卡维地洛对心力衰竭时兰尼碱受体的作用

Effect of carvedilol on ryanodine receptor in heart failure

目的探讨卡维地洛对心力衰竭(heartfailure,HF)(简称心衰)时兰尼碱受体/钙释放通道(ryanodinereceptor,RyR)的作用。方法采用腹主动脉缩窄术建立幼鼠心衰模型,术后6周随机分为2组:心衰组和卡维地洛治疗组。另设假手术对照组。卡维地洛灌胃给药,术后每日观察幼鼠的呼吸、皮毛颜色、活动量、体重等发育状况。4周后行高频超声检测。超速离心分离肌质网(SR),荧光分光光度仪检测钙离子(Ca2+)的重吸收和渗漏。结果与假手术组(n=20)比较,HF组(n=20)幼鼠左室舒张末期内径(LVEDD)(P<0.05)、左室收缩末期内径(LVESD)、室间隔舒张末期厚度(IVSTd)、室间隔收缩末期厚度(IVSTs)、左室后壁舒张末期厚度(LVPWTd)、左室后壁收缩末期厚度(LVPWTs)均明显升高(P<0.01),短轴缩短率(FS)、射血分数(EF)均明显降低(P<0.01);与HF组比较,卡维地洛治疗组(n=20)LVEDD(P<0.05)、LVESD、IVSTd、IVSTs、LVPWTd、LVPWTs均明显降低(P<0.01),FS、EF均明显升高(P<0.01)。若分别向含有三组SR的缓冲液中仅加入SRCa2+ATP酶抑制剂—毒胡萝卜内酯(thapsigargin),HF组较假手术组、卡维地洛治疗组有明显的Ca2+渗漏(P<0.01);若毒胡萝卜内酯和FKBP抑制剂—FK506一起加入三组SR缓冲液中,假手术组、卡维地洛治疗组、HF组均出现明显的Ca2+渗漏(P<0.01);与仅加入毒胡萝卜内酯比较,假手术组和卡维地洛治疗组的Ca2+渗漏明显增多(P<0.01),HF组的Ca2+渗漏未见明显增加(P>0.05)。结论HF时心肌Ca2+渗漏明显,卡维地洛通过恢复HF时心肌RyRFKBP12.6的结合,从而抑制Ca2+的渗漏,提高心脏功能并有效抑制心室重塑。

Objective The release of intracellular stores of Ca^2 ＋ occurs virtually in all types of cells by a means of amplifying external signals that modulate intracellular signaling events. In cardiac myocytes,type 2 ryanodine receptor （RyR2） is activated during excitation-contraction （E-C） coupling by Ca^2＋ -induced Ca^2＋ release （CICR） triggered by Ca^2＋ influx across the sarcolemma, The hyperadrenergic state of heart failure results in leaky RyR2 channels attributable to PKA hyperphosphorylation and depletion of the stabilizing FKS06 binding protein, FKBP12. 6. Dysregulation of sarcoplasmic reticulum （SR） Ca^2＋ release via RyR2 could contribute to defects in Ca^2＋ signaling in failing hearts. Researchers tested the hypothesis that improved cardiac muscle function attributable to β-AR blockade is associated with restoration of normal RyR2 channel function in patients with heart failure. The authors aimed to observe change of RyR in junior mouse with HF and the effect of β-adrenoreceptor blocker on RyR in HF n this experiment. Methods The animal model of congestive heart failure was established by constriction of abdominal aorta. Five weeks old mice were randomly divided into 3 groups ： （ 1 ） HF group without treatment （ n = 20） ; （2） HF group treated with carvedilol （ n = 20） ; （3） Sham-operated group （ n = 20）. Carvedilol was administered through direct gastric gavage. After 4 weeks of treatment the high frequency ultrasound was performed. Myocardial SR was fractionated with velocity centrifugation. The time courses of Ca^2＋ uptake and leak were determined by fluorescent spectrophotometr. Results Compared with the sham-opereted group, left ventricular diastolic dimension （LVEDD） （ P 〈 0. 05 ）, left ventricular systolic dimension （ LVESD）, interventricular septal thickness at end-diastole（ IVSTd）, interventricular septal thickness at end-systole （IVSTs）, left ventricular posterior wall thickness at end-diastole （ LVPWTd）, and left ventricular posterior wall thickness at endsystole （LVPWTs） were all significantly increased （P 〈 0. 01 ）. Ejection fraction （EF） and fractional shortening （FS） were decreased （ P 〈0. 01 ） in HF group without treatment. LVEDD （ P 〈0. 05 ）, LVESD,IVSTd, IVSTs, LVPWTd and LVPWTs were all prominently decresed （ P 〈 0. 01 ） . EF and FS were increased （ P 〈 0. 01 ） in cases of HF treated with carvedilol when compared with HF group without treatment. After adding thapsigargin to the buffer including SR of three groups, there were fewer Ca^2＋ leak in sham-operated group and HF group treated with carvedilol than that of HF group without treatment （ P 〈0. 01 ）, while after adding FK506 and thapsigargin together to the buffer including SR of three groups, there were marked Ca^2＋ leak in sham-operated group and HF group treated with carvedilol （ P 〈 0. 01 ）. However,there was no additional increase in Ca^2＋ leak in HF group compared with that of the group where only thapsigargin was added （P 〉 0. 05）. Conclusion There is more cardiac Ca^2＋ leak in HF. Carvedilol can inhibite Ca^2＋ leak by restoring the contactation of FKBP12. 6 back to RyR in HF to improve cardiac function and prevent left ventricle from remodeling.