Author + information
- Zhiming Yang,
- Yanan Zhao,
- Huiyu Yang,
- Bin Liang and
- Jingjing Xue
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).
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) and heart rate (HR) were measured every week by a tail-cuff occlusion. Reactive oxygen species (ROS), subunits of NAD(P)H oxidase, superoxide dismutase (SOD), the ennin-angiotensin system (RAS) components, inflammatory cytokines (ICs), 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).
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 1 receptor (AT1-R), IL-1β, IL-6, glutamate, NE and tyrosine hydroxylase (TH) and lower levels of SOD, IL-10, 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).
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 inflammatory cytokines and neurotransmitters in the PVN.