title: Berberine alleviates the cerebrovascular contractility in streptozotocin-induced diabetic rats through modulation of intracellular Ca²⁺ handling in smooth muscle cells.
abstract: BACKGROUND
  Vascular dysfunction is a distinctive phenotype in diabetes mellitus. Current treatments mostly focus on the tight glycemic control and few of these treatments have been designed to directly recover the vascular dysfunction in diabetes. As a classical natural medicine, berberine has been explored as a possible therapy for DM. In addition, it is reported that berberine has an extra-protective effect in diabetic vascular dysfunction. However, little is known whether the berberine treatment could ameliorate the smooth muscle contractility independent of a functional endothelium under hyperglycemia. Furthermore, it remains unknown whether berberine affects the arterial contractility by regulating the intracellular Ca(2+) handling in vascular smooth cells (VSMCs) under hyperglycemia.
  
  
  METHODS
  Sprague-Dawley rats were used to establish the diabetic model with a high-fat diet plus injections of streptozotocin (STZ). Berberine (50, 100, and 200 mg/kg/day) were intragastrically administered to control and diabetic rats for 8 weeks since the injection of STZ. The intracellular Ca(2+) handling of isolated cerebral VSMCs was investigated by recording the whole-cell L-type Ca(2+) channel (CaL) currents, assessing the protein expressions of CaL channel, and measuring the intracellular Ca(2+) in response to caffeine. Our results showed that chronic administration of 100 mg/kg/day berberine not only reduced glucose levels, but also inhibited the augmented contractile function of cerebral artery to KCl and 5-hydroxytryptamine (5-HT) in diabetic rats. Furthermore, chronic administration of 100 mg/kg/day berberine significantly inhibited the CaL channel current densities, reduced the α1C-subunit expressions of CaL channel, decreased the resting intracellular Ca(2+) ([Ca(2+)]i) level, and suppressed the Ca(2+) releases from RyRs in cerebral VSMCs isolated from diabetic rats. Correspondingly, acute application of 10 μM berberine could directly inhibit the hyperglycemia-induced CaL currents and suppress the hyperglycemia-induced Ca(2+) releases from RyRs in cerebral VSMCs isolated from normal control rats.
  
  
  CONCLUSIONS
  Our study indicated that berberine alleviated the cerebral arterial contractility in the rat model of streptozotocin-induced diabetes via regulating the intracellular Ca(2+) handling of smooth muscle cells.
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
authors.forename: Yu-Guang
authors.initials: YG
authors.lastname: Ma
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
authors.forename: Yin-Bin
authors.initials: YB
authors.lastname: Zhang
authors.affiliation: Department of Aerospace Physiology, Key Laboratory of Aerospace Medicine of Ministry of Education, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
authors.forename: Yun-Gang
authors.initials: YG
authors.lastname: Bai
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Dai
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Aerospace Physiology, Key Laboratory of Aerospace Medicine of Ministry of Education, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. manjiangxie@hotmail.com.
authors.forename: Man-Jiang
authors.initials: MJ
authors.lastname: Xie
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China. guanhaitao@cscoorg.cn.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Guan
mesh_terms: D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D059305:Diet, High-Fat; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D020746:Calcium Channels, L-Type; D001599:Berberine; D002118:Calcium
keywords: Berberine; Ca2+ releases; Contractile function; L-type Ca2+ channel (CaL); Vascular smooth muscle cells (VSMCs)