Pathophysiological and molecular pharmacological studies on the role of reactive oxygen species in disorder of circulatory function.

活性氧在循环功能障碍中作用的病理生理学和分子药理学研究。

• 批准号: 11470514
• 负责人: ITOH Takeo
• 金额: $ 8.83万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470514/
• 关键词: superoxide; reactive oxygen species; hydrogen peroxide; prostaglandin; vascular smooth muscle; endothelial cells; vasorelaxation; hyperpolarization

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 … More 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

通过测定光泽精化学发光信号，研究了有和无内皮的兔隐动脉中超氧化物的产生水平。蛋白激酶C（PKC）激活剂佛波醇12，13-二丁酸酯（PDBu）可增强内皮细胞和非内皮细胞的化学发光信号。在此条件下，超氧化物歧化酶（SOD）大大减弱了化学发光信号。GF 109203（PKC的选择性抑制剂）和二苯碘氯[NAD（P）H氧化酶的抑制剂]均抑制化学发光信号。上述结果提示，PKC激活NAD（P）H可促进血管平滑肌细胞（可能也包括内皮细胞）产生超氧化物，次黄嘌呤+黄嘌呤氧化酶产生的超氧化物可抑制去甲肾上腺素（NAd）引起的兔肠系膜动脉去内皮条收缩。超氧化物歧化酶（SOD）可增强这种超氧化物诱导的反应，但过氧化氢酶（CAT）或抗氧化剂（AS）可抑制这种反应。 ...更多信息 抗坏血酸上述结果提示，在生理条件下，SOD可将超氧阴离子分解为H_2O_2，从而抑制NAD诱导的血管平滑肌收缩; H_2O_2可使平滑肌细胞膜超极化，而双氯芬酸钠（COX抑制剂）和格列本脲（K_2通道抑制剂）可抑制H_2O_2<ATP>的超极化。结果提示H_2O_2通过激活K_2通道，增加了三尖杉酯碱的合成，使平滑肌细胞膜超极化<ATP>。在β-七叶皂苷处理的兔肠系膜动脉平滑肌中，NAd + GTP可增强0.3 μM Ca^&lt;2+&gt;引起的平滑肌收缩。H_2O_2对有或无NAd和GTP时的Ca^&lt;2+&gt;收缩均无影响，提示H_2O_2对兔肠系膜动脉平滑肌收缩蛋白的Ca^&lt;2+&gt;敏感性无直接作用。少

项目成果

Takayuki Asano: "Roles of epithelium on H_2O_2-induced inhibition of acetylcholine-contraction in rabbit intrapul-monary bronchiole"British Journal of Pharmacology. 132・6. 1271-1280 (2001)

Takayuki Asano：“上皮细胞对 H_2O_2 诱导的兔肺内细支气管乙酰胆碱收缩抑制的作用”英国药理学杂志 132・6（2001）。

Seigo Fujimoto: "Mechanisms of hydrogen peroxide-induced relaxation in rabbit mesenteric small artery"European Journal of Pharmacology. 412・3. 261-300 (2001)

Seigo Fujimoto：“过氧化氢诱导兔肠系膜小动脉松弛的机制”欧洲药理学杂志 412・3（2001）。

Masuo Ohashi: "Possible mechanisms underlying the vasodilatation induced by olprinone, a phosphodiesterase III inhibitor, in rabbit coronary artery."British Journal of Pharmacology. 129・5. 1000-1006 (2000)

Masuo Ohashi：“磷酸二酯酶 III 抑制剂奥普利酮在兔冠状动脉中引起血管舒张的可能机制。”英国药理学杂志 129・5（2000 年）。

Yoshikatsu Suzuki: "Modified histamine-induced NO-mediated relaxation in resistance arteries in pre-eclampsia."European Journal of Pharmacology. 410・1. 7-13 (2000)

Yoshikatsu Suzuki：“先兆子痫中经修饰的组胺诱导的 NO 介导的动脉松弛。”欧洲药理学杂志 410・1（2000 年）。

Takayuki Asano, Tomonori Hattori, Toyohiro Tada, Junko Kajikuri, Toshio Kamiya, Michihiro Saitoh, Yasuo Yamada, Makoto Itoh, Takeo Itoh.: "Role of the epithelium in opposing H_2O_2-induced modulation of acetylcholine-induced contractions in rabbit intrapu

Takayuki Asano、Tomonori Hattori、Toyohiro Tada、Junko Kajikuri、Toshio Kamiya、Michihiro Saitoh、Yasuo Yamada、Makoto Itoh、Takeo Itoh.：“上皮细胞在对抗 H_2O_2 诱导的兔体内乙酰胆碱诱导收缩的调节中的作用