2-氨基-5-磷酰基戊酸酯对大鼠坐骨神经慢性压迫性损伤的机械痛敏和热痛敏的影响

目的:建立大鼠坐骨神经慢性压迫性损伤(CCI)动物模型,腹腔注射N-甲基-D-天冬氨酸(NMDA)受体竞争性拮抗剂2-氨基-5-磷酰基戊酸酯(AP5)后观察腹腔用药对大鼠坐骨神经慢性压迫性损伤(CCI)动物模型机械痛敏和热痛敏的影响.方法:48只成年Wistar大鼠,雌雄不拘,随机分成3组,即Ⅰ组,假手术组(Sham),8只大鼠;Ⅱ组,CCI组,8只大鼠;Ⅲ组,治疗组,32只大鼠再分为4个亚组,Ⅲa组(CCI+NS),mb组[CCI+AP50.1mg/(kg·d)]、Ⅷc组(CCI+AP50.2 mg/kg)、Ⅲd组(CCI+AP50.5 mg/kg),每个亚组8只大鼠.48只大鼠分别于术前(0 d)及术后1、3、5、7、14、21 d测量每组大鼠的机械性缩足反射阈值(MWT)和热缩腿潜伏期(TWL).结果:CCI组从术后第3天开始直到本实验观察的术后第21天,MWT和TWL均明显降低,与假手术组Sham相比具有显著性(P＜0.01);CCI加生理盐水组大鼠与CCI组大鼠的MWT和TWL相比无明显改变(P＞0.05);腹腔注射AP5各个剂量的CCI组在术后5～21 d的MWT和TWL明显增加,与给药前和生理盐水组相比具有显著性(P＜0.01).结论:腹腔注射AP5有明显减轻大鼠CCI模型的机械性痛敏和热痛敏的作用.     

鞘内注射氯胺酮对镜像痛大鼠热痛敏的影响及可能机制

目的：探讨氯胺酮鞘内注射对镜像痛大鼠热痛敏的影响及可能机制.方法：30只雄性SD大鼠建立大鼠坐骨神经镜像痛模型,随机分为3组（n=10）：Ⅰ组鞘内注射生理盐水,Ⅱ组鞘内注射氯胺酮25 μg,Ⅲ组鞘内注射氯胺酮50 μg,分别测定鞘内给药前（T1）、给药后2 h（T2）、4 h（T3）、6 h（T4）的大鼠热缩足反射潜伏期（TWL）、运动功能.每组大鼠在给药6h后处死,取出腰段脊髓背角,石蜡切片,采用免疫组化检测单核细胞趋化蛋白-1（MCP-1）的表达.结果：鞘内给药后,Ⅱ组、Ⅲ组在各时间点与Ⅰ组及给药前相比,两侧TWL明显延长,比较有显著差异（P＜0.01）.Ⅰ组MCP-1平均积分光密度值（IOD）表达明显高于Ⅱ组和Ⅲ组（P＜0.01）,鞘内注射氯胺酮后大鼠运动功能不受明显影响.结论：鞘内注射氯胺酮可抑制镜像痛大鼠的热痛觉过敏,该作用可能与抑制脊髓背角的MCP-1表达有关.     

术前给予巴氯酚延迟坐骨神经松结扎神经病理痛的形成

目的研究术前鞘内注射GABAB受体激动剂巴氯酚(Bac)对慢性神经病理痛大鼠痛阈的影响,探讨脊髓GABA能系统在神经病理痛调节中的作用。方法建立慢性坐骨神经结扎损伤模型(CCI),SD大鼠32只随机分成4组:假手术组,大鼠左侧坐骨神经分离,但不结扎,术前鞘内注射生理盐水10μL;神经结扎组,大鼠左侧坐骨神经松结扎,术前鞘内注射生理盐水10μL;Bac 1组,大鼠左侧坐骨神经松结扎前10 min,鞘内注射Bac 0.03μg;Bac 2组,大鼠左侧坐骨神经松结扎前10min,鞘内注射Bac 0.3μg。术后第1、3、5、7、10、14天测大鼠机械刺激缩足反射阈值(MWT)和热刺激缩足反射潜伏期(TWL)以及运动功能。结果术后第1~14天神经结扎组大鼠MWT和TWL较假手术组大鼠明显降低(P<0.05);术前给Bac 0.3μg的坐骨神经结扎大鼠与术前给生理盐水的坐骨神经结扎大鼠比较,术后第1~5天MWT和TWL明显升高(P<0.05)。结论坐骨神经结扎前鞘内注射Bac 0.3μg可延缓大鼠神经病理性疼痛的形成。     

N-乙酰天冬氨酰谷氨酸肽酶抑制剂对神经病理性疼痛大鼠脊髓水平瞬时感受器电位香草酸受体1表达的影响

目的:研究鞘内注射N-乙酰天冬氨酰谷氨酸(N-acetylaspartylglutamate,NAAG)肽酶抑制剂(2-PMPA)对神经病理性疼痛大鼠的镇痛作用及脊髓水平瞬时感受器电位香草酸受体l(TRPV1)表达的影响。方法:取鞘内置管成功的雄性SD大鼠24只,体重200²50 g,随机分为3组(n=8):假手术组(sham组)、坐骨神经慢性压迫性损伤组(CCI组)和2-PMPA治疗组(2-PMPA组)。sham组只暴露坐骨神经,但不结扎,术后鞘内注射生理盐水;CCI组坐骨神经结扎后鞘内注射生理盐水;2-PMPA组坐骨神经结扎后鞘内注射2-PMPA 100μg。所有组每次给药剂量均为10μl,每日1次,连续7 d。分别于术前及术后7 d时,以热缩足潜伏期(TWL)和机械缩足阈值(MWT)测定大鼠痛阈,然后处死大鼠,采用免疫荧光和Western blot法测定脊髓水平TRPV1的表达。结果:三组大鼠术后7 d TWL和MWT值分别为(17.8±1.1)、(5.5±1.0)、(12.0±1.4)s和(13.1±1.2)、(4.3±0.9)、(10.5±1.0)g。与sham组比较,CCI组术后7 d时TWL和MWT值均降低,脊髓TRPV1表达水平显著升高,差异有统计学意义(P<0.05);与CCI组比较,2-PMPA组术后7 d时TWL和MWT值均升高,脊髓TRPV1表达水平显著降低,差异有统计学意义(P<0.05)。结论:鞘内注射NAAG肽酶抑制剂可以有效地治疗神经病理性疼痛,其作用机制可能与抑制脊髓水平TRPV1的表达有关。     

Cav3.2通道对背根节慢性压迫痛大鼠脊髓CaMKⅡ表达的影响

目的:观察Cav3.2通道对背根节慢性压迫痛大鼠脊髓CaMKⅡ表达的影响,探讨Cav3.2-CaMKⅡ通路在神经病理性疼痛中的作用。方法:雄性SD大鼠60只,体重250±20 g,随机分为5组,每组12只(其中行为学实验8只,免疫印迹实验4只)。分别是正常对照组(C组);模型组(CCD组);生理盐水组(NS组);错义寡聚核苷酸组(MS-Cav3.2组);反义寡聚核苷酸组(AS-Cav3.2组)。分别于鞘内置管前(T1),鞘内置管后3 d(T2),鞘内给药后1 d(T3)、4 d(T4),CCD模型制备后5d(T5)、10 d(T6)、15 d(T7)检测大鼠机械缩腿阈值(mechanical withdrawal threshold,MWT)和热缩足潜伏期(thermal withdrawal latency,TWL)。并于CCD模型制备后5 d,各组取4只大鼠处死,取脊髓腰膨大,采用免疫印迹法检测Cav3.2及CaMKⅡ的表达。结果:与C组比较,CCD组大鼠在模型制备后第5 d、10 d、15 d时MWT及TWL均显著降低。鞘内注射NS和Cav3.2错义寡聚核苷酸对CCD大鼠MWT及TWL无影响,鞘内注射Cav3.2反义寡聚核苷酸可增加CCD大鼠MWT和TWL,减轻大鼠机械痛敏和热痛敏。C组大鼠脊髓Cav3.2和CaMKⅡ蛋白均有表达。大鼠在制备CCD模型后5 d Cav3.2及CaMKⅡ蛋白表达均显著增加。鞘内注射NS及Cav3.2错义寡聚核苷酸对Cav3.2及CaMKⅡ蛋白表达无影响,鞘内注射Cav3.2反义寡聚核苷酸则可显著抑制Cav3.2及CaMKⅡ蛋白的表达。结论:抑制脊髓Cav3.2通道的表达可降低慢性背根节压迫痛大鼠脊髓CaMKⅡ的表达。     

术前给予巴氯酚延迟坐骨神经松结扎神经病理痛的形成

目的研究术前鞘内注射GABAB受体激动剂巴氯酚（Bac）对慢性神经病理痛大鼠痛阈的影响，探讨脊髓GABA能系统在神经病理痛调节中的作用。方法建立慢性坐骨神经结扎损伤模型（CCI），SD大鼠32只随机分成4组：假手术组，大鼠左侧坐骨神经分离，但不结扎，术前鞘内注射生理盐水10μL；神经结扎组，大鼠左侧坐骨神经松结扎，术前鞘内注射生理盐水10μL；Bac1组，大鼠左侧坐骨神经松结扎前10min，鞘内注射Bac0．03旭；Bac2组，大鼠左侧坐骨神经松结扎前10min，鞘内注射Bac0．3,ug。术后第1、3、5．7、10、14天测大鼠机械刺激缩足反射阈值（MWT）和热刺激缩足反射潜伏期（TWL）以及运动功能。结果术后第1～14天神经结扎组大鼠MWT和个TWL较假手术组大鼠明显降低（P〈0．05）；术前给Bac0．3越的坐骨神经结扎大鼠与术前给生理盐水的坐骨神经结扎大鼠比较，术后第1～5天MWT和TWL明显升高（P〈0．05）。结论坐骨神经结扎前鞘内注射Bac0．3μg可延缓大鼠神经病理性疼痛的形成。     

舒芬太尼对神经病理性疼痛大鼠脊髓背角P2X3受体表达的影响

目的:研究舒芬太尼对神经病理性疼痛大鼠脊髓P2X3受体表达的影响。方法:SD雄性大鼠36只,随机分成3组:假手术组(Sham组);对照组(CCI组);舒芬太尼组(CCI+Suf组)。CCI和CCI+Suf组制备坐骨神经慢性压迫模型(chronic constriction injury,CCI)。Sham组和CCI组术后每天腹腔注射生理盐水(0.1 ml/100 g),CCI+Suf组术后每天腹腔注射舒芬太尼(0.02 ml/100 g)。每组分别在术前、术后1、3、7、14天给药30分钟后,测定热缩足潜伏期(thermal withdrawal latency,TWL)。于术后第7、14天TWL测定后,随机选取6只大鼠L4-5节段脊髓,应用免疫组化法检测脊髓P2X3受体表达水平。结果:与Sham组比较,CCI组和CCI+Suf组TWL缩短,P2X3受体表达上调(P<0.05)。与CCI组比较,CCI+Suf组TWL延长,P2X3受体表达下调(P<0.05)。结论:舒芬太尼可以抑制脊髓P2X3受体的表达上调,并减轻大鼠神经病理性痛。     

右美托咪定及舒芬太尼联合鞘内注射对CCI模型大鼠的镇痛效应

目的:研究右美托咪定及舒芬太尼联合鞘内注射对CCI模型大鼠的镇痛效应.方法:鞘内置管成功的雄性SD大鼠50只,随机分成5组:假手术组(Sham组);模型对照组(CCI组);右美托咪定组(Dex组);舒芬太尼组(Suf组);右美托咪定+舒芬太尼组(DS组).Dex组、Suf组、DS组分别于术后1～14d每天鞘内注射右美托咪定(dexmedetomidine,Dex)2 μg/(kg.d)、舒芬太尼(sufentanil,Suf)1 μg/d、Dex 1 μg/(kg.d)+Suf 0.5 μg/d;各组药物总容量均配成20μl,CCI组注射等体积0.9％生理盐水.每组分别在术前、术后l、3、7、14d给药30 min后,测定机械痛阈和热痛阈.于术后第7、14d痛阈值测定后,分批提取大鼠L4～6节段脊髓(n=5/组),应用免疫组化法检测脊髓背角Fos蛋白表达水平.结果:与Sham组相比,CCI组、Dex组、Suf组及DS组术后机械痛阈和热痛阈显著降低(P＜0.05),术后7 d c-fos蛋白表达上调(P＜0.05).与CCI模型组相比,Dex组、Suf组及DS组在术后3d、7d、14 d机械痛阈和热痛阈显著升高(P＜0.05),c-fos蛋白表达水平在术后7d差异显著(P＜0.05).与DS组相比,Dex组及Suf组在术后3d、7d、14 d机械痛阈及热痛阈显著降低(P＜0.05),c-fos蛋白在术后7d表达显著增加(P＜0.05).结论:鞘内联合应用右美托咪定及舒芬太尼治疗神经病理性疼痛具有显著的协调镇痛作用,能有效缓解CCI模型大鼠的机械痛敏及热痛敏.     

二甲双胍治疗坐骨神经结扎诱发大鼠神经病理性疼痛的效应

目的:探讨二甲双胍治疗坐骨神经慢性压迫损伤(chronic constriction injury,CCI)诱发大鼠神经病理性疼痛的效应。方法:SPF级健康雌性SD大鼠48只,7～9周龄,180～200 g,采用随机数字表法将其分为正常对照组(Naive组)、假手术组(Sham组)、CCI组和CCI+二甲双胍组(Met组),每组12只。二甲双胍采用灌胃方式给药,每次剂量45 mg/kg,从CCI建模前3 d开始给药,每天2次,持续至建模后第7天。分别于建模前(基线水平),术后3 d、7 d、10 d、14 d记录建模侧(左侧)后足机械缩足反射阈值(MWT)、热缩足潜伏期(TWL)和冷刺激诱发缩足次数(TNCW);第3、14天使用CatWalk步态分析系统测定各组大鼠的步态。结果:与Naive组比较,CCI组和Met组大鼠左足MWT降低、TWL缩短、TNCW减少(P0.05);CCI组大鼠左侧足印面积缩小、完整足印的平均强度减弱、站立时间缩短、步周长减小、摆动时间延长,并持续至建模后第14天(P0.05);Met组大鼠左侧足印面积缩小、完整足印的平均强度减弱;Sham组上述指标无明显改变。与CCI组相比,Met组大鼠左足MWT升高、TWL延长、TNCW增加(P0.05); Met组大鼠左侧足印面积增大、完整足印的平均强度增强、站立时间延长以及步周长增加(P0.05),摆动时间无明显改变。结论:二甲双胍可缓解CCI诱发神经病理性疼痛大鼠机械痛觉过敏和冷热痛觉过敏,且能改善神经病理性疼痛大鼠的步态。     

鞘内注射IRF8反义寡核苷酸对CCI模型大鼠痛阈的影响

目的:探讨鞘内注射小胶质细胞干扰素调节因子8(interferon regulatory factor 8,IRF8)反义寡核苷酸(oligodeoxynucleotide,ODN)对大鼠慢性坐骨神经缩窄损伤(chronic constriction injury of sciatic nerve,CCI)模型疼痛行为的影响。方法:雄性SD大鼠40只随机分为4组:Sham组、AS组、MM组、NS组,每组10只。除Sham组外,其他三组均鞘内置管并制备CCI模型,AS组、MM组、NS组依次于CCI后12 h鞘内注射IRF8反义/错义ODN、等体积生理盐水,1次/d,连续6 d。制模前测量各组大鼠的基础阈值,制模后1、3、5、7、10、12、14 d对大鼠进行疼痛行为测定。制模后7、14 d western blot检测IRF8、离子钙接合蛋白Iba1表达。结果:与Sham组比较,NS组、MM组大鼠神经损伤后右后爪机械痛阈和热痛阈均显著降低(P<0.05),脊髓IRF8、Iba1蛋白表达显著增强(P<0.05)。AS组于CCI后第10 d起右足机械痛阈和热痛阈下降,但仍高于MM组、NS组(P<0.05)。CCI后第7、14 d IRF8、Iba1蛋白表达,AS组较MM组、NS组显著减弱(P<0.05),但仍强于Sham组(P<0.05)。AS组第14 d IRF8、Iba1蛋白表达较第7 d增强(P<0.05)。结论:经鞘内注射IRF8反义寡核苷酸可抑制脊髓内IRF8表达和小胶质细胞活化而缓解CCI大鼠神经病理性疼痛。     

钙通道与疼痛

现已公认神经系统钙通道参与伤害性信息的传导,其阻滞剂的镇痛效应也已被证实。特别是选择性强并具有可逆性的N-型电压敏感型钙通道阻滞剂———ziconotide,其蛛网膜下腔注射能产生良好的镇痛作用,长期应用也不出现耐受,现已被美国FDA批准可用于慢性疼痛治疗。     

“四步法”建立标准通道在经皮肾镜碎石取石术中的应用效果

目的探讨"四步法"建立标准通道在经皮肾镜碎石取石术中的应用效果。方法回顾性分析2016年8月至2018年4月在重庆陆军军医大学新桥医院泌尿外科行经皮肾镜碎石取石术的92例患者的病例资料,按治疗方法分为对照组和观察组,每组各46例。对照组患者给予常规的标准通道碎石术治疗,观察组患者实施"四步法"建立标准通道取石术治疗。观察并比较两组患者的手术时间、术中出血量、术后相关指标、结石清除率以及并发症等指标。结果观察组患者的手术时间(60. 3±4. 3 min)、术中出血量(97. 3±11. 9 ml)均低于对照组(73. 1±3. 5 min,151. 2±12. 3ml),差异具有统计学意义(P <0. 05)。观察组患者的下床活动时间(33. 6±3. 2 h)、术后置管时间(5. 1±2. 3 d)和住院时间(12. 6±3. 0 d)均低于对照组(53. 1±3. 5 h,8. 6±1. 5 d,19. 3±3. 6 d),差异具有统计学意义(P <0. 05)。观察组患者的结石清除率(91. 3%)明显高于对照组(80. 4%),差异具有统计学意义(P <0. 05)。观察组患者的并发症发生率(6. 5%)明显低于对照组(21. 7%),差异具有统计学意义(P <0. 05)。结论 "四步法"建立标准通道在经皮肾镜碎石取石术中的应用效果显著,能够减少术中出血量、置管时间和住院时间,提高结石的清除率,减少并发症的发生,安全、有效,值得在临床上推广应用。     

Dual Variation in SCN5A and CACNB2b Underlies the Development of Cardiac Conduction Disease without Brugada Syndrome

Background: Inherited loss of function mutations in SCN5A have been linked to overlapping syndromes including cardiac conduction disease and Brugada syndrome (BrS). The mechanisms responsible for the development of one without the other are poorly understood. Methods: Direct sequencing was performed in a family with cardiac conduction disease. Wild‐type (WT) and mutant channels were expressed in TSA201 cells for electrophysiological study. Green fluorescent protein (GFP)‐fused WT or mutant genes were used to assess channel trafficking. Results: A novel SCN5A mutation, P1008S, was identified in all family members displaying first‐degree atrioventricular block, but not in unaffected family members nor in 430 reference alleles. Peak P1008S current was 11.77% of WT (P < 0.001). Confocal microscopy showed that WT channels tagged with GFP were localized on the cell surface, whereas GFP‐tagged P1008S channels remained trapped in intracellular organelles. Trafficking could be rescued by incubation at room temperature, but not by incubation with mexiletine (300 μM) at 37°C. We also identified a novel polymorphism (D601E) in CACNB2b that slowed inactivation of L‐type calcium current (I_Ca,L), significantly increased total charge. Using the Luo‐Rudy action potential (AP) model, we show that the reduction in sodium current (I_Na) can cause loss of the right ventricular epicardial AP dome in the absence but not in the presence of the slowed inactivation of I_Ca,L. Slowed conduction was present in both cases. Conclusions: Our results suggest genetic variations leading to a loss‐of‐function in I_Na coupled with a gain of function in I_Ca,L may underlie the development of cardiac conduction disease without BrS. (PACE 2010; 33:274–285)     

Change of Atrial Refractory Period after Short Duration of Rapid Atrial Pacing: Regional Differences and Possible Mechanisms

It is unknown whether there are regional differences in the cimnge of atrial effective refractory period (EBP) after a short duration of rapid atriai pacing. Furthermore, the effects of calcium channel and potassium channel on this phenomenon have not been extensively investigated. In opened-chest dogs, the endocardial monophasic action potential duration at 90% repolarization (APD₉₀) from the right atrial appendage, and ERP from seven atrial sites were measured before and after rapid atrial pacing at 800 beats/min for 30 minutes. Both atrial ERP and APD₉₀ significantly shortened after rapid atrial pacing. The postpacing atria EBP and APD₉₀ shortening persisted for 1.19 ± 3 and 123 ± 4 seconds after cessation of pacing, respectively. There was no significant difference in the magnitude or recovery course of atrial ERP shortening after pacing among the seven atrial sites. Pretreatment with nicorandil and d-sotalol had no effects on the magnitude or recovery course of atrial EBP shortening after pacing. However, the degree of ERP and APD₉₀shortening after pacing was significantly atten uated in the verapamil and ryanodine groups; furthermore, the recovery of ERP and APD₉₀ after cessation of pacing was faster in the two groups. In conclusion, shortening of atrial EBP induced by short-duration rapid atrial pacing was uniform in both atria. Both the adenosine triphosphatase (ATP) dependent potassium current and rapid component of the delayed rectifier did not significantly influence this phenomenon, but both the verapamil and ryanodine could significantly attenuate the degree of atrial ERP and APD₉₀ shortening.     

Cromakalim对大鼠缺氧性肺动脉高压的治疗作用

对慢性缺氧3wk大鼠静脉注射钾通道开放剂克罗卡林(Cromakalim,150μg/kg)和钾通道阻断剂格列本脲(Glybenclamide,200μg/kg),以研究其对大鼠肺循环及心血管功能的影响。20只大鼠随机分为两组,均给予缺氧3wk。Ⅰ组先给予Glybenclamide,然后给予Cromakalim;Ⅱ组先给予Cromakalim,再给予Glybenclamide。结果:缺氧大鼠在先给予Glybenclamide后,其肺循环无明显变化,给予Cromakalim后可见肺动脉压明显降低;而先给予Cromakalim即可见缺氧大鼠肺动脉压明显降低,再给予Glybenclamide,则可逆转Cromakalim对肺血管的舒张反应,从而导致肺动脉压升高。这些结果提示,钾通道活性的改变在缺氧性肺动脉高压发病机制中起到十分重要的作用,Cromakalim可作为治疗肺动脉压的有效药物之一。     

Antinociceptive effect of Brazilian armed spider venom toxin Tx3-3 in animal models of neuropathic pain

Venoms peptides have produced exceptional sources for drug development to treat pain. In this study we examined the antinociceptive and side effects of Tx3-3, a peptide toxin isolated from Phoneutria nigriventer venom, which inhibits high-voltage-dependent calcium channels (VDCC), preferentially P/Q and R-type VDCC. We tested the effects of Tx3-3 in animal models of nociceptive (tail-flick test), neuropathic (partial sciatic nerve ligation and streptozotocin-induced diabetic neuropathy), and inflammatory (intraplantar complete Freund’s adjuvant) pain. In the tail-flick test, both intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of Tx3-3 in mice caused a short-lasting effect (ED₅₀ and 95% confidence intervals of 8.8 [4.1-18.8] and 3.7 [1.6-8.4] pmol/site for i.t. and i.c.v. injection, respectively), without impairing motor functions, at least at doses 10-30 times higher than the effective dose. By comparison, ω-conotoxin MVIIC, a P/Q and N-type VDCC blocker derived from Conus magus venom, caused significant motor impairment at doses close to efficacious dose in tail flick test. Tx3-3 showed a long-lasting antinociceptive effect in neuropathic pain models. Intrathecal injection of Tx3-3 (30 pmol/site) decreased both mechanical allodynia produced by sciatic nerve injury in mice and streptozotocin-induced allodynia in mice and rats. On the other hand, i.t. injection of Tx3-3 did not alter inflammatory pain. Taken together, our data show that Tx3-3 shows prevalent antinociceptive effects in the neuropathic pain models and does not cause adverse motor effects at antinociceptive efficacious doses, suggesting that this peptide toxin holds promise as a novel therapeutic agent for the control of neuropathic pain.     

Ion Channels and Migraine

Migraine is one of the most common neurological disorders. Despite its prevalence, the basic physiology of the molecules and mechanisms that contribute to migraine headache is still poorly understood, making the discovery of more effective treatments extremely difficult. The consistent presence of head‐specific pain during migraine suggests an important role for activation of the peripheral nociceptors localized to the head. Accordingly, this review will cover the current understanding of the biological mechanisms leading to episodic activation and sensitization of the trigeminovascular pain pathway, focusing on recent advances regarding activation and modulation of ion channels.     

Electrophysiological Remodeling in Human Atrial Fibrillation

Atrial fibrillation (AF) is a progressive disease characterized by cumulative electrophysiological and structural remodeling of the atria. Cellular electrophysiological studies have revealed marked reductions in the densities of the L-type voltage-gated Ca²⁺ current, I_Ca,L, the transient outward K⁺ current, I_TO, and the ultra-rapid delayed rectifier K⁺ current, I_Kur, in atrial myocytes from patients in persistent or permanent AF. The density of the muscarinic K⁺ current (I_KACh) is also reduced, however the inward rectifier K⁺ current (I_K1) density is increased. The net shortening or lengthening of the action potential is dependent on the balance between changes in inward and outward currents. The prominent reduction in I_Ca,L appears to be sufficient to explain the observed decreases in action potential duration and effective refractory period that are characteristic of the fibrillating atria. Earlier studies have shown that calcium overload and perturbations in calcium handling play prominent roles in AF induced atrial remodeling. More recently, we have shown that AF is associated with evidence of oxidative injury to atrial tissue, and suggested that oxidative stress may directly contribute to the pathophysiology of AF. It is anticipated that insights gleaned from mechanistic studies will facilitate the development of improved pharmacological approaches to treat AF and to prevent the progression of arrhythmia. (PACE 2003; 26[Pt. II]:1572–1575)     

氯通道阻断剂对血小板胞浆游离钙和血小板聚集的影响

目的　探讨氯通道在血小板胞浆游离钙和血小板聚集功能调节中的作用。方法　新鲜分离人血小板,以凝血酶为诱导剂,观察氯通道阻断剂DIDS、NFA和钙通道阻断剂SK&F96365、Nife dipine对血小板胞浆游离钙和血小板聚集的单独作用和相互作用。结果　氯通道阻断剂DIDS、NFA可以浓度依赖性地抑制凝血酶 ( 1U/ml)诱导的血小板聚集,对静息血小板胞浆游离钙无明显影响;DIDS、SK&F96365、Nifedipine可以明显降低凝血酶诱导的血小板聚集、钙释放和钙内流,与对照组比较,P<0. 05;DIDS与SK&F96365联合,对凝血酶诱导的血小板聚集、钙释放和钙内流的抑制比各自单独抑制作用明显增高(P<0. 05),两者的作用相互增强;DIDS与Nifedipine联合,对凝血酶诱导的血小板钙释放的抑制比各自单独抑制作用明显增高 (P<0. 05 ),两者可相互增强;NFA与SK&F96365联合,对凝血酶诱导的血小板钙释放的抑制比各自的单独作用明显降低 (P<0. 05 ),两者可相互减弱;NFA与Nifedipine联合,对凝血酶诱导的血小板聚集、钙释放和钙内流的抑制比各自的单独作用明显降低(P<0. 05),两者可相互减弱。结论　氯通道阻断剂DIDS、NFA对人静息血小板胞浆钙浓度无影响;DIDS可抑制凝血酶诱导的血小板聚集、钙释放和钙内流,NFA仅抑制凝血酶诱导的钙释放;氯通道阻断剂和     

Improving genetic diagnostics of skeletal muscle channelopathies

ABSTRACT

Introduction

Skeletal muscle channelopathies are rare inherited conditions that cause significant morbidity and impact on quality of life. Some subsets have a mortality risk. Improved genetic methodology and understanding of phenotypes have improved diagnostic accuracy and yield.