【摘要】 目的探讨应用心脏营养素-1（cardiotrophin-1,CT-1）治疗失神经骨骼肌萎缩的有效剂量和安全剂量,观察不同剂量的CT-1对正常骨骼肌、心肌和血管平滑肌的副作用。方法取Swiss小鼠80只,随机分成8组,每组分别于胫神经切断术后连续腹腔注射重组小鼠CT-1（rm CT-1）40、60、80、100、120、140、160μg·kg^-1·d^-1,剩余1组腹腔注射等体积CT-1溶媒,28 d后称量失神经侧腓肠肌、正常侧腓肠肌和心脏的湿重;测量胸主动脉平滑肌厚度;检测正常腓肠肌中α-actin和MHCⅡa以及心肌中β-MHC的表达、胸主动脉血管平滑肌细胞中α-actin的含量。结果采用腹腔注射给药,当CT-1用量达到60μg·kg^-1·d^-1时,开始对失神经骨骼肌产生营养作用,并呈剂量依赖性增强,当给药剂量超过100μg·kg^-1·d^-1后,出现对正常骨骼肌、心肌和血管平滑肌的影响。给药剂量达到120麒·k0·d11时,开始促进心肌pMHCmRNA的表达,增加正常心脏的湿重。当给药剂量达到140嘏·l(g11·d.1时,开始促进正常骨骼肌a-actin和MHCⅡa mRNA的表达,以及骨骼肌湿重的增加,同时提高了主动脉血管平滑肌a-acfin的含量,增加了血管平滑肌的厚度。结论腹腔注射CT-1防治失神经骨骼肌萎缩的有效剂量为60腭-kg一·d～,最高安全剂量为100熠·l[g11·d～。当给药剂量达到120μg·kg^-1·d^-1时,开始出现心肌肥厚,当给药剂量达到140μg·kg^-1·d^-1时,可导致正常骨骼肌的肥大和血管平滑肌的增厚。更多还原

【Abstract】 Objective To definite the minimum starting dosage and the maximum recommended dosage of CT-1 to treat denervation muscle atrophy,and investigate the undesirable effects of CT-1 on normal skeletal muscle,myecardium and smooth muscle.Methods Eighty Swiss mice were randomly divided into 8 groups. Denervation muscle atrophy model was created by transecting the tibial nerve.Intraperituneal injection of 40,60, 80,100,120,140 and 160μg’kg^-1·d^-1mCT-1 and equal volume of vehicle was administered respectively according to group assignment for one month after tibial nerve removal.Northern blot analysis was employed to assay the expression of mRNA ofα-actin and MHCⅡa in contralateral gastrocnemius muscle,andβ-MHC of myocardinm.Western blot was employed to evaluate the content ofα-actin in smooth muscle cells of the aorta.At the same time,the wet weight of gastrocnemius muscle and heart,the thickness of smooth muscle of aorta were assayed.Results It was proved in our study that CT-1 alleviated denervation atrophy in a dose-dependent manner.The effective dose was in a range from 60μg·kg^-1·d^-1to 160μg·kg·d^-1.But when the given dose was beyond 120μg·kg^-1·d^-1,CT-1 may display its adverse effects on myocardium,smooth muscle and normal skeletal muscle such as inducing overexpression ofβ-MI-IC mRNA in myocardium,α-actin and MHCⅡa mRNA in normal skeletal muscle,and increasing the content ofα-actin in smooth muscle.Overdose of CT-1 increased the wet weight of heart and normal gastrocnemius muscle,and thickness of smooth muscle the in aorta.Conclusion The minimum starting dosage is 60μg·kg^-1·d^-1,and the maximum recorumended dosage is 100μg·kg^-1·d^-1when CT-1 is administrated intraperitoneally to treat denervation atrophy.Overdose may result in myocardial hypertrophy(>120μg·kg^-1·d^-1),hypertrophy of normal skeletal muscle,and thickening of vascular smooth muscle(>140μg·kg^-1·d^-1).更多还原