| Co-Investigator(Kenkyū-buntansha) |
NISHIKINI Toshio Dokkyo University School of Medicine, Associate Professor, 医学部, 助教授 (80291946)
ISHIMITSU Toshihiko Dokkyo University School of Medicine, Associate Professor, 医学部, 助教授 (80232346)
KOBAYASHI Naohiko Dokkyo University School of Medicine, Assistant Professor, 医学部, 講師 (90254945)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Vasoactive substances and intracellular signal transmission play important roles in hypertensive heart disease. We evaluated 1)cardioprotective effects of celiprolol (β_1 blocker) on cardiovascular remodeling in DOCA salt hypertensive rats (DOCA rats). Upregulated preproendothelin 1, endothelin A receptor, TGF-β_1, c-fos, and extracellular signal-regulated kinase activities in heart of DOCA rats were suppressed by celiprolol. Celiprolol improved cardiac remodeling. Also, upregulated VCAM-1, p22phox, p47phox, gp91phox, nox1, NF-κβ 13, c-Src, p441p42 extracellular signal-regulated kinases and downregulated eNOS, P13K, Akt in heart of DOCA rats were improved by celiprolol. These findings suggest that cardioprotective effects of celiprolol may be mediated by suppressed expression of endothelin 1, TGF-β_1, VCAM-1, NF-Kβ and relating signal transmission, and by increased eNOS via stimulation of the PI3K-Akt signaling pathway. 2)cardioprotective effects of aminoguanidine (AG ; iNOS inhibitor) and Y-27632 (Rho-kinase inhibitor) on cardiovascular remodeling in hypertensive failing heart of rats. Hypertensive failing heart was induced in Dahl salt sensitive rats by high salt feeding for 12 weeks. Upregulated iNOS and ERK activities in failing heart were inhibited by AG and upregulated Rho-Rho-kinase pathway in failing heart was suppressed by Y-27632, respectively. Both AG and Y-27632 improved cardiac remodeling by different mechanisms and these agents may be potential therapeutic strategy for heart failure.
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