In vivo evaluation of antimyotonic efficacy of β-adrenergic drugs in a rat model of myotonia.
In vivo evaluation of antimyotonic efficacy of β-adrenergic drugs in a rat model of myotonia.
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DOI：
10.1016/j.neuropharm.2012.09.006
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发表时间：
2013-02
影响因子：
4.7
通讯作者：
Conte Camerino D
中科院分区：
文献类型：
--
作者：
Desaphy JF;Costanza T;Carbonara R;Conte Camerino D
钠通道阻滞剂美西律被认为是治疗强直性肌综合征的一线药物，强直性综合征是一组以膜过度兴奋为特征的肌肉疾病。我们以前发现，β肾上腺素能受体调节剂克伦特罗和心得安阻断电压门控钠通道的方式类似于美西律，而沙丁胺醇和纳多洛尔则不能。我们现在建立了一种药理学的先天性肌强直大鼠模型，用于进行体内抗强直性药物的临床前试验。Ip诱导大鼠肌强直。肌肉氯通道阻滞剂9-AC(9-AC)30 mg/kg，以翻正反射时间(TRR)为评价指标。注射9-AC后30min，TRR由对照组S的0.5%延长至最大∼4时，几小时后逐渐恢复。注射9-AC后20分钟口服美西律显著抑制TRR延长，半数有效剂量(ED50)为12 mg/kg。普萘洛尔和克伦特罗均产生与美西律相似的剂量依赖的抗肌张力作用，其ED50值接近20 mg/kg。40 mg/kg美西律和心得安的抗肌强直作用持续2小时。我们还用膜片钳方法证明，两种心得安对HEK293细胞表达的骨骼肌hNav1.4通道具有相似的阻断作用。这两个对映体(15 mg/kg)在肌强直大鼠体内也显示出类似的抗肌强直活性。在所测试的药物中，普萘洛尔的R(+)对映体可能值得在人类中进一步研究，因为它在大鼠模型中具有抗肌张力作用，但在β-肾上腺素能途径上缺乏显著活性。本研究提供了一种新的、有用的先天性肌强直的体内临床前模型，以使最有前景的抗肌强直药物个体化，以便在人类身上进行测试。用9-乙酰胆碱(9-AC)建立大鼠先天性肌强直的体内药理模型►。注射。对抗肌张力药物进行►A临床前筛选。►、普萘洛尔和克伦特罗的抗肌张力作用与美西律相当。普萘洛尔对映体►均阻断体外骨骼肌hNav1.4钠通道。►和心得安对映体在体内具有相似的抗肌强直作用。
The sodium channel blocker mexiletine is considered the first-line drug in myotonic syndromes, a group of muscle disorders characterized by membrane over-excitability. We previously showed that the β-adrenoceptor modulators, clenbuterol and propranolol, block voltage-gated sodium channels in a manner reminiscent to mexiletine, whereas salbutamol and nadolol do not. We now developed a pharmacological rat model of myotonia congenita to perform in vivo preclinical test of antimyotonic drugs. Myotonia was induced by i.p. injection of 30 mg/kg of anthracene-9-carboxylic acid (9-AC), a muscle chloride channel blocker, and evaluated by measuring the time of righting reflex (TRR). The TRR was prolonged from <0.5 s in control conditions to a maximum of ∼4 s, thirty minutes after 9-AC injection, then gradually recovered in a few hours. Oral administration of mexiletine twenty minutes after 9-AC injection significantly hampered the TRR prolongation, with an half-maximum efficient dose (ED50) of 12 mg/kg. Both propranolol and clenbuterol produced a dose-dependent antimyotonic effect similar to mexiletine, with ED50 values close to 20 mg/kg. Antimyotonic effects of 40 mg/kg mexiletine and propranolol lasted for 2 h. We also demonstrated, using patch-clamp methods, that both propranolol enantiomers exerted a similar block of skeletal muscle hNav1.4 channels expressed in HEK293 cells. The two enantiomers (15 mg/kg) also showed a similar antimyotonic activity in vivo in the myotonic rat. Among the drugs tested, the R(+)-enantiomer of propranolol may merit further investigation in humans, because it exerts antimyotonic effect in the rat model, while lacking of significant activity on the β-adrenergic pathway. This study provides a new and useful in vivo preclinical model of myotonia congenita in order to individuate the most promising antimyotonic drugs to be tested in humans. ► An in vivo pharmacological model of myotonia congenita was developed in the rat using 9-AC i.p. injection. ► A preclinical screening of antimyotonic drugs was performed. ► Propranolol and clenbuterol exert antimyotonic activity comparable to mexiletine. ► Both propranolol enantiomers block skeletal muscle hNav1.4 sodium channels in vitro. ► Both propranolol enantiomers exert similar antimyotonic effect in vivo.
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影响因子：
5.6
作者：
Desaphy JF;Dipalma A;Costanza T;Carbonara R;Dinardo MM;Catalano A;Carocci A;Lentini G;Franchini C;Camerino DC
通讯作者：
Camerino DC
影响因子：
5
作者：
Bankston, John R.;Kass, Robert S.
通讯作者：
Kass, Robert S.
影响因子：
--
作者：
Su, Tzu-Rong;Zei, Wen-Shan;Lin, Min-Jon
通讯作者：
Lin, Min-Jon
影响因子：
11.2
作者：
FURMAN, RE;BARCHI, RL
通讯作者：
BARCHI, RL
DOI：
10.1038/ncpneuro0239
发表时间：
2006-07-01
期刊：
NATURE CLINICAL PRACTICE NEUROLOGY
影响因子：
--
作者：
Chrestian, Nicolas;Puymirat, Jack;Dupre, Nicolas
通讯作者：
Dupre, Nicolas