title: Beneficial effects of combination of valsartan and amlodipine on salt-induced brain injury in hypertensive rats.
abstract: The optimum antihypertensive treatment for prevention of hypertensive stroke has yet to be elucidated. This study was undertaken to examine the benefit of a combination of valsartan, an angiotensin II type 1 (AT1) receptor blocker, and amlodipine, a calcium channel blocker, in prevention of high-salt-induced brain injury in hypertensive rats. High-salt-loaded stroke-prone spontaneously hypertensive rats (SHRSPs) were given 1) vehicle, 2) valsartan (2 mg/kg/day), 3) amlodipine (2 mg/kg/day), or 4) a combination of valsartan and amlodipine for 4 weeks. The effects on brain injury were compared between all groups. High-salt loading in SHRSPs caused the reduction of cerebral blood flow (CBF), cerebral hypoxia, white matter lesions, glial activation, AT1 receptor up-regulation, endothelial nitric-oxide synthase (eNOS) uncoupling, inducible nitric-oxide synthase induction, and nitroxidative stress. Valsartan, independently of blood pressure, enhanced the protective effects of amlodipine against brain injury, white matter lesions, and glial activation in salt-loaded SHRSPs. These beneficial effects of valsartan added to amlodipine were associated with an additive improvement in CBF and brain hypoxia because of an additive improvement in cerebral arteriolar remodeling and vascular endothelial dysfunction. Furthermore, valsartan added to amlodipine enhanced the attenuation of cerebral nitroxidative stress through an additive suppression of eNOS uncoupling. Valsartan, independently of blood pressure, augmented the protective effects of amlodipine against brain injury in salt-loaded hypertensive rats through an improvement in brain circulation attributed to nitroxidative stress. Our results suggest that the combination of valsartan and amlodipine may be a promising strategy for the prevention of salt-related brain injury in hypertensive patients.
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan.
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Dong
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kataoka
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Tokutomi
authors.forename: Hisato
authors.initials: H
authors.lastname: Nako
authors.forename: Taishi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kensuke
authors.initials: K
authors.lastname: Toyama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sueta
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Koibuchi
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
mesh_terms: D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D015220:Calcium Channels / Q000187:drug effects; D002339:Carotid Arteries / Q000033:anatomy & histology / Q000187:drug effects; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000139:chemically induced; D008297:Male; D009569:Nitric Oxide / Q000032:analysis / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000032:analysis / Q000096:biosynthesis; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis / Q000096:biosynthesis; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D044140:Receptor, Angiotensin, Type 1; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; D017311:Amlodipine; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D000068756:Valsartan; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D014633:Valine