Autonomic and cholinergic mechanisms mediating cardiovascular and temperature effects of donepezil in conscious mice.
Autonomic and cholinergic mechanisms mediating cardiovascular and temperature effects of donepezil in conscious mice.
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自主神经和胆碱能机制介导多奈哌齐对清醒小鼠的心血管和温度影响。
DOI：
10.1152/ajpregu.00360.2019
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Hoover,DonaldB
中科院分区：
文献类型：
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作者：
Polichnowski,AaronJ;Williamson,GeoffreyA;Blair,TeshaE;Hoover,DonaldB
多奈哌齐是一种中枢作用的乙酰胆碱酯酶（AChE）抑制剂，在炎症性疾病中具有治疗潜力;然而，潜在的自主神经和胆碱能机制仍不清楚。在这里，我们评估了多奈哌齐对清醒成年雄性C57 BL/6小鼠的平均动脉压（MAP）、心率（HR）、HR变异性和体温的影响，以研究所涉及的自主神经通路。使用药理学方法评估多奈哌齐的中枢与外周胆碱能作用，包括与外周作用的AChE抑制剂新斯的明进行比较。药物治疗包括多奈哌齐（2.5或5 mg/kg sc）、甲基硫酸新斯的明（80或240 μg/kg ip）、硫酸阿托品（5 mg/kg ip）、甲基溴化阿托品（5 mg/kg ip）或生理盐水。与生理盐水相比，多奈哌齐2.5和5 mg/kg使HR降低36 ± 4%和44 ± 3%（n= 10，P< 0.001）。与生理盐水相比，多奈哌齐2.5和5 mg/kg使体温降低13 ± 2%和22 ± 2%（n= 6，P< 0.001）。多奈哌齐组在心动过缓峰值出现后MAP轻度升高（P< 0.001）。硫酸阿托品和甲基溴化阿托品可阻断多奈哌齐引起的心动过缓反应，但只有硫酸阿托品可减弱体温过低。在同时给予硫酸阿托品的小鼠中，对多奈哌齐的升压反应相似;然而，同时给予甲基溴化阿托品可增强MAP的增加。新斯的明不改变HR或体温，但确实导致MAP早期升高。尽管有明显的心动过缓，多奈哌齐并没有增加正常化的高频HR变异性。我们的结论是，多奈哌齐引起显着的心动过缓和体温过低的清醒小鼠通过激活毒蕈碱受体，同时增加MAP通过自主神经和胆碱能途径，仍有待阐明。
Donepezil is a centrally acting acetylcholinesterase (AChE) inhibitor with therapeutic potential in inflammatory diseases; however, the underlying autonomic and cholinergic mechanisms remain unclear. Here, we assessed effects of donepezil on mean arterial pressure (MAP), heart rate (HR), HR variability, and body temperature in conscious adult male C57BL/6 mice to investigate the autonomic pathways involved. Central versus peripheral cholinergic effects of donepezil were assessed using pharmacological approaches including comparison with the peripherally acting AChE inhibitor, neostigmine. Drug treatments included donepezil (2.5 or 5 mg/kg sc), neostigmine methyl sulfate (80 or 240 μg/kg ip), atropine sulfate (5 mg/kg ip), atropine methyl bromide (5 mg/kg ip), or saline. Donepezil, at 2.5 and 5 mg/kg, decreased HR by 36 ± 4% and 44 ± 3% compared with saline (n= 10,P< 0.001). Donepezil, at 2.5 and 5 mg/kg, decreased temperature by 13 ± 2% and 22 ± 2% compared with saline (n= 6,P< 0.001). Modest (P< 0.001) increases in MAP were observed with donepezil after peak bradycardia occurred. Atropine sulfate and atropine methyl bromide blocked bradycardic responses to donepezil, but only atropine sulfate attenuated hypothermia. The pressor response to donepezil was similar in mice coadministered atropine sulfate; however, coadministration of atropine methyl bromide potentiated the increase in MAP. Neostigmine did not alter HR or temperature, but did result in early increases in MAP. Despite the marked bradycardia, donepezil did not increase normalized high-frequency HR variability. We conclude that donepezil causes marked bradycardia and hypothermia in conscious mice via the activation of muscarinic receptors while concurrently increasing MAP via autonomic and cholinergic pathways that remain to be elucidated.