| Co-Investigator(Kenkyū-buntansha) |
TAKEUCHI Takumi The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 助教授 (90167487)
SUZUKI Etsu The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (40313134)
HIRATA Yasunobu The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 助教授 (70167609)
KITAMURA Tadaichi The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (70010551)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
To study the mechanisms of vascular dysfunction in diabetes mellitus, we examined the responses of the aorta and corpus cavernosum to adrenomedullin (AM) and ANG II in obese Zucker (OZ), lean Zucker (LZ), and OZ rats administered fluvastatin (OZ + Flu). AM-induced endothelium-dependent vasorelaxation was impaired in OZ rats compared with LZ rats, and fluvastatin restored AM-induced, endothelium-dependent vasorelaxation (%Deltatension at 10(-7)mol/l AM ; LZ, -85.1 +/- 3.1% ; OZ, -50.7 +/- 2.5% ; OZ + Flu, -75.6 +/- 2.7%). Expression of endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in response to AM (10(-7)mol/l) were also diminished in OZ rats. Fluvastatin restored the eNOS expression and Akt phosphorylation [eNOS expression (relative intensity) : LZ, 2.3 +/- 0.4 ; OZ, 1.0 +/- 0.2 ; OZ + Flu, 1.8 +/- 0.3 ; Akt phosphorylation (relative intensity) : LZ, 2.3 +/- 0.2 ; OZ, 1.0 +/- 0.3 ; OZ + Flu, 1.9 +/- 0.2]. ANG II-induced vasoconstriction was enhanced in the aortic rings of OZ rats compared with LZ rats, and this enhanced vasoconstriction was partially normalized by fluvastatin and was abolished when the aorta of OZ rats was preincubated with the Rho kinase inhibitor Y-27632. GTPgammaS-induced contraction of permeabilized aortic smooth muscle cells, which is an indicator of the Rho-dependent Ca(2+) sensitization of contraction, was enhanced in OZ rats compared with LZ rats, and this enhanced contraction was suppressed in OZ + Flu rats. These results suggested that endothelium-dependent vasorelaxation was impaired, Ca(2+) sensitization of contraction was augmented in blood vessels of OZ rats and that fluvastatin restored vascular function by activating the Akt-dependent pathway and inhibiting the Rho-dependent pathway.
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