小鼠α_(1)肾上腺素受体分布及其对右美托咪定急性毒性的介导作用  

Influence of peripheral alpha 1-adrenergic receptors on the toxicity of dexmedetomidine

作　　者：史贝贝 王震 王晓璇 周培岚 苏瑞斌 SHI Beibei;WANG Zhen;WANG Xiaoxuan;ZHOU Peilan;SU Ruibin(Nanjing University of Traditional Chinese Medicine,Nanjing 210023,China;Academy of Military Medical Sciences,Beijing 100850,China)

机构地区：[1]南京中医药大学,江苏南京210023 [2]军事医学研究院,北京100850

出　　处：《中国药理学与毒理学杂志》2025年第3期216-223,共8页Chinese Journal of Pharmacology and Toxicology

基　　金：国家自然科学基金(82273909)。

摘　　要：目的探究α_(1)肾上腺素受体(α_(1)-AR)在小鼠组织器官中的分布及其对右美托咪定(DMED)急性毒性的介导作用。方法①取正常C57BL/6J小鼠,采用实时荧光定量PCR检测小鼠心、心尖、肺、肺大叶尖部、肝、肾、腹主动脉及脑组织(前额叶皮质、海马、纹状体、脑干、丘脑、嗅球和其余脑组织)中α_(1A)-AR、α_(1B)-AR、α_(1D)-AR、α_(2A)-AR、α_(2B)-AR和α_(2C)-AR mRNA相对表达量,分析心、肺组织中基因表达差异。②C57BL/6J小鼠分为α_(2)肾上腺素受体(α_(2)-AR)拮抗剂阿替美唑(ATI 0.005、0.010、0.020、0.025、0.040和0.050 mg·kg^(-1),im)组及α_(1)-AR拮抗剂哌唑嗪(1 mg·kg^(-1),im)组,给药15 min后,两组iv给予DMED 0.2 mg·kg^(-1),观察小鼠翻正反射消失率和诱导时间。③C57BL/6J小鼠iv给予DMED(16.38、20.48、25.60、32.00、40.00和50.00 mg·kg^(-1)),观察24 h内小鼠死亡率,并拟合致死率的剂量-效应曲线和计算半数致死剂量(LD_(50))。将C57BL/6J小鼠分为ATI(1、2、4和8 mg·kg^(-1),im)组和哌唑嗪(1 mg·kg^(-1),im)组,给药15 min后,两组iv给予DMED(25.60 mg·kg^(-1)),记录小鼠24 h内死亡数,HE染色观察小鼠肺组织病理变化。结果①α_(1)-AR的3种亚型在小鼠各组织器官中均较高表达,α_(2A)-AR和α_(2C)-AR基因在中枢神经系统表达较高,α_(2B)-AR基因在脑干和外周组织中表达较高。完整心脏组织及心尖、肺大叶尖部组织中α_(1)-AR各亚型mRNA表达水平均高于α_(2)-AR各亚型(P<0.05)。②ATI 0.005~0.050 mg·kg^(-1)剂量依赖性拮抗DMED 0.2 mg·kg^(-1)诱导的翻正反射消失,缩短小鼠的制动时间,哌唑嗪1 mg·kg^(-1)不能对抗DMED 0.2 mg·kg^(-1)的翻正反射消失效应。③DMED使小鼠死亡的LD_(50)为26.73 mg·kg^(-1),其95%CI为23.606~30.000 mg·kg^(-1),选择近LD_(50)的25.60 mg·kg^(-1) DMED作为后续毒性对抗的模型剂量。ATI 1、2、4和8 mg·kg^(-1)不能对抗DMED 25.60 mg·kg^(-1)致死作用,且高剂量ATI会使小鼠死亡�OBJECTIVE To investigateα_(1)-adrenergic receptors(α_(1)-AR)distribution in mouse tissues and its function on dexmetomidine(DMED)induced toxic effects.METHODS①Real-time fluorescence quantita-tive PCR was used to detect the relative expression ofα_(1A)-AR,α_(1B)-AR,α_(1D)-AR,α_(2A)-AR,α_(2B)-AR andα_(2C)-AR mRNAs in the heart,apical potion of heart,lungs,apical potion of lung,liver,kidneys,abdominal aorta,prefrontal cortex,hippocampus,striatum,brainstem,thalamus,olfactory bulb,and the rest of the brain tissues of the mouse.The relative expression of mRNA were analyzed.②C57BL/6J mice were pretreated withα_(2) adrenergic receptor antagonist atipamezole ATI(0.005,0.010,0.020,0.025,0.040,0.050 mg·kg^(-1),im),orα_(1)-adrenoceptor antagonist prazosin(1 mg·kg^(-1),im)for 15 min,and then DMED(0.20 mg·kg^(-1),iv)was given to observe the rate of the loss of righting reflex and the immobilization time in mice.③C57BL/6J mice were treated with DMED(16.38,20.48,25.60,32.00,40.00,and 50.00 mg·kg^(-1),iv)to observe the lethality of the mice in 24 h.The dose-effect relationship curves of the lethality rate and the half lethal-dose(LD_(50))were detected.ATI(1,2,4,and 8 mg·kg^(-1),im)or prazosin(1 mg·kg^(-1),im)were pretreated 15 min followed by the administration of DMED(25.60 mg·kg^(-1),iv).The lethality of the mice were recorded for 24 h.HE staining to observe the lung tissue damage in the mice.RESULTS①The mRNA expression levels of threeα_(1)-AR subtype were higher than those ofα_(2)-AR subtype.α_(2A)-AR andα_(2C)-AR were highly expressed in the central nervous system.α_(2B)-AR was highly expressed in the brainstem and peripheral tissues.The mRNA expres-sion levels ofα_(1)-AR subtypes were higher than those ofα_(2)-AR subtypes in heart,apical potion of heart or lung(P<0.05).②ATI(0.005 to 0.05 mg·kg^(-1),im)dose dependently antagonized the loss of righting reflex and decreased the immobilization time induced by DMED(0.20 mg·kg^(-1),iv).In contrast,prazosin(1 mg·kg^(-1),im)had no effect on the l

关 键 词：α_(1)肾上腺素受体 α_(2)肾上腺素受体 右美托咪定 毒性 

分 类 号：R992[医药卫生—毒理学]