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 25?g/d?,the high-salt diet control group[?8%NaCl+ICV aCSF?,the high-salt diet with MET group[8%NaCl+ICV MET 25?g/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,?-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.