PMID- 25533877 OWN - NLM STAT- MEDLINE DCOM- 20161031 LR - 20181202 IS - 1868-601X (Electronic) IS - 1868-4483 (Linking) VI - 7 IP - 1 DP - 2016 Feb TI - Therapy with the Combination of Amlodipine and Irbesartan Has Persistent Preventative Effects on Stroke Onset Associated with BDNF Preservation on Cerebral Vessels in Hypertensive Rats. PG - 79-87 LID - 10.1007/s12975-014-0383-5 [doi] AB - Although calcium channel blockers, angiotensin II receptor blockers, and combination therapy are effective for hypertensive patients, the significant differences among them against stroke onset are undetermined. In this study, we investigated the significant beneficial effects of the combination therapy using amlodipine and irbesartan against stroke onset in hypertensive rats. The animals were fed an 8% sodium diet and assigned to (1) vehicle, (2) amlodipine (2 mg/kg/day), (3) irbesartan (20 mg/kg/day), and (4) amlodipine + irbesartan groups. The drugs were given orally until 35 days, and incidences of stroke-related signs and mortality and blood pressure (BP) were monitored. Cerebral blood flow (CBF), brain water content, weight of the brain and left ventricle, and histological evaluations were conducted for the treated groups at 42 days after the start of the high-salt diet. Amlodipine and the combination therapy significantly reduced BP compared with the vehicle. Although the rates of stroke-related signs and mortality were high in the vehicle group, the rats in the treatment groups were mostly healthy until 35 days. After all drugs were discontinued, stroke onset was frequently seen in the monotherapy groups until 42 days, but no signs were observed in the combination therapy group. Although there were no significant differences in CBF or brain edema, the combination therapy reduced blood-brain barrier disruption, white matter injury, and reactive astrocytes compared with irbesartan, and the combination also inhibited left ventricular hypertrophy and preserved brain-derived neurotrophic factor (BDNF) expression on cerebral vessels compared to the monotherapies. These data suggest that the combination therapy had a persistent preventive effect on stroke onset in hypertensive rats, and the effects might be associated with BDNF preservation on cerebral vessels. FAU - Hasegawa, Yu AU - Hasegawa Y AD - Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan. FAU - Nakagawa, Takashi AU - Nakagawa T AD - Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan. FAU - Uekawa, Ken AU - Uekawa K AD - Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan. FAU - Ma, Mingjie AU - Ma M AD - Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan. FAU - Lin, Bowen AU - Lin B AD - Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan. FAU - Kusaka, Hiroaki AU - Kusaka H AD - Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan. FAU - Katayama, Tetsuji AU - Katayama T AD - Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan. FAU - Sueta, Daisuke AU - Sueta D AD - Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan. FAU - Toyama, Kensuke AU - Toyama K AD - Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan. FAU - Koibuchi, Nobutaka AU - Koibuchi N AD - Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan. FAU - Kim-Mitsuyama, Shokei AU - Kim-Mitsuyama S AD - Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556, Japan. kimmitsu@gpo.kumamoto-u.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141223 PL - United States TA - Transl Stroke Res JT - Translational stroke research JID - 101517297 RN - 0 (Angiotensin II Type 1 Receptor Blockers) RN - 0 (Biphenyl Compounds) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Calcium Channel Blockers) RN - 0 (Tetrazoles) RN - 1J444QC288 (Amlodipine) RN - J0E2756Z7N (Irbesartan) SB - IM MH - Amlodipine/administration & dosage/*pharmacology MH - Angiotensin II Type 1 Receptor Blockers/administration & dosage/*pharmacology MH - Animals MH - Biphenyl Compounds/administration & dosage/*pharmacology MH - Blood Pressure/drug effects MH - Blood-Brain Barrier/drug effects MH - Brain-Derived Neurotrophic Factor/*drug effects MH - Calcium Channel Blockers/administration & dosage/*pharmacology MH - Disease Models, Animal MH - Drug Therapy, Combination MH - Irbesartan MH - Rats MH - Rats, Inbred SHR MH - Stroke/*prevention & control MH - Tetrazoles/administration & dosage/*pharmacology OTO - NOTNLM OT - Amlodipine OT - BDNF OT - Combination therapy OT - Irbesartan OT - SHRSP OT - Stroke EDAT- 2014/12/24 06:00 MHDA- 2016/11/01 06:00 CRDT- 2014/12/24 06:00 PHST- 2014/10/30 00:00 [received] PHST- 2014/12/08 00:00 [accepted] PHST- 2014/12/05 00:00 [revised] PHST- 2014/12/24 06:00 [entrez] PHST- 2014/12/24 06:00 [pubmed] PHST- 2016/11/01 06:00 [medline] AID - 10.1007/s12975-014-0383-5 [pii] AID - 10.1007/s12975-014-0383-5 [doi] PST - ppublish SO - Transl Stroke Res. 2016 Feb;7(1):79-87. doi: 10.1007/s12975-014-0383-5. Epub 2014 Dec 23.