Metformin Ameliorates Salt-sensitive Hypertension Via Attenuating Oxidative Stress In Hypothalamic Paraventricular Nucleus

Objective:This study was designed to determine whether metformin,an antidiabetic agent,exerts antihypertensive effects in rats with salt-sensitive hypertension through attenuation of oxidative stress in the hypothalamic paraventricular nucleus（PVN）.Methods:Dahl salt-sensitive rats received a high-salt（HS,8%NaCl）diet or a normal-salt（NS,0.3%NaCl）diet and were treated with intracerebroventricular（ICV）infusion of metformin or vehicle for 6 weeks.The rats were divided into 4 groups:the normal-salt diet control group[0.3%NaCl+intracerebroventricular（ICV）artificial cerebrospinal fluid（aCSF）],the normal-salt diet with MET group（0.3%NaCl+ICV MET 25μg/d）,the high-salt diet control group[（8%NaCl+ICV aCSF）,the high-salt diet with MET group[8%NaCl+ICV MET 25μg/d].Mean arterial pressure（MAP）was measured by carotid artery intubation at the end of 6^th week.Reactive oxygen species（ROS）,subunits of NAD（P）H oxidase,superoxide dismutase（SOD）,the rennin-angiotensin system（RAS）components,neurotransmitters levels in the PVN were determined by immunofluorescence,immunohistochemistry,western blot,high-performance liquid chromatography（HPLC）.Norepinephrine（NE,an indicator of sympathetic activity）levels in plasma were examined by enzyme-linked immunosorbent assay（ELISA）.Results:High-salt rats had significantly increased MAP,plasma norepinephrine compared with normal-salt rats（P<0.05）.ICV infusion of metformin decreased MAP,plasma norepinephrine in high-salt rats（P<0.05）.In addition,high-salt rats showed higher levels of NOX-2,NOX-4,ROS,angiotensin-converting enzyme（ACE）,angiotensin II type 1receptor（AT1-R）,glutamate,NE and tyrosine hydroxylase（TH）and lower levels of SOD,γ-aminobutyric acid（GABA）and the 67-kDa isoform of glutamate decarboxylase（GAD67）in the PVN compared with normal-salt rats（P<0.05）.These above biochemical changes associated with salt-sensitive hypertension were significantly prevented by ICV infusion of metformin in high-salt rats（P<0.05）.Conclusion:Our findings suggest that ICV infusion of metformin significantly decreases the sympathetic activity and blood pressure in salt-induced hypertension by attenuating oxidative stress,suppressing the activation of RAS and restoring the balance of neurotransmitters in the PVN.