低钾血症时机体钾离子变化规律及其调节机制的实验研究
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摘要
目的:使用低钾饲料饲喂家兔建立缺钾动物模型,观察饲喂不同时间后家兔血浆钾离子浓度变化,测定红细胞、心肌、骨骼肌等细胞或组织的钾离子含量,探究机体缺钾时钾离子在不同组织的变化规律并探讨其间可能存在的相关性变化。同时测定机体不同细胞和组织中Na~+-K~+-ATPase的活性、蛋白含量及mRNA表达情况,寻找缺钾机体不同细胞或组织钾离子变化的调节机制。试图通过钳制补钾技术,观察低钾家兔补钾过程中不同组织对钾离子的摄取情况,为临床能迅速、安全有效地纠正低钾血症提供实验依据。
方法:
1用低钾饲料饲喂建立低血钾动物模型
清洁级健康家兔48只,雄性,兔龄12~14周,体重2.0~2.7 kg(由河北医科大学实验动物中心提供),随机分为6组,每组8只,分别进行正常饲料饲喂或进行不同时间的低钾饲料饲喂。对照组(T_0组)、低钾3天组(T_1组)、低钾6天组(T_2组)、低钾9天组(T_3组)、低钾12天组(T_4组)、低钾15天组(T_5组)。所有家兔购入后均进行一周的正常饲料饲喂100g/d,自由饮普通水,一周后将T_0组家兔处死取材,其余家兔进行低钾饲料饲喂,每只家兔喂食低钾饲料100 g/d,自由饮蒸馏水。T_1组:低钾饲喂3天处死取材,T_2组:低钾饲喂6天处死取材,T_3组:低钾饲喂9天处死取材,T_4组:低钾饲喂12天处死取材,T_5组:低钾饲喂15天处死取材。
各组分别于观察结束当天经耳中央动脉取血1 ml测定血浆钾离子、钠离子及血红蛋白浓度,经股静脉抽血分离红细胞测定红细胞钾离子浓度,开胸摘取心脏测定心肌组织钾离子、钠离子含量,取家兔右下肢比目鱼肌测定骨骼肌钾离子、钠离子含量。
血浆钾、钠离子浓度采用离子选择性电极测量法测定,血红蛋白浓度采用分光光度比色法测定。
红细胞、心肌、比目鱼肌钾、钠离子含量采用火焰原子吸收光度计测定。
2低钾家兔不同组织细胞Na~+-K~+-ATPase活性及α_1,α_2亚基蛋白和mRNA表达的实验研究
清洁级健康家兔48只,雄性,兔龄12~14周,体重2.0~2.7 kg(由河北医科大学实验动物中心提供),随机分为6组,每组8只,分别进行正常饲料饲喂或进行不同时间的低钾饲料饲喂。对照组(T_0组)、低钾3天组(T_1组)、低钾6天组(T_2组)、低钾9天组(T_3组)、低钾12天组(T_4组)、低钾15天组(T_5组)。所有家兔购入后均进行一周的正常饲料饲喂100g/d,自由饮普通水,一周后将T_0组家兔处死取材,其余家兔进行低钾饲料饲喂,每只家兔喂食低钾饲料100g/d,自由饮蒸馏水。T_1组:低钾饲喂3天处死取材,T_2组:低钾饲喂6天处死取材,T_3组:低钾饲喂9天处死取材,T_4组:低钾饲喂12天处死取材,T_5组:低钾饲喂15天处死取材。
模型制备完成后,分别于观察结束当天经耳缘静脉注射4%戊巴比妥1ml/kg,麻醉成功后,迅速固定,开胸摘取心脏,同时迅速剪去家兔右下肢兔毛,分别暴露分离比目鱼肌和股静脉,割取比目鱼肌并去除筋膜,经股静脉抽血提取红细胞。分别测定红细胞、心肌组织、比目鱼肌组织Na~+-K~+-ATPase活性和心肌组织、比目鱼肌组织Na~+-K~+-ATPaseα_1,α_2亚基蛋白及mRNA表达。
红细胞、心肌、比目鱼肌Na~+-K~+-ATPase活性的测定按照考马斯亮蓝蛋白测定试剂盒检测总蛋白含量后用超微量ATP酶测试盒检比色法测定。
心肌、比目鱼肌Na~+-K~+-ATPaseα_1和α_2亚基蛋白表达采用Western Blot蛋白质印迹法测定。
心肌、比目鱼肌Na~+-K~+-ATPaseα_1和α_2亚基mRNA表达采用real time-PCR法(实时定量PCR法)测定。
3低钾家兔红细胞与心肌、骨骼肌钾离子含量相关性的研究
清洁级健康家兔48只,雄性,兔龄12~14周,体重2.0~2.7 kg(由河北医科大学实验动物中心提供),随机分为6组,每组8只,分别进行正常饲料饲喂或进行不同时间的低钾饲料饲喂。对照组(T_0组)、低钾3天组(T_1组)、低钾6天组(T_2组)、低钾9天组(T_3组)、低钾12天组(T_4组)、低钾15天组(T_5组)。所有家兔购入后均进行一周的正常饲料饲喂100g/d,自由饮普通水,一周后将T_0组家兔处死取材,其余家兔进行低钾饲料饲喂,每只家兔喂食低钾饲料100g/d,自由饮蒸馏水。T_1组:低钾饲喂3天处死取材,T_2组:低钾饲喂6天处死取材,T_3组:低钾饲喂9天处死取材,T_4组:低钾饲喂12天处死取材,T_5组:低钾饲喂15天处死取材。
模型制备完成后,分别于观察结束当天经耳缘静脉注射4%戊巴比妥1ml/kg,麻醉成功后,迅速固定,开胸摘取心脏。同时迅速剪去家兔右下肢兔毛,分别暴露分离比目鱼肌和股静脉,割取比目鱼肌并去除筋膜,经股静脉抽血提取红细胞。分别测定红细胞、心肌组织、比目鱼肌钾离子含量。对红细胞钾离子含量与心肌组织、骨骼肌组织钾离子含量进行相关性分析。
4低钾家兔补钾后心肌组织、骨骼肌组织钾离子含量的变化
清洁级健康家兔16只,雄性,兔龄12~14周,体重2.0~2.7 kg(河北医科大学实验动物中心提供),随机分为2组,每组8只,分别为补钾对照组(RC组)和补钾实验组(RE组)。家兔购入后正常饲喂一周开始低钾饲喂进行模型制备。RC组给予正常饮食15天(每只家兔喂食正常饲料100g/d,自由饮普通水),RE组给予低钾饮食15天(每只家兔喂食低钾饲料100g/d,自由饮蒸馏水)。RE组模型制备完成后静脉泵入KCl行补钾实验,RC组作为其对照组同时给予补钾。两组家兔麻醉成功后,固定,插入尿管,排出膀胱余尿,收集1 h产生的尿液并测定尿液钾离子浓度,测定基础肾脏排钾量,然后建立液路持续泵入KCl并监测血浆钾离子浓度变化,钳制血浆钾离子浓度于5.5mmol/L并稳定至少1 h,停止泵钾,立即留取心脏及比目鱼肌标本以测定心脏及比目鱼肌钾离子含量,输注期间继续收集尿液以测定输注期间肾脏排钾量。
计录RC组及RE组总的钾离子摄取量、肾脏排钾量、心肌(比目鱼肌)钾离子摄取量及平均钾离子摄取率。
结果:
1低钾饲料饲喂建立低血钾动物模型
1.1低钾饲喂期间动物未见明显不适,对低钾饲料耐受良好。
1.2各组家兔体重及兔龄比较差异无统计学意义。
1.3血浆钾、钠离子浓度和血红蛋白浓度的变化
T_1、T_2、T_3、T_4、T_5组血浆钾离子浓度较正常对照组(T_0组)逐渐降低,差异有统计学意义(P<0.05);T_1、T_2、T_3、T_4、T_5组血浆钠离子浓度和血红蛋白浓度与正常对照组(T_0组)比较差异无统计学意义(P>0.05)。
1.4红细胞钾离子、钠离子含量的变化
T_1、T_2、T_3、T_4、T_5组红细胞钾离子含量较正常对照组(T_0组)逐渐降低,差异有统计学意义(P<0.05);T_1、T_2、T_3、T_4、T_5组红细胞钠离子含量较正常对照组(T_0组)增加,差异有统计学意义(P<0.05)。
1.5心肌钾离子、钠离子含量的变化
T_1组心肌钾离子含量较正常对照组(T_0)无明显降低(P>0.05),T_2、T_3、T_4、T_5组心肌钾离子含量较正常对照组(T_0)降低,差异有统计学意义(P<0.05);T_1、T_2、T_3、T_4、T_5组心肌钠离子含量与正常对照组(T_0)比较,无统计学意义(P>0.05)。
1.6比目鱼肌钾离子、钠离子含量的变化
T_1、T_2、T_3、T_4、T_5组比目鱼肌钾离子含量较正常对照组(T_0组)降低,差异有统计学意义(P <0.05):T_1、T_2、T_3、T_4、T_5组比目鱼肌钠离子含量较正常对照组(T_0组)增加,差异有统计学意义(P<0.05)。
2低钾家兔不同组织细胞Na~+-K~+-ATPase活性及α_1,α_2亚基的蛋白及mRNA表达
2.1红细胞Na~+-K~+-ATPase活性的变化
T_1组红细胞Na~+-K~+-ATPase活性与正常对照组(T_0组)比较差异无统计学意义(P >0.05),T_2、T_3、T_4、T_5组红细胞Na~+-K~+-ATPase活性较逐渐降低,差异有统计学意义(P<0.05)。
2.2心肌Na~+-K~+-ATPase活性的变化
T_1、T_2组心肌Na~+-K~+-ATPase活性与正常对照组(T_0组)比较差异无统计学意义(P >0.05),T_3、T_4、T_5组心肌Na~+-K~+-ATPase活性逐渐升高,差异有统计学意义(P<0.05)。
2.3比目鱼肌Na~+-K~+-ATPase活性的变化
T_1、T_2、T_3、T_4、T_5组比目鱼肌Na~+-K~+-ATPase活性逐渐降低,差异有统计学意义(P<0.05)。
2.4红细胞钾离子的含量与红细胞Na~+-K~+-ATPase活性的相关性。
对红细胞钾离子含量与红细胞Na~+-K~+-ATPase活性进行相关性分析表现为正相关,回归线性方程为Y=0.08X-0.31,决定系数R~2=0.766,( P < 0.05)。
2.5心肌钾离子含量与心肌组织Na~+-K~+-ATPase活性的相关性
对心肌钾离子含量与心肌组织Na~+-K~+-ATPase活性进行相关性分析表现为负相关,回归线性方程为Y=18.41-0.09X,决定系数R~2=0.434,( P<0.05)。
2.6比目鱼肌钾离子含量与比目鱼肌组织Na~+-K~+-ATPase活性的相关性
对比目鱼肌钾离子含量与比目鱼肌Na~+-K~+-ATPase活性进行相关性分析表现为正相关,回归线性方程为Y=0.25X-7.94,决定系数R~2=0.870,( P<0.05)。
2.7红细胞Na~+-K~+-ATPaseα_1和α_2亚基的蛋白表达
α_1亚基蛋白表达水平,T_3组与正常对照组(T_0组)比较差异无统计学意义(P>0.05),T_5组较正常对照组(T_0组)降低,差异有统计学意义(P<0.05);α_2亚基蛋白表达水平,T_3、T_5组较正常对照组(T_0组)降低,T_5组较T_3组降低,差异有统计学意义(P<0.05)。
2.8心肌组织Na~+-K~+-ATPaseα_1和α_2亚基的蛋白表达
α_1亚基蛋白表达水平,T_3,T_5组均较正常对照组(T_0组)升高, T_5组较T_3组升高,差异有统计学意义(P <0.05);α_2亚基蛋白表达水平,T_3,T_5组均较正常对照组(T_0组)降低,T_5组较T_3组降低,差异有统计学意义(P <0.05)。
2.9比目鱼肌组织Na~+-K~+-ATPaseα_1和α_2亚基的蛋白表达
α_1亚基蛋白表达水平,T_3组与正常对照组(T_0组)比较,差异无统计学意义(P>0.05),T_5组较正常对照组(T_0组)及T_3组均降低,差异有统计学意义(P<0.05);α_2亚基蛋白表达水平,T_3,T_5组均较正常对照组(T_0组)降低,且T_5组低于T_3组,差异有统计学意义(P <0.05)。
2.10心肌组织Na~+-K~+-ATPaseα_1和α_2亚基的mRNA表达
T_3、T_5组较正常对照组(T_0组)升高,T_5组较T_3组升高,差异有统计学意义(P<0.05);α_2亚基mRNA表达水平,T_3、T_5组较正常对照组(T_0组)降低,T_5组较T_3组降低,较差异有统计学意义(P <0.05)。
2.11比目鱼肌组织Na~+-K~+-ATPaseα_1和α_2亚基的mRNA表达
T_3组与正常对照组(T_0组)比较,差异无统计学意义(P>0.05),T_5组正常对照组(T_0)及T_3组降低,差异有统计学意义(P<0.05);α_2亚基mRNA表达水平,T_3,T_5组较正常对照组(T_0)降低,T_5组较T_3组降低,差异有统计学意义(P <0.05)。
3低钾家兔红细胞钾离子含量与心肌、骨骼肌钾离子含量的相关性
3.1低钾过程中红细胞与心肌组织钾离子含量的相关性
对低钾过程中红细胞钾离子含量与心肌组织钾离子含量进行相关性分析表现为正相关,回归线性方程为Y=0.37X~+58.24,决定系数R~2=0.666( P<0.05)。
3.2低钾过程中红细胞与比目鱼肌组织钾离子含量的相关性
对低钾过程中红细胞钾离子含量与比目鱼肌组织钾离子含量进行相关性分析表现为正相关,回归线性方程为Y=0.81X~+15.01,决定系数R~2=0.822( P<0.05)。
4低钾家兔补钾后心肌组织、骨骼肌组织钾离子含量的变化
4.1补钾结束时,RE组输注KCl的总剂量较RC组高,差异有统计学意义(P<0.05);肾脏排钾量RE组较RC组增高,差异有统计学意义(P <0.05)。
4.2补钾后心肌钾离子摄取量和平均心肌钾离子摄取率的比较
RE组心肌钾离子摄取量较RC组心肌钾离子摄取量升高,差异有统计学意义(P<0.05);RE组平均心肌钾离子摄取率较RC组平均心肌钾离子摄取率升高,差异有统计学意义(P <0.05)。
4.3补钾后比目鱼肌钾离子摄取量和平均比目鱼肌钾离子摄取率的比较
RE组比目鱼肌钾离子摄取量较RC组比目鱼肌钾离子摄取量升高,差异有统计学意义(P<0.05);RE组平均比目鱼肌钾离子摄取率较RC组平均比目鱼肌钾离子摄取率升高,差异有统计学意义(P<0.05)。
4.4心肌组织与比目鱼肌组织比较在钳制补钾过程中摄钾速率明显增高,差异有统计学意义(P<0.05)。
4.5在钳制补钾过程中随着时间的延长,机体总钾摄取量逐渐下降。
结论:
1本实验采用低钾饲料饲喂家兔可使其血浆钾离子降低,成功制备家兔缺钾模型。
2低钾饲料饲喂家兔后可使家兔血浆钾离子浓度,红细胞、心肌组织、比目鱼肌钾离子含量逐渐降低。
3缺钾可使红细胞、比目鱼肌Na~+-K~+-ATPase活性逐渐降低,心肌组织Na~+-K~+-ATPase活性升高,红细胞、比目鱼肌Na~+-K~+-ATPase活性分别与红细胞、比目鱼肌钾离子含量呈正相关;心肌组织Na~+-K~+-ATPase活性与心肌组织钾离子含量呈负相关。
4在缺钾过程中红细胞、比目鱼肌、心肌Na~+-K~+-ATPaseα_1和α_2亚基反应性不同,在红细胞及比目鱼肌α_1和α_2亚基蛋白表达及mRNA表达水平逐渐降低;在心肌组织,α_1亚基蛋白表达及mRNA表达水平逐渐升高,α_2亚基蛋白表达及mRNA表达水平逐渐降低。
5缺钾过程中红细胞钾离子含量与心肌组织、比目鱼肌钾离子含量呈正相关
6补钾时缺钾家兔总钾离子摄取量明显增加,肾脏排钾量也明显增加,其中心肌组织摄钾率明显高于骨骼肌组织摄钾率。在钳制补钾过程中随着时间的延长,机体总钾摄取量逐渐降低。
Objective: K~+-depleted rabbit models were prepared with a low-K cotent diet in this study, plasma potassium ion (K~+) concentration, K~+ content, Na~+-K~+-ATPase activity and Na~+-K~+-ATPaseα_1,α_2 isoform protein expression in erythrocyte(RBC), myocardium and skeletal muscle, Na~+-K~+-ATPaseα_1,α_2 isoform mRNA expression in myocardium and skeletal muscle were measured when rabbits were fed different days, to investigate correlation between K~+ content and Na~+-K~+-ATPase activity in RBC, myocardium and skeletal muscle, respectively, and to explore correlation between RBC K content and myocadial or skeletal muscle K~+ content. Total K~+ infusion dosage, renal K~+ excretion and K~+ uptake rate of myocardium and skeletal muscle were observed after clamping of plasma K~+ by KCl infusion.
Methods:
1 Prepared animal models with a low-K content diet Forty-eight healthy male rabbits weighing 2.0~2.7kg were randomly divided into 6 groups (n=8/group) : normal control group (group T_0) ,K-depleted-3-day group (group T_1) , K-depleted-6-day group (group T_2) , K-depleted-9-day group (group T_3) , K-depleted-12-day group (group T_4) , K-depleted-15-day group (group T_5).All rabbits were fed a normal diet for a week before model preparation.Group T_0 were given a normal diet only(100g standard chow/day each rabbit,free access to normal water),groupT_1,T_2,T_3,T_4,T_5 were fed with a low-K content diet (100g low-K content chow/day each rabbit,free access to distilled water)for 3 days,6 days, 9 days, 12 days, 15 days,respectively. On the day that models were prepared, rabbits in group T_0,T_1,T_2,T_3,T_4,T_5 were anesthetized by 4% pentobarbital (1ml/kg) given through auricular vein, 1ml blood for measuring plama K~+, sodium(Na~+) and hemoglobin concentration was sampled through central auricular artery , their thoracic cavity were opend and hearts were excised, at the moment, soleus muscle and femoral vein were separated and exposed, then soleus muscle was amputated ,blood was taken from femoral vein for separating RBC,to measure K~+ and Na~+ content in RBC, myocardium and soleus muscle.
Plasma K~+ and Na~+ concentrations were measured by ion-sensitive electrodes, hemoglobin concentration by spectrophotometric method. K~+ contents and Na~+ contents in RBC, myocardium and soleus muscle were measured by flame atomic absorption photometry.
2 Protein and mRNA expression of Na~+-K~+-ATPaseα_1,α_2 isoform in RBC, myocardium and soleus muscle of K~+-depleted rabbits
Forty-eight healthy male rabbits weighing 2.0~2.7kg were randomly divided into 6 groups (n=8/group) : normal control group (group T_0) ,K~+-depleted-3-day group (group T_1) , K~+-depleted-6-day group (group T_2) , K~+-depleted-9-day group (group T_3) , K~+-depleted-12-day group (group T_4) , K~+-depleted-15-day group (group T_5).All rabbits were fed a normal diet for a week before model preparation.Group T_0 were given a normal diet only(100g standard chow/day each rabbit,free access to normal water),groupT_1,T_2,T_3,T_4,T_5 were fed with a low-K content diet (100g low-K~+ content chow/day each rabbit,free access to distilled water)for 3 days,6 days, 9 days, 12 days, 15 days,respectively. When animal models were prepared, hearts and soleus muscle of rabbits in group T_0,T_1,T_2,T_3,T_4,T_5 were cut off after blood sampling ,to measure plasma K~+, Na, hemoglobin concentration, K~+ and Na~+ content in RBC, myocardium and soleus muscle.On the day that models were prepared, rabbits in group T_0,T_1,T_2,T_3,T_4,T_5 were anesthetized by 4% pentobarbital (1ml/kg) given through auricular vein, their thoracic cavity were opend and hearts were excised, at the moment, soleus muscle and femoral vein were separated and exposed, then soleus muscle was amputated ,blood was taken from femoral vein for separating RBC, to measure Na~+-K~+-ATPase activity and Na~+-K~+-ATPaseα_1,α_2 isoform protein and mRNA expression in RBC, myocardium, soleus muscle.
Na~+-K~+-ATPase activity of RBC, myocardium and soleus muscle were measured with an ultramicro-ATPase test box after total protein quantity with a coomssie brilliant blue protein measurement test box. Na~+-K~+-ATPaseα_1 andα_2 isoform protein expression in RBC, myocardium and soleus muscle were measured by western blot. Na~+-K~+-ATPaseα_1 andα_2 isoform mRNA expression in myocardium and soleus muscle were measured by real-time PCR.
3 Correlation between RBC K~+ content and mycardial K content or soleus K~+ content in K-depleted rabbits
Forty-eight healthy male rabbits weighing 2.0~2.7 kg were randomly divided into 6 groups (n=8/group) : normal control group (group T_0) ,K~+-depleted-3-day group (group T_1) , K~+-depleted-6-day group (group T_2) , K~+-depleted-9-day group (group T_3) , K~+-depleted-12-day group (group T_4) , K~+-depleted-15-day group (group T_5).All rabbits were fed a normal diet for a week before model preparation.Group T_0 were given a normal diet only(100g standard chow/day each rabbit,free access to normal water),groupT_1,T_2,T_3,T_4,T_5 were fed with a low-K content diet (100g low-K content chow/day each rabbit,free access to distilled water)for 3 days,6 days, 9 days, 12 days, 15 days,respectively. When animal models were prepared, hearts and soleus muscle of rabbits in group T_0,T_1,T_2,T_3,T_4,T_5 were cut off after blood sampling ,to measure plasma K~+, Na, hemoglobin concentration, K~+ and Na~+ content in RBC, myocardium and soleus muscle.On the day that models were prepared, rabbits in group T_0,T_1,T_2,T_3,T_4,T_5 were anesthetized by 4% pentobarbital (1ml/kg) given through auricular vein, their thoracic cavity were opend and hearts were excised, at the moment, soleus muscle and femoral vein were separated and exposed, then soleus muscle was amputated ,blood was taken from femoral vein for separating RBC, to measure K~+ content in RBC, myocardium and soleus muscle.
K~+ contents in RBC, myocardium and soleus muscle were measured by flame atomic absorption photometry.
Analyze relationship between RBC K~+ content and mycardial K~+ content or soleus K~+ content
4 Change of K~+ content in myocardium and soleus muscle in K~+-depleted rabbits after K~+ repletion
Sixteen healthy male rabbits weighing 2.0~2.7kg were randomly divided into 2 groups (n=8/group) : repletion control group (group RC) and repletion experimental group (group RE).All rabbits were fed a normal diet for a week before model preparation.Group RC were given a normal diet only(100 g standard chow/day each rabbit,free access to normal water),group RE were fed with a low-K~+ content diet (100 g low-K~+ content chow/day each rabbit,free access to distilled water)for 15 days. Rabbits in group RC and RE were used for intravenous potassium repletion experiment. After rabbits were anesthetized, a urinary catheter was incerted for collecting urine to measure renal K~+ excretion in 1 hour, then KCl infusions began and continued until the plasma K~+ reached the set-point 5.5mmol/L and were stable for 1 h.KCl infusions were then immediately stopped,the hearts and soleus muscle of animals were excised. Urine during KCl infusion was collected to measure K~+ content in urine.
Total K uptake of grop RC and RE was expressed as total K infusion dosage after K~+ clamping was stopped, renal K~+ excretion was expressed as total K~+ content in urine .Myocardial(Soleus) K~+ uptake of group RC during KCl infusions was calculated as the difference between myocardial (soleus) K~+ content in each heart (soleus muscle) after KCl infusion and mean myocardial (soleus) K~+ content in group T_0; myocardial(soleus) K~+ uptake of group RE during KCl infusions was calculated as the difference between myocardial (soleus) K~+ content in each heart (soleus muscle) after KCl infusion and mean myocardial (soleus) K~+ content in group T_5;mean myocardial (soleus) K~+ uptake rate of each rabbit was calculated by respective myocardial (soleus) K~+ uptake divided by duration of K~+ infusion .
Result:
1 Prepared animal models with a low-K ~+content diet
1.1 Animals were clinically unaffected and the low-K~+ content dietary regimens were well tolerated.
1.2 There is no difference of the rabbits’weight and ages in each groups.
1.3 The change of plasma K~+, Na~+ and hemoglobin concentration
Compared with group T_0, plasma K~+ concentration in group T_1,T_2,T_3,T_4,T_5 gradually decreased,the statistical differcence was significant(P<0.05); no significant difference in plasma Na~+ and hemoglobin concentration was observed in group T_0,T_1,T_2,T_3,T_4,T_5(P>0.05).
1.4 The change of RBC K~+,Na ~+content
Compared with group T_0, RBC K~+ content in group T_1,T_2,T_3,T_4,T_5 gradually decreased,the statistical differcence was significant(P<0.05); compared with group T_0, RBC Na~+ content in group T_1,T_2,T_3,T_4,T_5 gradually increased,the statistical differcence was significant(P<0.05).
1.5 The change of myocardial K~+,Na~+ content
Compared with group T_0, there was no significant decrease in myocardial K~+ content of group T_1,(P >0.05), myocardial K~+ content in groupT_2, T_3,T_4,T_5 decreased,the statistical differcence was significant(P <0.05);there was no significant increse in myocardial Na~+ content in T_1,T_2,T_3,T_4,T_5 compared with group T_0(P >0.05).
1.6 The change of soleus K~+,Na~+ content
Compared with group T_0, soleus K~+ content in group T_1,T_2,T_3,T_4,T_5 gradually decreased,the statistical differcence was significant(P<0.05); compared with group T_0, soleus Na~+ content in group T_1,T_2,T_3,T_4,T_5 gradually increased,the statistical differcence was significant(P<0.05).
2 Protein and mRNA expression of Na~+-K~+-ATPaseα_1,α_2 isoform in RBC, myocardium and soleus muscle of K~+-depleted rabbits
2.1 The change of RBC Na~+-K~+-ATPase activity
Compared with group T_0, RBC Na~+-K~+-ATPase activity in group T_1 decreased, but the statistical differcence was not significant(P >0.05), RBC Na~+-K~+-ATPase activity in group T_2,T_3,T_4,T_5 decreased,the statistical differcence was significant(P <0.05)
2.2 The change of myocardial Na~+-K~+-ATPase activity
Compared with group T_0, there was no significant increase in myocardial Na~+-K~+-ATPase activity in group T_1,T_2 (P >0.05), but myocardial Na~+-K~+-ATPase activity in group T_3 , T_4,T_5 increased,the statistical differcence was significant(P <0.05).
2.3 The change of soleus Na~+-K~+-ATPase activity
Compared with group T_0, RBC Na~+-K~+-ATPase activity in group T_1,T_2,T_3,T_4,T_5 decreased, the statistical differcence was significant(P <0.05)
2.4 Relationship between RBC K and Na~+-K~+-ATPase activity
During K depletion,both RBC K content and Na~+-K~+-ATPase activity gradually decreased, linear regression analysis showed a positive linear relationship between RBC Na~+-K~+-ATPaseb activity and RBC K content, linear regression equation was Y=0.08X-0.31, R~2=0.766, P < 0.05.
2.5 Relationship between myocardial K and Na~+-K~+-ATPase activity
During K depletion, myocardial K content gradually decreased ,however, myocardial Na~+-K~+-ATPase activity gradually increased, linear regression analysis showed a negative linear relationship between myocardial Na~+-K~+-ATPaseb activity and myocardial K content, linear regression equation was Y=18.41-0.09X,R~2=0.434, P < 0.05.
2.6 Relationship between soleus K and Na~+-K~+-ATPase activity
During K depletion,both soleus K content and Na~+-K~+-ATPase activity gradually decreased, linear regression analysis showed a positive linear relationship between soleus Na~+-K~+-ATPaseb activity and soleus K content, linear regression equation was Y=0.25X-7.94,R~2=0.870, P< 0.05.
2.7 Protein expression of RBC Na~+-K~+-ATPaseα_1 andα_2 isoform
Compared with group T_0, there was no significant decrease in RBC Na~+-K~+-ATPaseα_1 isoform protein expression in group T_3(P>0.05) ,RBC Na~+-K~+-ATPaseα_1 isoform protein expression in group T_5 decreased, the statistical differcence was significant(P<0.05); compared with group T_0, RBC Na~+-K~+-ATPaseα_2 isoform protein expression in group T_3,T_5 decreased, the statistical differcence was significant(P<0.05).
2.8 Protein expression of myocardial Na~+-K~+-ATPaseα_1 andα_2 isoform
Compared with group T_0, myocardial Na~+-K~+-ATPaseα_1 isoform protein expression in group T_3,T_5 increased, the statistical differcence was significant(P<0.05), myocardial Na~+-K~+-ATPaseα_2 isoform protein expression in group T_3,T_5 decreased, the statistical differcence was significant(P <0.05).
2.9 Protein expression of soleus Na~+-K~+-ATPaseα_1 andα_2 isoform
Compared with group T_0, there was no significant decrease in soleus Na~+-K~+-ATPaseα_1 isoform protein expression in group T_3(P>0.05) , soleus Na~+-K~+-ATPaseα_1 isoform protein expression in group T_5 decreased, the statistical differcence was significant(P<0.05); compared with group T_0, soleus Na~+-K~+-ATPaseα_2 isoform protein expression in group T_3,T_5 decreased, the statistical differcence was significant(P<0.05).
2.10 mRNA expression of myocardial Na~+-K~+-ATPaseα_1 andα_2 isoform
Compared with group T_0, myocardial Na~+-K~+-ATPaseα_1 isoform mRNA expression in group T_3,T_5 increased, the statistical differcence was significant(P<0.05), myocardial Na~+-K~+-ATPaseα_2 isoform mRNA expression in group T_3,T_5 decreased, the statistical differcence was significant(P <0.05).
2.11 mRNA expression of soleus Na~+-K~+-ATPaseα_1 andα_2 isoform
Compared with group T_0, there was no significant decrease in soleus Na~+-K~+-ATPaseα_1 isoform mRNA expression in group T_3(P>0.05) , soleus Na~+-K~+-ATPaseα_1 isoform mRNA expression in group T_5 decreased, the statistical differcence was significant(P<0.05); compared with group T_0, soleus Na~+-K~+-ATPaseα_2 isoform mRNA expression in group T_3,T_5 decreased, the statistical differcence was significant(P<0.05).
3 Correlation between RBC K~+ content and mycardial K~+ content or soleus K~+ content in K~+-depleted rabbits
3.1 Relationship between RBC K~+ content and myocardial K~+ content during K~+ depletion
Linear regression analysis showed a positive linear relationship between RBC K~+ content and myocardial K~+ content, linear regression equation was Y=0.37X~+58.24,R~2=0.666, P<0.05. 3.2 Relationship between RBC K~+ content and soleus K~+ content during K~+ depletion
Linear regression analysis showed a positive linear relationship between RBC K~+ content and soleus K~+ content, linear regression equation was Y=0.81X~+15.01,R~2=0.822, P<0.05.
4 Change of K~+ content in myocardium and soleus muscle in K~+-depleted rabbits after K~+ repletion
4.1 When K~+ repletion were stopped, total KCl infusion dosage was higher in group RE than in group RC, the statistical differcence was significant(P<0.05); total renal K excretion was higher in group RE than in group RC, the statistical differcence was significant(P<0.05).
4.2 The comparison of myocardial K~+ uptake and mean myocardial K~+ uptake rate after potassium repletion
Compared with group RC, myocardial K~+ uptake in group RE was higher, the statistical differcence was significant(P <0.05), mean myocardial K~+ uptake rate in group RE was higher, the statistical differcence was significant(P <0.05).
4.3 The comparison of soleus K~+ uptake and mean soleus K~+ uptake rate after potassium repletion
Compared with group RC, soleus K~+ uptake in group RE was higher, the statistical differcence was significant(P <0.05), mean soleusl K~+ uptake rate in group RE was higher, the statistical differcence was significant(P <0.05).
4.4 During clamping plasma K~+ concentration by KCl infusion, K~+ uptake rate of myocardiaum was higher than that of soleus muscle, the statistical differcence was significant(P <0.05).
4.5 Body total K~+ uptake gradually decreased during clamping plasma K~+ by KCl infusion.
Conclusion:
1 The present study prepared K~+-depleted rabbit models successfully used a low-K~+ content diet,which induced a plasma K~+ decrease in experimental rabbits.
2 Plasma K~+ concentation,RBC K~+ content,myocardial K~+ content and soleus K~+ content of experimental rabbits gradually decreased afer they were fed with the low-K~+ content chaw.
3 Potassium depletion induced a down regulation in RBC Na~+-K~+-ATPase activity and soleus Na~+-K~+-ATPase activity but an upregulation in myocardial Na~+-K~+-ATPase activity;linear regression analysis of data from K-depleted and contral rabbits showed a positive linear relationship between Na~+-K~+-ATPaseb activity and K~+ content in RBC and soleus muscle respectively and a negative linear relationship between Na~+-K~+-ATPaseb activity and K content in myocardium.
4 RBC K~+ content was positively correlated with myocardial K~+ content and soleus K~+ content during K depletion.
5 During K~+ depletion, the responsivity of Na~+-K~+-ATPaseα_1 andα_2 isoform was different in RBC,myocardium and soleus muscle: mRNA and protein expression ofα_1 andα_2 isoform gradually decreased in RBC and soleus muscle, mRNA and protein expression ofα_1 isoform gradually increased but that ofα_2 isoform gradually decreased in myocardium.
6 Total K~+ uptake and renal K~+ excretion incresed significantly in K~+-deplted rabbits,and K~+ uptake rate in myocardium was hiagher than that in soleus muscle, during K~+ repletion. Body total K~+ uptake gradually decreased during clamping plasma K~+ by KCl infusion.
方法:
1用低钾饲料饲喂建立低血钾动物模型
清洁级健康家兔48只,雄性,兔龄12~14周,体重2.0~2.7 kg(由河北医科大学实验动物中心提供),随机分为6组,每组8只,分别进行正常饲料饲喂或进行不同时间的低钾饲料饲喂。对照组(T_0组)、低钾3天组(T_1组)、低钾6天组(T_2组)、低钾9天组(T_3组)、低钾12天组(T_4组)、低钾15天组(T_5组)。所有家兔购入后均进行一周的正常饲料饲喂100g/d,自由饮普通水,一周后将T_0组家兔处死取材,其余家兔进行低钾饲料饲喂,每只家兔喂食低钾饲料100 g/d,自由饮蒸馏水。T_1组:低钾饲喂3天处死取材,T_2组:低钾饲喂6天处死取材,T_3组:低钾饲喂9天处死取材,T_4组:低钾饲喂12天处死取材,T_5组:低钾饲喂15天处死取材。
各组分别于观察结束当天经耳中央动脉取血1 ml测定血浆钾离子、钠离子及血红蛋白浓度,经股静脉抽血分离红细胞测定红细胞钾离子浓度,开胸摘取心脏测定心肌组织钾离子、钠离子含量,取家兔右下肢比目鱼肌测定骨骼肌钾离子、钠离子含量。
血浆钾、钠离子浓度采用离子选择性电极测量法测定,血红蛋白浓度采用分光光度比色法测定。
红细胞、心肌、比目鱼肌钾、钠离子含量采用火焰原子吸收光度计测定。
2低钾家兔不同组织细胞Na~+-K~+-ATPase活性及α_1,α_2亚基蛋白和mRNA表达的实验研究
清洁级健康家兔48只,雄性,兔龄12~14周,体重2.0~2.7 kg(由河北医科大学实验动物中心提供),随机分为6组,每组8只,分别进行正常饲料饲喂或进行不同时间的低钾饲料饲喂。对照组(T_0组)、低钾3天组(T_1组)、低钾6天组(T_2组)、低钾9天组(T_3组)、低钾12天组(T_4组)、低钾15天组(T_5组)。所有家兔购入后均进行一周的正常饲料饲喂100g/d,自由饮普通水,一周后将T_0组家兔处死取材,其余家兔进行低钾饲料饲喂,每只家兔喂食低钾饲料100g/d,自由饮蒸馏水。T_1组:低钾饲喂3天处死取材,T_2组:低钾饲喂6天处死取材,T_3组:低钾饲喂9天处死取材,T_4组:低钾饲喂12天处死取材,T_5组:低钾饲喂15天处死取材。
模型制备完成后,分别于观察结束当天经耳缘静脉注射4%戊巴比妥1ml/kg,麻醉成功后,迅速固定,开胸摘取心脏,同时迅速剪去家兔右下肢兔毛,分别暴露分离比目鱼肌和股静脉,割取比目鱼肌并去除筋膜,经股静脉抽血提取红细胞。分别测定红细胞、心肌组织、比目鱼肌组织Na~+-K~+-ATPase活性和心肌组织、比目鱼肌组织Na~+-K~+-ATPaseα_1,α_2亚基蛋白及mRNA表达。
红细胞、心肌、比目鱼肌Na~+-K~+-ATPase活性的测定按照考马斯亮蓝蛋白测定试剂盒检测总蛋白含量后用超微量ATP酶测试盒检比色法测定。
心肌、比目鱼肌Na~+-K~+-ATPaseα_1和α_2亚基蛋白表达采用Western Blot蛋白质印迹法测定。
心肌、比目鱼肌Na~+-K~+-ATPaseα_1和α_2亚基mRNA表达采用real time-PCR法(实时定量PCR法)测定。
3低钾家兔红细胞与心肌、骨骼肌钾离子含量相关性的研究
清洁级健康家兔48只,雄性,兔龄12~14周,体重2.0~2.7 kg(由河北医科大学实验动物中心提供),随机分为6组,每组8只,分别进行正常饲料饲喂或进行不同时间的低钾饲料饲喂。对照组(T_0组)、低钾3天组(T_1组)、低钾6天组(T_2组)、低钾9天组(T_3组)、低钾12天组(T_4组)、低钾15天组(T_5组)。所有家兔购入后均进行一周的正常饲料饲喂100g/d,自由饮普通水,一周后将T_0组家兔处死取材,其余家兔进行低钾饲料饲喂,每只家兔喂食低钾饲料100g/d,自由饮蒸馏水。T_1组:低钾饲喂3天处死取材,T_2组:低钾饲喂6天处死取材,T_3组:低钾饲喂9天处死取材,T_4组:低钾饲喂12天处死取材,T_5组:低钾饲喂15天处死取材。
模型制备完成后,分别于观察结束当天经耳缘静脉注射4%戊巴比妥1ml/kg,麻醉成功后,迅速固定,开胸摘取心脏。同时迅速剪去家兔右下肢兔毛,分别暴露分离比目鱼肌和股静脉,割取比目鱼肌并去除筋膜,经股静脉抽血提取红细胞。分别测定红细胞、心肌组织、比目鱼肌钾离子含量。对红细胞钾离子含量与心肌组织、骨骼肌组织钾离子含量进行相关性分析。
4低钾家兔补钾后心肌组织、骨骼肌组织钾离子含量的变化
清洁级健康家兔16只,雄性,兔龄12~14周,体重2.0~2.7 kg(河北医科大学实验动物中心提供),随机分为2组,每组8只,分别为补钾对照组(RC组)和补钾实验组(RE组)。家兔购入后正常饲喂一周开始低钾饲喂进行模型制备。RC组给予正常饮食15天(每只家兔喂食正常饲料100g/d,自由饮普通水),RE组给予低钾饮食15天(每只家兔喂食低钾饲料100g/d,自由饮蒸馏水)。RE组模型制备完成后静脉泵入KCl行补钾实验,RC组作为其对照组同时给予补钾。两组家兔麻醉成功后,固定,插入尿管,排出膀胱余尿,收集1 h产生的尿液并测定尿液钾离子浓度,测定基础肾脏排钾量,然后建立液路持续泵入KCl并监测血浆钾离子浓度变化,钳制血浆钾离子浓度于5.5mmol/L并稳定至少1 h,停止泵钾,立即留取心脏及比目鱼肌标本以测定心脏及比目鱼肌钾离子含量,输注期间继续收集尿液以测定输注期间肾脏排钾量。
计录RC组及RE组总的钾离子摄取量、肾脏排钾量、心肌(比目鱼肌)钾离子摄取量及平均钾离子摄取率。
结果:
1低钾饲料饲喂建立低血钾动物模型
1.1低钾饲喂期间动物未见明显不适,对低钾饲料耐受良好。
1.2各组家兔体重及兔龄比较差异无统计学意义。
1.3血浆钾、钠离子浓度和血红蛋白浓度的变化
T_1、T_2、T_3、T_4、T_5组血浆钾离子浓度较正常对照组(T_0组)逐渐降低,差异有统计学意义(P<0.05);T_1、T_2、T_3、T_4、T_5组血浆钠离子浓度和血红蛋白浓度与正常对照组(T_0组)比较差异无统计学意义(P>0.05)。
1.4红细胞钾离子、钠离子含量的变化
T_1、T_2、T_3、T_4、T_5组红细胞钾离子含量较正常对照组(T_0组)逐渐降低,差异有统计学意义(P<0.05);T_1、T_2、T_3、T_4、T_5组红细胞钠离子含量较正常对照组(T_0组)增加,差异有统计学意义(P<0.05)。
1.5心肌钾离子、钠离子含量的变化
T_1组心肌钾离子含量较正常对照组(T_0)无明显降低(P>0.05),T_2、T_3、T_4、T_5组心肌钾离子含量较正常对照组(T_0)降低,差异有统计学意义(P<0.05);T_1、T_2、T_3、T_4、T_5组心肌钠离子含量与正常对照组(T_0)比较,无统计学意义(P>0.05)。
1.6比目鱼肌钾离子、钠离子含量的变化
T_1、T_2、T_3、T_4、T_5组比目鱼肌钾离子含量较正常对照组(T_0组)降低,差异有统计学意义(P <0.05):T_1、T_2、T_3、T_4、T_5组比目鱼肌钠离子含量较正常对照组(T_0组)增加,差异有统计学意义(P<0.05)。
2低钾家兔不同组织细胞Na~+-K~+-ATPase活性及α_1,α_2亚基的蛋白及mRNA表达
2.1红细胞Na~+-K~+-ATPase活性的变化
T_1组红细胞Na~+-K~+-ATPase活性与正常对照组(T_0组)比较差异无统计学意义(P >0.05),T_2、T_3、T_4、T_5组红细胞Na~+-K~+-ATPase活性较逐渐降低,差异有统计学意义(P<0.05)。
2.2心肌Na~+-K~+-ATPase活性的变化
T_1、T_2组心肌Na~+-K~+-ATPase活性与正常对照组(T_0组)比较差异无统计学意义(P >0.05),T_3、T_4、T_5组心肌Na~+-K~+-ATPase活性逐渐升高,差异有统计学意义(P<0.05)。
2.3比目鱼肌Na~+-K~+-ATPase活性的变化
T_1、T_2、T_3、T_4、T_5组比目鱼肌Na~+-K~+-ATPase活性逐渐降低,差异有统计学意义(P<0.05)。
2.4红细胞钾离子的含量与红细胞Na~+-K~+-ATPase活性的相关性。
对红细胞钾离子含量与红细胞Na~+-K~+-ATPase活性进行相关性分析表现为正相关,回归线性方程为Y=0.08X-0.31,决定系数R~2=0.766,( P < 0.05)。
2.5心肌钾离子含量与心肌组织Na~+-K~+-ATPase活性的相关性
对心肌钾离子含量与心肌组织Na~+-K~+-ATPase活性进行相关性分析表现为负相关,回归线性方程为Y=18.41-0.09X,决定系数R~2=0.434,( P<0.05)。
2.6比目鱼肌钾离子含量与比目鱼肌组织Na~+-K~+-ATPase活性的相关性
对比目鱼肌钾离子含量与比目鱼肌Na~+-K~+-ATPase活性进行相关性分析表现为正相关,回归线性方程为Y=0.25X-7.94,决定系数R~2=0.870,( P<0.05)。
2.7红细胞Na~+-K~+-ATPaseα_1和α_2亚基的蛋白表达
α_1亚基蛋白表达水平,T_3组与正常对照组(T_0组)比较差异无统计学意义(P>0.05),T_5组较正常对照组(T_0组)降低,差异有统计学意义(P<0.05);α_2亚基蛋白表达水平,T_3、T_5组较正常对照组(T_0组)降低,T_5组较T_3组降低,差异有统计学意义(P<0.05)。
2.8心肌组织Na~+-K~+-ATPaseα_1和α_2亚基的蛋白表达
α_1亚基蛋白表达水平,T_3,T_5组均较正常对照组(T_0组)升高, T_5组较T_3组升高,差异有统计学意义(P <0.05);α_2亚基蛋白表达水平,T_3,T_5组均较正常对照组(T_0组)降低,T_5组较T_3组降低,差异有统计学意义(P <0.05)。
2.9比目鱼肌组织Na~+-K~+-ATPaseα_1和α_2亚基的蛋白表达
α_1亚基蛋白表达水平,T_3组与正常对照组(T_0组)比较,差异无统计学意义(P>0.05),T_5组较正常对照组(T_0组)及T_3组均降低,差异有统计学意义(P<0.05);α_2亚基蛋白表达水平,T_3,T_5组均较正常对照组(T_0组)降低,且T_5组低于T_3组,差异有统计学意义(P <0.05)。
2.10心肌组织Na~+-K~+-ATPaseα_1和α_2亚基的mRNA表达
T_3、T_5组较正常对照组(T_0组)升高,T_5组较T_3组升高,差异有统计学意义(P<0.05);α_2亚基mRNA表达水平,T_3、T_5组较正常对照组(T_0组)降低,T_5组较T_3组降低,较差异有统计学意义(P <0.05)。
2.11比目鱼肌组织Na~+-K~+-ATPaseα_1和α_2亚基的mRNA表达
T_3组与正常对照组(T_0组)比较,差异无统计学意义(P>0.05),T_5组正常对照组(T_0)及T_3组降低,差异有统计学意义(P<0.05);α_2亚基mRNA表达水平,T_3,T_5组较正常对照组(T_0)降低,T_5组较T_3组降低,差异有统计学意义(P <0.05)。
3低钾家兔红细胞钾离子含量与心肌、骨骼肌钾离子含量的相关性
3.1低钾过程中红细胞与心肌组织钾离子含量的相关性
对低钾过程中红细胞钾离子含量与心肌组织钾离子含量进行相关性分析表现为正相关,回归线性方程为Y=0.37X~+58.24,决定系数R~2=0.666( P<0.05)。
3.2低钾过程中红细胞与比目鱼肌组织钾离子含量的相关性
对低钾过程中红细胞钾离子含量与比目鱼肌组织钾离子含量进行相关性分析表现为正相关,回归线性方程为Y=0.81X~+15.01,决定系数R~2=0.822( P<0.05)。
4低钾家兔补钾后心肌组织、骨骼肌组织钾离子含量的变化
4.1补钾结束时,RE组输注KCl的总剂量较RC组高,差异有统计学意义(P<0.05);肾脏排钾量RE组较RC组增高,差异有统计学意义(P <0.05)。
4.2补钾后心肌钾离子摄取量和平均心肌钾离子摄取率的比较
RE组心肌钾离子摄取量较RC组心肌钾离子摄取量升高,差异有统计学意义(P<0.05);RE组平均心肌钾离子摄取率较RC组平均心肌钾离子摄取率升高,差异有统计学意义(P <0.05)。
4.3补钾后比目鱼肌钾离子摄取量和平均比目鱼肌钾离子摄取率的比较
RE组比目鱼肌钾离子摄取量较RC组比目鱼肌钾离子摄取量升高,差异有统计学意义(P<0.05);RE组平均比目鱼肌钾离子摄取率较RC组平均比目鱼肌钾离子摄取率升高,差异有统计学意义(P<0.05)。
4.4心肌组织与比目鱼肌组织比较在钳制补钾过程中摄钾速率明显增高,差异有统计学意义(P<0.05)。
4.5在钳制补钾过程中随着时间的延长,机体总钾摄取量逐渐下降。
结论:
1本实验采用低钾饲料饲喂家兔可使其血浆钾离子降低,成功制备家兔缺钾模型。
2低钾饲料饲喂家兔后可使家兔血浆钾离子浓度,红细胞、心肌组织、比目鱼肌钾离子含量逐渐降低。
3缺钾可使红细胞、比目鱼肌Na~+-K~+-ATPase活性逐渐降低,心肌组织Na~+-K~+-ATPase活性升高,红细胞、比目鱼肌Na~+-K~+-ATPase活性分别与红细胞、比目鱼肌钾离子含量呈正相关;心肌组织Na~+-K~+-ATPase活性与心肌组织钾离子含量呈负相关。
4在缺钾过程中红细胞、比目鱼肌、心肌Na~+-K~+-ATPaseα_1和α_2亚基反应性不同,在红细胞及比目鱼肌α_1和α_2亚基蛋白表达及mRNA表达水平逐渐降低;在心肌组织,α_1亚基蛋白表达及mRNA表达水平逐渐升高,α_2亚基蛋白表达及mRNA表达水平逐渐降低。
5缺钾过程中红细胞钾离子含量与心肌组织、比目鱼肌钾离子含量呈正相关
6补钾时缺钾家兔总钾离子摄取量明显增加,肾脏排钾量也明显增加,其中心肌组织摄钾率明显高于骨骼肌组织摄钾率。在钳制补钾过程中随着时间的延长,机体总钾摄取量逐渐降低。
Objective: K~+-depleted rabbit models were prepared with a low-K cotent diet in this study, plasma potassium ion (K~+) concentration, K~+ content, Na~+-K~+-ATPase activity and Na~+-K~+-ATPaseα_1,α_2 isoform protein expression in erythrocyte(RBC), myocardium and skeletal muscle, Na~+-K~+-ATPaseα_1,α_2 isoform mRNA expression in myocardium and skeletal muscle were measured when rabbits were fed different days, to investigate correlation between K~+ content and Na~+-K~+-ATPase activity in RBC, myocardium and skeletal muscle, respectively, and to explore correlation between RBC K content and myocadial or skeletal muscle K~+ content. Total K~+ infusion dosage, renal K~+ excretion and K~+ uptake rate of myocardium and skeletal muscle were observed after clamping of plasma K~+ by KCl infusion.
Methods:
1 Prepared animal models with a low-K content diet Forty-eight healthy male rabbits weighing 2.0~2.7kg were randomly divided into 6 groups (n=8/group) : normal control group (group T_0) ,K-depleted-3-day group (group T_1) , K-depleted-6-day group (group T_2) , K-depleted-9-day group (group T_3) , K-depleted-12-day group (group T_4) , K-depleted-15-day group (group T_5).All rabbits were fed a normal diet for a week before model preparation.Group T_0 were given a normal diet only(100g standard chow/day each rabbit,free access to normal water),groupT_1,T_2,T_3,T_4,T_5 were fed with a low-K content diet (100g low-K content chow/day each rabbit,free access to distilled water)for 3 days,6 days, 9 days, 12 days, 15 days,respectively. On the day that models were prepared, rabbits in group T_0,T_1,T_2,T_3,T_4,T_5 were anesthetized by 4% pentobarbital (1ml/kg) given through auricular vein, 1ml blood for measuring plama K~+, sodium(Na~+) and hemoglobin concentration was sampled through central auricular artery , their thoracic cavity were opend and hearts were excised, at the moment, soleus muscle and femoral vein were separated and exposed, then soleus muscle was amputated ,blood was taken from femoral vein for separating RBC,to measure K~+ and Na~+ content in RBC, myocardium and soleus muscle.
Plasma K~+ and Na~+ concentrations were measured by ion-sensitive electrodes, hemoglobin concentration by spectrophotometric method. K~+ contents and Na~+ contents in RBC, myocardium and soleus muscle were measured by flame atomic absorption photometry.
2 Protein and mRNA expression of Na~+-K~+-ATPaseα_1,α_2 isoform in RBC, myocardium and soleus muscle of K~+-depleted rabbits
Forty-eight healthy male rabbits weighing 2.0~2.7kg were randomly divided into 6 groups (n=8/group) : normal control group (group T_0) ,K~+-depleted-3-day group (group T_1) , K~+-depleted-6-day group (group T_2) , K~+-depleted-9-day group (group T_3) , K~+-depleted-12-day group (group T_4) , K~+-depleted-15-day group (group T_5).All rabbits were fed a normal diet for a week before model preparation.Group T_0 were given a normal diet only(100g standard chow/day each rabbit,free access to normal water),groupT_1,T_2,T_3,T_4,T_5 were fed with a low-K content diet (100g low-K~+ content chow/day each rabbit,free access to distilled water)for 3 days,6 days, 9 days, 12 days, 15 days,respectively. When animal models were prepared, hearts and soleus muscle of rabbits in group T_0,T_1,T_2,T_3,T_4,T_5 were cut off after blood sampling ,to measure plasma K~+, Na, hemoglobin concentration, K~+ and Na~+ content in RBC, myocardium and soleus muscle.On the day that models were prepared, rabbits in group T_0,T_1,T_2,T_3,T_4,T_5 were anesthetized by 4% pentobarbital (1ml/kg) given through auricular vein, their thoracic cavity were opend and hearts were excised, at the moment, soleus muscle and femoral vein were separated and exposed, then soleus muscle was amputated ,blood was taken from femoral vein for separating RBC, to measure Na~+-K~+-ATPase activity and Na~+-K~+-ATPaseα_1,α_2 isoform protein and mRNA expression in RBC, myocardium, soleus muscle.
Na~+-K~+-ATPase activity of RBC, myocardium and soleus muscle were measured with an ultramicro-ATPase test box after total protein quantity with a coomssie brilliant blue protein measurement test box. Na~+-K~+-ATPaseα_1 andα_2 isoform protein expression in RBC, myocardium and soleus muscle were measured by western blot. Na~+-K~+-ATPaseα_1 andα_2 isoform mRNA expression in myocardium and soleus muscle were measured by real-time PCR.
3 Correlation between RBC K~+ content and mycardial K content or soleus K~+ content in K-depleted rabbits
Forty-eight healthy male rabbits weighing 2.0~2.7 kg were randomly divided into 6 groups (n=8/group) : normal control group (group T_0) ,K~+-depleted-3-day group (group T_1) , K~+-depleted-6-day group (group T_2) , K~+-depleted-9-day group (group T_3) , K~+-depleted-12-day group (group T_4) , K~+-depleted-15-day group (group T_5).All rabbits were fed a normal diet for a week before model preparation.Group T_0 were given a normal diet only(100g standard chow/day each rabbit,free access to normal water),groupT_1,T_2,T_3,T_4,T_5 were fed with a low-K content diet (100g low-K content chow/day each rabbit,free access to distilled water)for 3 days,6 days, 9 days, 12 days, 15 days,respectively. When animal models were prepared, hearts and soleus muscle of rabbits in group T_0,T_1,T_2,T_3,T_4,T_5 were cut off after blood sampling ,to measure plasma K~+, Na, hemoglobin concentration, K~+ and Na~+ content in RBC, myocardium and soleus muscle.On the day that models were prepared, rabbits in group T_0,T_1,T_2,T_3,T_4,T_5 were anesthetized by 4% pentobarbital (1ml/kg) given through auricular vein, their thoracic cavity were opend and hearts were excised, at the moment, soleus muscle and femoral vein were separated and exposed, then soleus muscle was amputated ,blood was taken from femoral vein for separating RBC, to measure K~+ content in RBC, myocardium and soleus muscle.
K~+ contents in RBC, myocardium and soleus muscle were measured by flame atomic absorption photometry.
Analyze relationship between RBC K~+ content and mycardial K~+ content or soleus K~+ content
4 Change of K~+ content in myocardium and soleus muscle in K~+-depleted rabbits after K~+ repletion
Sixteen healthy male rabbits weighing 2.0~2.7kg were randomly divided into 2 groups (n=8/group) : repletion control group (group RC) and repletion experimental group (group RE).All rabbits were fed a normal diet for a week before model preparation.Group RC were given a normal diet only(100 g standard chow/day each rabbit,free access to normal water),group RE were fed with a low-K~+ content diet (100 g low-K~+ content chow/day each rabbit,free access to distilled water)for 15 days. Rabbits in group RC and RE were used for intravenous potassium repletion experiment. After rabbits were anesthetized, a urinary catheter was incerted for collecting urine to measure renal K~+ excretion in 1 hour, then KCl infusions began and continued until the plasma K~+ reached the set-point 5.5mmol/L and were stable for 1 h.KCl infusions were then immediately stopped,the hearts and soleus muscle of animals were excised. Urine during KCl infusion was collected to measure K~+ content in urine.
Total K uptake of grop RC and RE was expressed as total K infusion dosage after K~+ clamping was stopped, renal K~+ excretion was expressed as total K~+ content in urine .Myocardial(Soleus) K~+ uptake of group RC during KCl infusions was calculated as the difference between myocardial (soleus) K~+ content in each heart (soleus muscle) after KCl infusion and mean myocardial (soleus) K~+ content in group T_0; myocardial(soleus) K~+ uptake of group RE during KCl infusions was calculated as the difference between myocardial (soleus) K~+ content in each heart (soleus muscle) after KCl infusion and mean myocardial (soleus) K~+ content in group T_5;mean myocardial (soleus) K~+ uptake rate of each rabbit was calculated by respective myocardial (soleus) K~+ uptake divided by duration of K~+ infusion .
Result:
1 Prepared animal models with a low-K ~+content diet
1.1 Animals were clinically unaffected and the low-K~+ content dietary regimens were well tolerated.
1.2 There is no difference of the rabbits’weight and ages in each groups.
1.3 The change of plasma K~+, Na~+ and hemoglobin concentration
Compared with group T_0, plasma K~+ concentration in group T_1,T_2,T_3,T_4,T_5 gradually decreased,the statistical differcence was significant(P<0.05); no significant difference in plasma Na~+ and hemoglobin concentration was observed in group T_0,T_1,T_2,T_3,T_4,T_5(P>0.05).
1.4 The change of RBC K~+,Na ~+content
Compared with group T_0, RBC K~+ content in group T_1,T_2,T_3,T_4,T_5 gradually decreased,the statistical differcence was significant(P<0.05); compared with group T_0, RBC Na~+ content in group T_1,T_2,T_3,T_4,T_5 gradually increased,the statistical differcence was significant(P<0.05).
1.5 The change of myocardial K~+,Na~+ content
Compared with group T_0, there was no significant decrease in myocardial K~+ content of group T_1,(P >0.05), myocardial K~+ content in groupT_2, T_3,T_4,T_5 decreased,the statistical differcence was significant(P <0.05);there was no significant increse in myocardial Na~+ content in T_1,T_2,T_3,T_4,T_5 compared with group T_0(P >0.05).
1.6 The change of soleus K~+,Na~+ content
Compared with group T_0, soleus K~+ content in group T_1,T_2,T_3,T_4,T_5 gradually decreased,the statistical differcence was significant(P<0.05); compared with group T_0, soleus Na~+ content in group T_1,T_2,T_3,T_4,T_5 gradually increased,the statistical differcence was significant(P<0.05).
2 Protein and mRNA expression of Na~+-K~+-ATPaseα_1,α_2 isoform in RBC, myocardium and soleus muscle of K~+-depleted rabbits
2.1 The change of RBC Na~+-K~+-ATPase activity
Compared with group T_0, RBC Na~+-K~+-ATPase activity in group T_1 decreased, but the statistical differcence was not significant(P >0.05), RBC Na~+-K~+-ATPase activity in group T_2,T_3,T_4,T_5 decreased,the statistical differcence was significant(P <0.05)
2.2 The change of myocardial Na~+-K~+-ATPase activity
Compared with group T_0, there was no significant increase in myocardial Na~+-K~+-ATPase activity in group T_1,T_2 (P >0.05), but myocardial Na~+-K~+-ATPase activity in group T_3 , T_4,T_5 increased,the statistical differcence was significant(P <0.05).
2.3 The change of soleus Na~+-K~+-ATPase activity
Compared with group T_0, RBC Na~+-K~+-ATPase activity in group T_1,T_2,T_3,T_4,T_5 decreased, the statistical differcence was significant(P <0.05)
2.4 Relationship between RBC K and Na~+-K~+-ATPase activity
During K depletion,both RBC K content and Na~+-K~+-ATPase activity gradually decreased, linear regression analysis showed a positive linear relationship between RBC Na~+-K~+-ATPaseb activity and RBC K content, linear regression equation was Y=0.08X-0.31, R~2=0.766, P < 0.05.
2.5 Relationship between myocardial K and Na~+-K~+-ATPase activity
During K depletion, myocardial K content gradually decreased ,however, myocardial Na~+-K~+-ATPase activity gradually increased, linear regression analysis showed a negative linear relationship between myocardial Na~+-K~+-ATPaseb activity and myocardial K content, linear regression equation was Y=18.41-0.09X,R~2=0.434, P < 0.05.
2.6 Relationship between soleus K and Na~+-K~+-ATPase activity
During K depletion,both soleus K content and Na~+-K~+-ATPase activity gradually decreased, linear regression analysis showed a positive linear relationship between soleus Na~+-K~+-ATPaseb activity and soleus K content, linear regression equation was Y=0.25X-7.94,R~2=0.870, P< 0.05.
2.7 Protein expression of RBC Na~+-K~+-ATPaseα_1 andα_2 isoform
Compared with group T_0, there was no significant decrease in RBC Na~+-K~+-ATPaseα_1 isoform protein expression in group T_3(P>0.05) ,RBC Na~+-K~+-ATPaseα_1 isoform protein expression in group T_5 decreased, the statistical differcence was significant(P<0.05); compared with group T_0, RBC Na~+-K~+-ATPaseα_2 isoform protein expression in group T_3,T_5 decreased, the statistical differcence was significant(P<0.05).
2.8 Protein expression of myocardial Na~+-K~+-ATPaseα_1 andα_2 isoform
Compared with group T_0, myocardial Na~+-K~+-ATPaseα_1 isoform protein expression in group T_3,T_5 increased, the statistical differcence was significant(P<0.05), myocardial Na~+-K~+-ATPaseα_2 isoform protein expression in group T_3,T_5 decreased, the statistical differcence was significant(P <0.05).
2.9 Protein expression of soleus Na~+-K~+-ATPaseα_1 andα_2 isoform
Compared with group T_0, there was no significant decrease in soleus Na~+-K~+-ATPaseα_1 isoform protein expression in group T_3(P>0.05) , soleus Na~+-K~+-ATPaseα_1 isoform protein expression in group T_5 decreased, the statistical differcence was significant(P<0.05); compared with group T_0, soleus Na~+-K~+-ATPaseα_2 isoform protein expression in group T_3,T_5 decreased, the statistical differcence was significant(P<0.05).
2.10 mRNA expression of myocardial Na~+-K~+-ATPaseα_1 andα_2 isoform
Compared with group T_0, myocardial Na~+-K~+-ATPaseα_1 isoform mRNA expression in group T_3,T_5 increased, the statistical differcence was significant(P<0.05), myocardial Na~+-K~+-ATPaseα_2 isoform mRNA expression in group T_3,T_5 decreased, the statistical differcence was significant(P <0.05).
2.11 mRNA expression of soleus Na~+-K~+-ATPaseα_1 andα_2 isoform
Compared with group T_0, there was no significant decrease in soleus Na~+-K~+-ATPaseα_1 isoform mRNA expression in group T_3(P>0.05) , soleus Na~+-K~+-ATPaseα_1 isoform mRNA expression in group T_5 decreased, the statistical differcence was significant(P<0.05); compared with group T_0, soleus Na~+-K~+-ATPaseα_2 isoform mRNA expression in group T_3,T_5 decreased, the statistical differcence was significant(P<0.05).
3 Correlation between RBC K~+ content and mycardial K~+ content or soleus K~+ content in K~+-depleted rabbits
3.1 Relationship between RBC K~+ content and myocardial K~+ content during K~+ depletion
Linear regression analysis showed a positive linear relationship between RBC K~+ content and myocardial K~+ content, linear regression equation was Y=0.37X~+58.24,R~2=0.666, P<0.05. 3.2 Relationship between RBC K~+ content and soleus K~+ content during K~+ depletion
Linear regression analysis showed a positive linear relationship between RBC K~+ content and soleus K~+ content, linear regression equation was Y=0.81X~+15.01,R~2=0.822, P<0.05.
4 Change of K~+ content in myocardium and soleus muscle in K~+-depleted rabbits after K~+ repletion
4.1 When K~+ repletion were stopped, total KCl infusion dosage was higher in group RE than in group RC, the statistical differcence was significant(P<0.05); total renal K excretion was higher in group RE than in group RC, the statistical differcence was significant(P<0.05).
4.2 The comparison of myocardial K~+ uptake and mean myocardial K~+ uptake rate after potassium repletion
Compared with group RC, myocardial K~+ uptake in group RE was higher, the statistical differcence was significant(P <0.05), mean myocardial K~+ uptake rate in group RE was higher, the statistical differcence was significant(P <0.05).
4.3 The comparison of soleus K~+ uptake and mean soleus K~+ uptake rate after potassium repletion
Compared with group RC, soleus K~+ uptake in group RE was higher, the statistical differcence was significant(P <0.05), mean soleusl K~+ uptake rate in group RE was higher, the statistical differcence was significant(P <0.05).
4.4 During clamping plasma K~+ concentration by KCl infusion, K~+ uptake rate of myocardiaum was higher than that of soleus muscle, the statistical differcence was significant(P <0.05).
4.5 Body total K~+ uptake gradually decreased during clamping plasma K~+ by KCl infusion.
Conclusion:
1 The present study prepared K~+-depleted rabbit models successfully used a low-K~+ content diet,which induced a plasma K~+ decrease in experimental rabbits.
2 Plasma K~+ concentation,RBC K~+ content,myocardial K~+ content and soleus K~+ content of experimental rabbits gradually decreased afer they were fed with the low-K~+ content chaw.
3 Potassium depletion induced a down regulation in RBC Na~+-K~+-ATPase activity and soleus Na~+-K~+-ATPase activity but an upregulation in myocardial Na~+-K~+-ATPase activity;linear regression analysis of data from K-depleted and contral rabbits showed a positive linear relationship between Na~+-K~+-ATPaseb activity and K~+ content in RBC and soleus muscle respectively and a negative linear relationship between Na~+-K~+-ATPaseb activity and K content in myocardium.
4 RBC K~+ content was positively correlated with myocardial K~+ content and soleus K~+ content during K depletion.
5 During K~+ depletion, the responsivity of Na~+-K~+-ATPaseα_1 andα_2 isoform was different in RBC,myocardium and soleus muscle: mRNA and protein expression ofα_1 andα_2 isoform gradually decreased in RBC and soleus muscle, mRNA and protein expression ofα_1 isoform gradually increased but that ofα_2 isoform gradually decreased in myocardium.
6 Total K~+ uptake and renal K~+ excretion incresed significantly in K~+-deplted rabbits,and K~+ uptake rate in myocardium was hiagher than that in soleus muscle, during K~+ repletion. Body total K~+ uptake gradually decreased during clamping plasma K~+ by KCl infusion.
引文
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