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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

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Abstract

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.

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Acknowledgments

This work was partially supported by a grant from Shionogi & CO., LTD. We thank Yuriko Shimamura, Miho Kataoka, Michie Uchikawa, Keiko Morozumi, Kazuko Noda, and Tomoko Moriyama for their support.

Disclosures

S. K-M received lecture fees and research grant from Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Sionogi, Takeda, and Kyowa Hakko Kirin.

Conflict of Interest

The authors report no conflict of interest.

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Authors and Affiliations

  1. 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

    Yu Hasegawa, Takashi Nakagawa, Ken Uekawa, Mingjie Ma, Bowen Lin, Hiroaki Kusaka, Tetsuji Katayama, Daisuke Sueta, Kensuke Toyama, Nobutaka Koibuchi & Shokei Kim-Mitsuyama

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  1. Yu Hasegawa
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  2. Takashi Nakagawa
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  3. Ken Uekawa
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  4. Mingjie Ma
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  11. Shokei Kim-Mitsuyama
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Correspondence to Shokei Kim-Mitsuyama.

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Hasegawa, Y., Nakagawa, T., Uekawa, K. et al. 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. Transl. Stroke Res. 7, 79–87 (2016). https://doi.org/10.1007/s12975-014-0383-5

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  • DOI: https://doi.org/10.1007/s12975-014-0383-5

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