title: The accumulation of brain water-free sodium is associated with ischemic damage independent of the blood pressure in female rats.
abstract: Estrogen deficiency worsens ischemic stroke outcomes. In ovariectomized (OVX(+)) rats fed a high-salt diet (HSD), an increase in the body Na(+)/water ratio, which characterizes water-free Na(+) accumulation, was associated with detrimental vascular effects independent of the blood pressure (BP). We hypothesized that an increase in brain water-free Na(+) accumulation is associated with ischemic brain damage in OVX(+)/HSD rats. To test our hypothesis we divided female Wistar rats into 4 groups, OVX(+) and OVX(-) rats fed HSD or a normal diet (ND), and subjected them to transient cerebral ischemia. The brain Na(+)/water ratio was increased even in OVX(+)/ND rats and augmented in OVX(+)/HSD rats. The increase in the brain Na(+)/water ratio was positively correlated with expansion of the cortical infarct volume without affecting the BP. Interestingly, OVX(+) was associated with the decreased expression of ATP1α3, a subtype of the Na(+) efflux pump. HSD increased the expression of brain Na(+) influx-related molecules and the mineralocorticoid receptor (MR). The pretreatment of OVX(+)/HSD rats with the MR antagonist eplerenone reduced brain water-free Na(+) accumulation, up-regulated ATP1α3, down-regulated MR, and reduced the cortical infarct volume. Our findings show that the increase in the brain Na(+)/water ratio elicited by estrogen deficiency or HSD is associated with ischemic brain damage BP-independently, suggesting the importance of regulating the accumulation of brain water-free Na(+). The up-regulation of ATP1α3 and the down-regulation of MR may provide a promising therapeutic strategy to attenuate ischemic brain damage in postmenopausal women.
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Electronic address: mansumiyoshi@yahoo.co.jp.
authors.forename: Manabu
authors.initials: M
authors.lastname: Sumiyoshi
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Keiko T
authors.initials: KT
authors.lastname: Kitazato
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yagi
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kurashiki
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Matsushita
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kinouchi
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kuwayama
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Satomi
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagahiro
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000473:pathology*; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D014867:Water; D012964:Sodium; C541459:Atp1a3 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Brain water-free sodium accumulation; Cerebral ischemia; High-salt intake; Hypertension; Mineralocorticoid receptor; Na(+)/K(+)-ATPase; Ovariectomy