005,118:12-19.
57.Akao M,Teshima Y,Marban E.Antiapoptotic effect of nicorandil mediated by mitochondrial ATP-sensitive potassium channels in cultured cardiac myocytes.Am Coll cardio,2002,40:803-810.
58.胡红玲,张珍祥,赵建平.缺氧肺动脉平滑肌细胞中线粒体ATP敏感 钾通道开放对细胞色素C的分布及细胞增殖的作用.生理学报,2006.58:262-268.
59.赵建平,郭治,周志刚.线粒体ATP敏感钾通道对大鼠肺动脉平滑肌细胞低氧诱导因子-1α表达及细胞增殖的作用.生理学报,2007,59:157-62.
60.胡红玲,汪涛,张珍祥等.线粒体膜电位对缺氧人肺动脉平滑肌细胞内氧自由基的变化及细胞增殖的作用.中华结核和呼吸杂志,2006,29:727-30.
61.王虹,解卫平,齐栩等.吡那地尔对豚鼠哮喘模型气道反应性及其结构的影响.中华内科杂志,2003,42:804-805.
1.Champion H C,Bivalacqua T J,D.Souza F M,et al.Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo,Effect on agonist- induced and flow-mediated vascular.Circ.Res,1999,84:1422- 1432.
2.Budts W,Pokreisz P,Nong Z,et al.Aerosol genetransfer with inducible nitric oxide synthase reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats.Circulation,2000,102:2880 - 2885.
3.Abdalla SA,Gallione CJ,Barst RJ,et al.Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia.Eur Respir J,2004,23:373-7.
4.Machado RD,Aldred MA,James V,et al.Mutations of the TGF-βtype Ⅱ receptor BMPR2 in pulmonary arterial hypertension.Hum Mutat,2006,27:121 - 132.
5.Aldred M,Vijayakrishnan J,James V,et al.BMPR2 gene rearrangements account for a sinificant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat, 2006,27:212-213.
6. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-pfamily. Med Genet, 2000, 37: 741 - 745.
7. M. Humbert, Z. Deng, G. Simonneau BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives, Eur Respir,2002,20:518-523.
8. Caldwell RL, Gadipatti R, Lane KB, HIV-1 TAT represses transcription of the bone morphogenic protein receptor-2 in U937 monocytic cells. Leukol Biol, 2006, 79: 192-201.
9. Miyazono K, Maeda S, Imamura T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev, 2005, 16: 251 - 263.
10. Aoki H, FujiiM, Imamura T, et al. Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction. Cell Sci, 2001, 114: 1483 - 1489.
11. Chen HB, Shen J, Xu L. Identification of phosphatases for Smad in the BMP/DPP pathway. Genes Dev, 2006, 20: 648 - 653.
12. Massague J. Integration of Smad and MAPK pathways: a link and a linker revisited. Genes Dev, 2003, 17: 2993 - 2997.
13. Nohe A, Hassel S, Ehrlich M, et al .The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. Biol Chem, 2002, 277: 5330 - 5338.
14. Kretzschmar M, Doody J, Massagu J. Opposing BMP and EGF signaling pathways converge on the TGF-β family mediator Smadl. Nature, 1997,389:618-622.
15.IshidaW, Hamamoto T, Kusanagi K. Smad6 is a Smadl /5-induced Smad inhibitor. Biol Chem, 2000, 275: 6075 - 6079.
16. Yu PB, Beppu H, Kawai N, et al. Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells. Biol Chem, 2005, 280: 24443 - 24450.
17. Rudarakanchana N, Flanagan JA, Chen H, et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet, 2002, 11: 1517 -1525.
18. Morrell NW, Yang X, Upton PD, et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-pi and bone morphogenetic proteins. Circulation, 2001, 104: 790 - 795.
19. Atkinson C, Stewart S, Upton PD, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation, 2002,105: 1672 - 1678.
20. Yang X, Long L, Southwood M, et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res, 2005, 96: 1053 - 1063.
21. Richter A, Yeager ME, Zaiman A, et al. Impaired transforming growth factor-βsignaling in idiopathic pulmonary arterial hypertension. Respir Crit Care Med, 2004, 170: 1340 - 1348.
22. Valdimarsdottir G, Goumans MJ, Rosendahl A, et al. Stimulation of Id1 expression by bone morphogenetic proetin is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation, 2002, 106: 2263 - 2270.
1.Brayden J E.Functional roles of K_(ATP),channels in vascular smooth muscles.Clin Exp Pharmacol Physiol,2002,29:312-316.
2.Ye D,Zhou W,Lee HC.Activation of rat mesenteric arterial K_(ATP)channels by 11,12-epoxyeicosatrienoic acid.Am.J.Physiol.Heart.Circ.Physiol,2005,288:H358-H364.
3.Mandegar M,Yuan J XJ.Role of K~+ channels in pulmonary hypertension.Vascular Pharmacol,2002,38:25-33.
4.钟小宁,梁国容,何志义,等.吡那地尔防治大鼠低氧性肺动脉高压肺血管重建的实验研究.中华结核和呼吸杂志,2000,23:727-9.
5.胡红玲,张珍祥,赵建平等.缺氧人肺动脉平滑肌细胞中线粒体ATP敏感钾通道开放对细胞色素C的分布及细胞增殖的作用.生理学报,2006,58(3):262-268.
6.Peng W,Michael JR,Hoidal JR.ET-1 modulates Kca-channels activity and arterial tension in normoxic and hypoxic human pulmonary vasculature.Am J Physiol,1998,275:L729-39.
7.Sato K,Morio Y,Morris KG,et al.Mechanism of hypoxic pulmonary vasoconstriction involves ET_A receptor-mediated inhibition of K_(ATP)channels.Am J Physiol,2000,278:L434-42.
8.Platoshyn O,Golovina VA,Bailey C,et al.Sustained membrane depolarization and pulmonary artery smooth muscles cell proliferation.Am J Physiol,2000,279:C1540-1549.
9.Nakayama K,Fukuta Y,Kiyoshi A,et al.(+)-[~3H]Isradipine and[~3H]Glyburide bindings to heart and lung membranes from rats with monocrotaline-induced pulmonary hypertension.Jpn J Pharmacol,1999,81:176-84.
10.Sweeney M,Yu Y,Platoshyn O,et al.Inhibition of endogenous TRP1 decreases capacitative Ca~(2+)entry and attenuates pulmonary artery smooth muscle cell proliferation.Am.J.Physiol.Lung.Cell.Mol.Physiol,2002,283:L144-L155.
11.Platoshyn O,Zhang S,McDaniel SS,et al.Cytochrome C activates K~+ channels before inducing apoptosis.Am J Physiol,2002,283:C1298-C1305.
12.Xu M,Wang Y,Ayub A,et al.Mitochondrial K_(ATP)channel activation reduces anoxic injury by restoring mitochondrial membrane potential.Am J Physiol Heart Circ Physiol,2001,281:H1295-H1303.
13.胡红玲,汪涛,张珍祥等.线粒体膜电位对缺氧人肺动脉平滑肌细胞内氧自由基的变化及细胞增殖的作用.中华结核和呼吸杂志,2006,29:727-30.
14.Krick S,Platoshyn O,Mcdaniel SS,et al.Augmented K+currents and mitochondrial membrane depolarization in pulmonary artery myocyte apoptosis.Am J Physiol Lung Cell Mol Physiol,2001,281:L887-L894.
15.WANG Tao,ZHANG Zhen xiang,XU Yong jian.Effect of mitochondrial KATP channel on voltage-gated K~+ channel in 24 hour-hypoxic human pulmonary artery smooth muscle cells.Chin Med J(Engl),2005,118:12-19.
2.Barnes PJ.Therapy of chronic obstructive pulmonary disease.Pharmacology&Therapeutics,2003,97:87-94.
3.Champion H C,Bivalacqua T J,D.Souza F M,et al.Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo,Effect on agonist- induced and flow-mediated vascular.Circ Res,1999,84:1422-1432.
4.Budts W,Pokreisz P,Nong Z,et al.Aerosol genetransfer with inducible nitric oxide synthase reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats.Circulation,2000,102:2880-2885.
5.解卫平,王虹,胡刚等.肺动脉高压治疗现状.国外医学呼吸分册,2000.28:8-12.
6.费允云,徐凯峰,蔡柏蔷.肺动脉高压治疗进展.国外医学呼吸分册,2003,23:169-172.
7.解卫平,丁建花,王虹等.K_(ATP)通道开放剂吡那地尔对兔肺动脉平滑肌细胞增殖的影响.中国临床药理学与治疗学,2005,10:20-23。
8.Xu M,Wang Y,Ayub A,et al.Mitochondrial K_(ATP)channel activation reduces anoxic injury by restoring mitochondrial membrane potential. Am J Physiol Heart Circ Physiol, 2001, 281: H1295-H1303.
9. Coghlan MJ, Carroll WA, Gopalakrishnan M. Recent developments in the biology and medicinal chemistry of potassium channel modulators: update from a decade of progress. Med Chem, 2001, 44: 1627-1653.
10. Lawson K. Potassium chaeel openers as potential therapeutic weapons in ion channel disease. Kidney Int, 2000, 57: 838-845.
11. Ye D, Zhou W, Lee HC. Activation of rat mesenteric arterial K_(Atp) channels by 11, 12-epoxyeicosatrienoic acid. Am. J. Physiol. Heart. Circ. Physiol, 2005, 288: H358-H364.
12. Wang J, Juhaszova M, Rubin LJ, et al. Hypoxia inhibits gene expression of voltage-gated K~+ channel asubunits in pulmonary artery smooth muscle cells. J Clin Invest, 1997, 100: 2347-53.
13. Sweeney M, Yuan JXJ. Hypoxic pulmonary vasoconstriction: role of voltage-gated potassium channels. Respir Res, 2000, 1: 40-48.
14. Presberg KW, Dincer HE. Pathophysiology of pulmonary hypertension due to lung disease. Curr Opin Pulm Med, 2003, 9: 131-138.
15. Jeffery T K, Wanstall J C. Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension. Pharmacol Thera Peutics, 2001, 92: 1-20.
16. Qi JG, Tang XY, Du JB, et al. Influence of high pulmonary blood flow on ultrastructure of intra-acinar pulmonary arteries in rats.Journal of Chinese Electron Microscopy Society,2002,21:380- 382.
17.Jeffery TK,Morrell NW.Molecular and celluar basis of pulmonary vascular remodeling in pulmonary hypertension.Prog Cardiovasc Dis,2002,45:173-202.
18.Strange JW,Wharton J,Phillips PG,et al.Recent insights into the pathogenesis and therapeutics of pulmonary hypertension.Clin Sci,2002,102:253-268.
19.Tang XY,Du JB,Qi JG,et al.Ultrastructure observation intra-acinar pulmonary arteries on experimental hypoxic pulmonary hypertension.Journal of Chinese Electron Microscopy Society,2004,23:522-525.
20.王虹,王祥,解卫平.埃他卡林对低氧性肺动脉高压肺组织增殖细胞核抗原表达的抑制作用.医药导报,2005,24:7-9.
21.Du JB,Yan H,Wei B,et al.Effect of L-arginine on collagen of high flow-induced pulmonary arterial remodeling.Cirl J,2005,69:603-608.
22.Shi Y,Du JB,Tang XY,et al.Pulmonary vascular microstructure in chronic pulmonary hypertension.Journal of Applied Clinical Pediatrics,2005,20:628-629.
23.Cowan KN,Jones PL,Rabinovitch M.Elastase and matrix metalloproteinase inhibitors induce regression and tenascin-C antisense prevents progression of vascular disease.J Clin Inves, 2000,105:21-34.
24.Kanazawa F,Nakanishi K,Osada H,et al.Expression of endothelin-1 in the brain and lung of rats exposed to permanent hypobaric hypoxia.Brain Res,2005,1036:145-54.
25.Ambalavanan N,Bulger A,Murphy-Ullrich J,et al.Endothelin-A receptor blockade prevents and partially reverses neonatal hypoxic pulmonary vascular remodeling.Pediatr Res,2005,57:631-6.
26.Ivy DD,Yanagisawa M,Gariepy CE,et al.Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats.Am J Physiol Lung Cell Mol Physiol,2002,282:L703-12.
27.Li KX,Fouty B,Mcmurtry IF,et al.Enhanced ET_A-receptor-mediated inhibition of Kv channels in hypoxic hypertensive rat pulmonary artery myocytes.Am J Physiol,1999,277:H363-H370.
28.Peng W,Michael JR,Hoidal JR.ET-1 modulates Kca-channels activity and arterial tension in normoxic and hypoxic human pulmonary vasculature.Am J Physiol,1998,275:L729-L739.
29.Sato K,Morio Y,Morris KG,et al.Mechanism of hypoxic pulmonary vasoconstriction involves ET_A receptor-mediated inhibition of K_(ATP)channels.Am J Physiol,2000,278:L434-L442.
30.李志斌,邹霞英,赖晃文.一氧化氮在慢性缺氧性肺动脉高压中的作用.中华结核和呼吸杂志,1999,22:367-8。
31. Hampl V, Bibova J, Banasova A, et al. Pulmonary vascular iNOS induction participates in the onset of chronic hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol, 2006, 290: L11-20.
32. Qi JG, Du JB, Jia JF. Endogenous nitric oxide regulates hypoxic pulmonary vascular remodeling in rats. Chinese Journal of Pediatrics. 1999,37: 104-106.
33. Park MH. Advances in diagnosis and treatment in patients with pulmonary arterial hypertension. Catheter Cardiovasc Interv, 2008, 71:205-13.
34. Wright JL, Levy RD, Churg A. Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment. Thorax , 2005, 60: 605-9.
35. Geraci MW, Gao B, Shepherd DC, et al. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. Clin Invest, 1999, 103: 1509-1515.
36. Yuan XJ, Goldman WF, Tod ML. Hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes. Am J Physiol (Lung Cell Mol Physiol), 1993, 264: L116-L123.
37. Mandegar M, Yuan JXJ. Role of K~+ channels in pulmonary hypertension. Vascular Pharmocol, 2002, 38: 25-33.
38. Michelakis ED, Weir EK. The pathobiology of pulmonary hypertension. In:Rich S, McLaughlin VV. Pulmonary Hypertension. Philadelphia: W.B.Saunders Company, 2001:419-32.
39. Platoshyn O, Yu Y, Golovina VA, et al. Chronic hypoxia decreases Kv channel expression and function in pulmonary artery myocytes. Am J Physiol (Lung Cell Mol Physiol), 2001, 280: L801-L812.
40. Yuan XJ, Wang J, Juhaszova M, et al. Attenuated K~+ channel gene transcription in primary pulmonary hypertension. Lancet, 1998, 351: 726-727.
41. Yuan JXJ, Aldinger AM, Juhaszova M, et al. Dysfunction voltage-gated K~+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation, 1998, 98: 1400-1406.
42. Peng W, Hoidal JR, Karwande HS, et al. Effect of chronic hypoxianon K~+ channels: regulation in human pulmonary vascular smooth muscle cells. Am J Physiol (Cell Physiol 41), 272: C1271-C1278.
43. Muraki S, Tohse N, Seki S, et al. Decrease in the Ca~(2+)-activated K~+ current of pulmonary arterial smooth muscle in pulmonary hypertension rats. Naunyn-Schmiedeberg's Arch Pharmacol, 2001, 364: 183-192.
44. Cornfield D, Resnik ER, Herron JM, et al. Chronic intrauterine pulmonary hypertension decreases calcium-sensitive potassium channel mRNA expression.Am J Physiol Lung Cell Mol Physiol,2000,279:L857-L862.
45.Platoshyn O,Golovina VA,Bailey C,et al.Sustained membrane depolarization and pulmonary artery smooth muscles cell proliferation.Am J Physiol,2000,279:C1540-9.
46.Berridge MJ.Inositol trisphosphate and calcium signalling.Nature,1993,361:315 - 325.
47.Somlyo AP.Somlyo AV.Signal transduction and regulation in smooth muscle.Nature,2002,372:231- 236.
48.Brayden JE.Functional roles of K_(ATP)channels in vascular smooth muscles.Clin Exp Pharmacol Physiol,2002,29:312-6.
49.Murphy ME,Brayden JE.Nitric oxide hyperpolarizes rabbit mesenteric arteries via ATP-sensitive potassium channels.Journal of Physiology,1995,486:47-58.
50.肖欣荣,程德云,陈文彬.ATP敏感性钾通道开放剂对大鼠慢性低氧性肺动脉高压的作用.中华结核和呼吸杂志,2003,26:97-100。
51.Smirnov S,Robertson TP,Ward JPT,et al.Chronic hypoxia is associated with reduced delayed rectifier K~+ current in rat pulmonary artery muscle cells.Am J Physiol,1994,266:H365-H370.
52.钟小宁,梁国容,何志义等.吡那地尔防治大鼠低氧性肺动脉高 压肺血管重建的实验研究.中华结核和呼吸杂志,2000,23:727-9.
53.Michelakis E,Mcmurtry S,Wu XC,et al.Dichloroacetate,a metabolic modulator,prevents and reverses chronic hypoxic pulmonary hypertension in rats:role of increased expression and activity of voltage-gated potassium channels.Circulation,2002,105:244-250.
54.Wang Hong,Xie Weiping,Qi xu,et al.Effects of Pinacidil on proliferation of cultured rabbit airway smooth muscle cells induced by endthelin-1.Chin Med J(Engl),2005,118:587-590.
55.Das B,Sarkar C.Cardiomrocyte mitochondrial K_(ATP)channels participate in the antiarrhythmic and antiirfarct effect of K_(ATP)activators during ischemia and reperfusion in an intact anesthetized rabbit model.Pol J Pharmacol,2003,55:771-786.
56.WANG Tao,ZHANG Zhen xiang,XU Yong jian.Effect of mitochondrial K_(ATP)channel on voltage-gated K~+ channel in 24hour-hypoxic human pulmonary artery smooth muscle cells.Chin Med J(Engl),2005,118:12-19.
57.Akao M,Teshima Y,Marban E.Antiapoptotic effect of nicorandil mediated by mitochondrial ATP-sensitive potassium channels in cultured cardiac myocytes.Am Coll cardio,2002,40:803-810.
58.胡红玲,张珍祥,赵建平.缺氧肺动脉平滑肌细胞中线粒体ATP敏感 钾通道开放对细胞色素C的分布及细胞增殖的作用.生理学报,2006.58:262-268.
59.赵建平,郭治,周志刚.线粒体ATP敏感钾通道对大鼠肺动脉平滑肌细胞低氧诱导因子-1α表达及细胞增殖的作用.生理学报,2007,59:157-62.
60.胡红玲,汪涛,张珍祥等.线粒体膜电位对缺氧人肺动脉平滑肌细胞内氧自由基的变化及细胞增殖的作用.中华结核和呼吸杂志,2006,29:727-30.
61.王虹,解卫平,齐栩等.吡那地尔对豚鼠哮喘模型气道反应性及其结构的影响.中华内科杂志,2003,42:804-805.
1.Champion H C,Bivalacqua T J,D.Souza F M,et al.Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo,Effect on agonist- induced and flow-mediated vascular.Circ.Res,1999,84:1422- 1432.
2.Budts W,Pokreisz P,Nong Z,et al.Aerosol genetransfer with inducible nitric oxide synthase reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats.Circulation,2000,102:2880 - 2885.
3.Abdalla SA,Gallione CJ,Barst RJ,et al.Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia.Eur Respir J,2004,23:373-7.
4.Machado RD,Aldred MA,James V,et al.Mutations of the TGF-βtype Ⅱ receptor BMPR2 in pulmonary arterial hypertension.Hum Mutat,2006,27:121 - 132.
5.Aldred M,Vijayakrishnan J,James V,et al.BMPR2 gene rearrangements account for a sinificant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat, 2006,27:212-213.
6. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-pfamily. Med Genet, 2000, 37: 741 - 745.
7. M. Humbert, Z. Deng, G. Simonneau BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives, Eur Respir,2002,20:518-523.
8. Caldwell RL, Gadipatti R, Lane KB, HIV-1 TAT represses transcription of the bone morphogenic protein receptor-2 in U937 monocytic cells. Leukol Biol, 2006, 79: 192-201.
9. Miyazono K, Maeda S, Imamura T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev, 2005, 16: 251 - 263.
10. Aoki H, FujiiM, Imamura T, et al. Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction. Cell Sci, 2001, 114: 1483 - 1489.
11. Chen HB, Shen J, Xu L. Identification of phosphatases for Smad in the BMP/DPP pathway. Genes Dev, 2006, 20: 648 - 653.
12. Massague J. Integration of Smad and MAPK pathways: a link and a linker revisited. Genes Dev, 2003, 17: 2993 - 2997.
13. Nohe A, Hassel S, Ehrlich M, et al .The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. Biol Chem, 2002, 277: 5330 - 5338.
14. Kretzschmar M, Doody J, Massagu J. Opposing BMP and EGF signaling pathways converge on the TGF-β family mediator Smadl. Nature, 1997,389:618-622.
15.IshidaW, Hamamoto T, Kusanagi K. Smad6 is a Smadl /5-induced Smad inhibitor. Biol Chem, 2000, 275: 6075 - 6079.
16. Yu PB, Beppu H, Kawai N, et al. Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells. Biol Chem, 2005, 280: 24443 - 24450.
17. Rudarakanchana N, Flanagan JA, Chen H, et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet, 2002, 11: 1517 -1525.
18. Morrell NW, Yang X, Upton PD, et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-pi and bone morphogenetic proteins. Circulation, 2001, 104: 790 - 795.
19. Atkinson C, Stewart S, Upton PD, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation, 2002,105: 1672 - 1678.
20. Yang X, Long L, Southwood M, et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res, 2005, 96: 1053 - 1063.
21. Richter A, Yeager ME, Zaiman A, et al. Impaired transforming growth factor-βsignaling in idiopathic pulmonary arterial hypertension. Respir Crit Care Med, 2004, 170: 1340 - 1348.
22. Valdimarsdottir G, Goumans MJ, Rosendahl A, et al. Stimulation of Id1 expression by bone morphogenetic proetin is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation, 2002, 106: 2263 - 2270.
1.Brayden J E.Functional roles of K_(ATP),channels in vascular smooth muscles.Clin Exp Pharmacol Physiol,2002,29:312-316.
2.Ye D,Zhou W,Lee HC.Activation of rat mesenteric arterial K_(ATP)channels by 11,12-epoxyeicosatrienoic acid.Am.J.Physiol.Heart.Circ.Physiol,2005,288:H358-H364.
3.Mandegar M,Yuan J XJ.Role of K~+ channels in pulmonary hypertension.Vascular Pharmacol,2002,38:25-33.
4.钟小宁,梁国容,何志义,等.吡那地尔防治大鼠低氧性肺动脉高压肺血管重建的实验研究.中华结核和呼吸杂志,2000,23:727-9.
5.胡红玲,张珍祥,赵建平等.缺氧人肺动脉平滑肌细胞中线粒体ATP敏感钾通道开放对细胞色素C的分布及细胞增殖的作用.生理学报,2006,58(3):262-268.
6.Peng W,Michael JR,Hoidal JR.ET-1 modulates Kca-channels activity and arterial tension in normoxic and hypoxic human pulmonary vasculature.Am J Physiol,1998,275:L729-39.
7.Sato K,Morio Y,Morris KG,et al.Mechanism of hypoxic pulmonary vasoconstriction involves ET_A receptor-mediated inhibition of K_(ATP)channels.Am J Physiol,2000,278:L434-42.
8.Platoshyn O,Golovina VA,Bailey C,et al.Sustained membrane depolarization and pulmonary artery smooth muscles cell proliferation.Am J Physiol,2000,279:C1540-1549.
9.Nakayama K,Fukuta Y,Kiyoshi A,et al.(+)-[~3H]Isradipine and[~3H]Glyburide bindings to heart and lung membranes from rats with monocrotaline-induced pulmonary hypertension.Jpn J Pharmacol,1999,81:176-84.
10.Sweeney M,Yu Y,Platoshyn O,et al.Inhibition of endogenous TRP1 decreases capacitative Ca~(2+)entry and attenuates pulmonary artery smooth muscle cell proliferation.Am.J.Physiol.Lung.Cell.Mol.Physiol,2002,283:L144-L155.
11.Platoshyn O,Zhang S,McDaniel SS,et al.Cytochrome C activates K~+ channels before inducing apoptosis.Am J Physiol,2002,283:C1298-C1305.
12.Xu M,Wang Y,Ayub A,et al.Mitochondrial K_(ATP)channel activation reduces anoxic injury by restoring mitochondrial membrane potential.Am J Physiol Heart Circ Physiol,2001,281:H1295-H1303.
13.胡红玲,汪涛,张珍祥等.线粒体膜电位对缺氧人肺动脉平滑肌细胞内氧自由基的变化及细胞增殖的作用.中华结核和呼吸杂志,2006,29:727-30.
14.Krick S,Platoshyn O,Mcdaniel SS,et al.Augmented K+currents and mitochondrial membrane depolarization in pulmonary artery myocyte apoptosis.Am J Physiol Lung Cell Mol Physiol,2001,281:L887-L894.
15.WANG Tao,ZHANG Zhen xiang,XU Yong jian.Effect of mitochondrial KATP channel on voltage-gated K~+ channel in 24 hour-hypoxic human pulmonary artery smooth muscle cells.Chin Med J(Engl),2005,118:12-19.