2000 Fiscal Year Final Research Report Summary
Pathophysiological and molecular pharmacological studies on the role of reactive oxygen species in disorder of circulatory function.
| Project/Area Number |
11470514
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Nagoya City University |
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Principal Investigator |
ITOH Takeo Nagoya City University Medical School, Professor, 医学部, 教授 (70159888)
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| Co-Investigator(Kenkyū-buntansha) |
FUJIMOTO Seigo Nagoya City University Medical School, Associate Professor, 医学部, 助教授 (60079994)
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| Project Period (FY) |
1999 – 2000
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| Keywords | superoxide / reactive oxygen species / hydrogen peroxide / prostaglandin / vascular smooth muscle / endothelial cells / vasorelaxation / hyperpolarization |
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| Research Abstract |
The level of superoxide production was investigated by measuring lucigenin chemiluminescence signals in rabbit saphenous arteries with and without endothelium. Phorbol 12, 13-dibutirate (PDBu), an activator of protein kinase C (PKC), increased the chemiluminescence signals in preparations with and without endothelium. Under the conditions, superoxide dismutase(SOD) greatly attenuated the chemiluminescence signals. Each GF109203 (a selective inhibitor of PKC) and diphenylene iodochloride [an inhibitor of NAD (P) H oxidase] inhibited the chemiluminescence signals. These results suggest that an activation of NAD (P) H by PKC enhances generation of superoxide in vascular smooth muscle cells (and possibly in endothelial cells).
Superoxide generated by hypoxanthine + xanthine oxidase inhibited the contraction induced by noradrenaline (NAd) in endothelium-denuded strips of rabbit mesenteric arteries. This superoxide-induced response was enhanced by SOD, but this was inhibited by catalase or as
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corbic acid. These results suggest that under physiological conditions, SOD breaks down superoxide to H_2O_2 that inhibits the NAd-induced contraction in vascular smooth muscles.
H_2O_2 hyperpolarized smooth muscle cell membrane, which was inhibited by diclofenac sodium (an inhibitor of cyclooxygenase), and by glibenclamide (an inhibitor of K_<ATP> channels). These results suggest that H_2O_2 increases the synthesis of prostaglandins that hyperpolarizes the smooth muscle cell membrane through an activation of K_<ATP> channels. It is also suggested that the H_2O_2-induced membrane hyperpolarization plays an important role on the H_2O_2-induced relaxation on NAd-contraction in rabbit mesenteric artery.
In β-escin-skinned smooth muscles of rabbit mesenteric arteries, NAd plus GTP enhanced the contraction induced by 0.3 μM Ca^<2+>. H_2O_2 had no effect on the Ca^<2+>-contraction in the presence and absence of NAd plus GTP, suggesting that H_2O_2 has no direct action on the Ca^<2+>-sensitivity of contractile proteins in vascular smooth muscles of rabbit mesenteric artery. Less
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