title: Tetrandrine, an alkaloid from S. tetrandra exhibits anti-hypertensive and sleep-enhancing effects in SHR via different mechanisms.
abstract: BACKGROUND
  Sleep disorders have been found to be associated with hypertension in both cross-sectional and longitudinal epidemiological studies. Tetrandrine, a major component of Stephania tetrandra, is well known as an antihypertensive agent. The anti-hypertension mechanism mainly relies on its L-type calcium channel blocking property. In the previous study, tetrandrine revealed both anti-hypertension and hypnotic effects in spontaneously hypertensive rats (SHRs).
  
  
  OBJECTIVE
  This study aims to elucidate whether the antihypertensive mechanism of tetrandrine in SHRs is relevant to its hypnotic effect.
  
  
  METHODS
  Sleep-wake behavior of the SHRs was detected by electroencephalography (EEG) and electromyography (EMG) recordings. Blood pressure was measured by noninvasive blood pressure tail cuff test. Immunohistochemistry was performed to evaluate the noradrenergic neuronal activity. The level of norepinephrine (NE) was detected by HPLC-ECD.
  
  
  RESULTS
  Amlodipine (100mg/kg, i.g.), the well-known L-type Ca2+channel blockers (CCBs) exhibited remarkable antihypertensive activities in SHRs, but did not show effects on sleep of SHRs. Tetrandrine (30 and 60mg/kg/day, i.g.) significantly suppressed blood pressure of SHRs. Meanwhile, tetrandrine (60mg/kg/day, i.g.) remarkably increased non-rapid eye movement sleep (NREMS) time, bouts and mean duration. The hypnotic effect of tetrandrine was potentiated by prazosin (0.5mg/kg, i.p.) but attenuated by yohimbine (2mg/kg, i.p.). Administration of tetrandrine (60mg/kg/day, i.g.) not only significantly decreased c-Fos positive ratio of noradrenergic neurons in the locus coeruleus (LC), but also significantly decrease NE in the endogenous sleep-wake regulating pathways including LC, hypothalamus and ventrolateral preoptic nucleus (VLPO).
  
  
  CONCLUSIONS
  In spite of a good potency in blocking L-type Ca2+channel, the hypnotic effects of tetrandrine may be related to its suppressing effects on the noradrenergic system other than to block calcium channels. As a multi-targets drug, tetrandrine might be favorable to the hypertension patients who suffered poor sleep.
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Yuan-Li
authors.initials: YL
authors.lastname: Huang
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Cui
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Xiang-Yu
authors.initials: XY
authors.lastname: Cui
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Jin-Zhi
authors.initials: JZ
authors.lastname: Song
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Zhao-Fu
authors.initials: ZF
authors.lastname: Sheng
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Zi-Jun
authors.initials: ZJ
authors.lastname: Wang
authors.affiliation: Department of pharmacology, Peking University, School of Basic Medical Science, 38 Xueyuan Road, Beijing, 100191, China. Electronic address: zhyh@hsc.pku.edu.cn.
authors.forename: Yong-He
authors.initials: YH
authors.lastname: Zhang
mesh_terms: D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D044182:Benzylisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003430:Cross-Sectional Studies; D004569:Electroencephalography; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006993:Hypnotics and Sedatives / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D011918:Rats, Inbred SHR; D012890:Sleep / Q000187:drug effects*; D031609:Stephania tetrandra / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D000959:Antihypertensive Agents; D044182:Benzylisoquinolines; D020746:Calcium Channels, L-Type; D006993:Hypnotics and Sedatives; D010936:Plant Extracts; C009438:tetrandrine; D009638:Norepinephrine
keywords: Hypertension; Hypnotic; Norepinephrine; Tetrandrine