| Budget Amount *help |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
By this grant, I obtained following data.
1) In untreated STZ rats,(1) ACh-induced relaxation, cGMP accumulation,(2) aortic superoxide generation, nitrotyrosine expression, and NAD(P) H oxidase activity were increased ;(3) plasma endothelin-1(ET-1) and aortic c-Jun(AP-1 component) protein expressions were increased. Pioglitazone treatment markedly corrected the above abnormalities. These results suggest that pioglitazone treatment improves endothelium-dependent relaxation by reducing oxidative stress via increased SOD activity, decreased NAD(P) H oxidase activity, and a decreased ET-1 level, and that this decreased ET-1 level may be attributable to an inhibition of the AP-1 signaling pathway.
2) In acute studies on OLETF mesenteric arteries, the ACh-induced relaxation was impaired and the relaxation became weaker at high ACh concentrations. Both metformin and AICAR(an activator of AMP-kinase(AMPK), which is also activated by metformin) suppressed both the ACh-induced EDCF-mediated contraction and the ACh-stimulated production of prostanoids(TXA2 and PGE2). Metformin treatment :(a) improved the ACh-induced NO-or EDHF-mediated relaxation and COX-mediated contraction,(b) reduced the EDCF-mediated contraction, and(c) suppressed the production of prostanoids. These results suggest that metformin improves endothelial functions in OLETF mesenteric arteries by suppressing vasoconstrictor prostanoids(at least partly via sustained AMPK activation).
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