Function of vascular endothelium and vasomotor nerve in atherosclerotic animals

动脉粥样硬化动物血管内皮和血管运动神经的功能

• 批准号: 12672213
• 负责人: AYAJIKI Kazuhide
• 金额: $ 2.37万
• 依托单位: Shiga University of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672213/
• 关键词: lingual, carotid and cerebral arteries; corpus cavernosum; endothelium; nitric oxide (NO); Ca^<2+>-dependent K^+-channel; cytochrome P450 3A4; hyperlipidemic rabbit and monkey; atherosclerosis; Ca2+依存性K+チャネル; 動脈硬化モデル動物; 血管内皮; 血管支配神経; Ca^<2+>感受

In order to examine the effects of atherosclerosis and hyperlipidemia on vascular function, endothelial function in normal animals was firstly examined (1, 2). Then, the effects of atherosclerosis and hyperlipidemia on the functions of endothelium and vasomotor nerves were examined in Watanabe heritable hyperlipidemic (WHHL) rabbits (3) and hyperlipidemic monkeys fed by a high cholesterol diet (4).1. In isolated monkey lingual arteries, acetylcholine-induced relaxation was mediated by nitric oxide (NO) and Ca^<2+>-dependent K^<+>-channel opening substarice(s) from arachidonic acid produced by cytochrome P450 3A4 isoform in the endothelium.2. In isolated dog corpus cavernosum, acetylcholine-induced relaxation was mediated by NO and substance(s) which opens Ca^<2+>-dependent K^<+>-channel of small conductance.3. Marked, patchy atherosclerotic lesions were observed in all WHHL rabbit carotid arteries. Endothelium-dependent relaxations induced by acetylcholine were significantly inhibited … More in the WHHL rabbit carotid arteries with atherosclerotic lesions. Inversely, endothelium-dependent relaxations by substance P were greater in the arteries with and without atherosclerosis from WHHL rabbits than those in the arteries from Japanese white rabbits. Therefore, atherosclerosis may inhibit the muscarinic receptor function. Long exposure to hyperlipidemia was expected to cause receptor-hypersensitivity of substance P in the endothelium.4. Atherosclerotic lesions were not observed in middle cerebral arteries (MCA) isolated from hyperlipidemic monkeys fed by a high cholesterol diet. Histamine-induced relaxation, which was mediated by endothelial NO, was significantly potentiated in the hyperlipidemic monkey MCA, compared to that in the arteries from control monkeys whereas the relaxation by Ca^<2+> ionophore A23187 did not differ between control and hyperlipidemic monkeys. Nicotine- induced relaxation in MCA, which was mediated by NO released from nitroxidergic (nitrergic) nerves, was not affected by hyperlipidemia. Therefore, hyperlipidemia did not affect endothelial and nitroxidergic nerve functions of monkey MCA, but enhanced NO-mediated relaxation caused by histamine, possibly due to upregulation of histamine receptor-mediated function in the endothelium.From the findings using hyperlipidemic rabbits and monkeys, atherosclerosis and hyperlipidemia may modify the specific receptor functions in the endothelium, but not generally affect the functions of endothelium and innervating nerves. Less

为了研究动脉粥样硬化和高脂血症对血管功能的影响，首先检查正常动物的内皮功能(1, 2)。然后，在渡边遗传性高脂血症(WHHL)兔(3)和高胆固醇饮食喂养的高脂猴(4)中检查了动脉粥样硬化和高脂血症对内皮和血管舒缩神经功能的影响。1．在离体猴舌动脉中，乙酰胆碱诱导的舒张是由一氧化氮(NO)和Ca 2+ 依赖性K 2+ 通道开放基质介导的，这些基质来自内皮细胞色素P450 3A4亚型产生的花生四烯酸。2．在离体狗海绵体中，乙酰胆碱诱导的松弛是由NO和打开小电导的Ca ^ 2+ 依赖性K ^ + 通道的物质介导的。3．在所有 WHHL 兔颈动脉中均观察到明显的斑片状动脉粥样硬化病变。在患有动脉粥样硬化病变的 WHHL 兔颈动脉中，乙酰胆碱诱导的内皮依赖性舒张受到显着抑制。相反，在有或没有动脉粥样硬化的 WHHL 兔子的动脉中，P 物质引起的内皮依赖性舒张作用比日本白兔的动脉更大。因此，动脉粥样硬化可能抑制毒蕈碱受体功能。长期暴露于高脂血症预计会引起内皮细胞P物质受体过敏。4．在从高胆固醇饮食喂养的高脂猴中分离出的大脑中动脉（MCA）中没有观察到动脉粥样硬化病变。与对照猴的动脉相比，由内皮NO介导的组胺诱导的松弛在高脂猴MCA中显着增强，而Ca 2+ 离子载体A23187的松弛在对照猴和高脂猴之间没有差异。尼古丁诱导的 MCA 松弛是由硝基氧化神经释放的 NO 介导的，不受高脂血症的影响。因此，高脂血症并不影响猴MCA的内皮和硝基氧化能神经功能，而是增强了组胺引起的NO介导的松弛，这可能是由于内皮细胞中组胺受体介导的功能上调所致。从高脂血症兔和猴的研究结果来看，动脉粥样硬化和高脂血症可能会改变内皮细胞中的特定受体功能，但不会改变内皮细胞中的特定受体功能。 通常影响内皮细胞和支配神经的功能。较少的

项目成果

Ayajiki, K., Fujioka, H., Toda, N., Okada, S., Minamiyama, Y., Imaoka, S., Funae, Y., Okamura, T.: "EDHF2000, edited by Paul M.Vanhoutte"Taylor & Francis, New York. 502 (2001)

Ayajiki, K.、Fujioka, H.、Toda, N.、Okada, S.、Minamiyama, Y.、Imaoka, S.、Funae, Y.、Okamura, T.：“EDHF2000，由 Paul M.Vanhoutte 编辑”

安屋敷 和秀, 戸田 昇, 岡村 富夫: "NO作動性神経と勃起障害。総説 NO病態生理-創薬への展開-"日本薬理学会誌. 119. 21-28 (2002)

Kazuhide Yasuyashiki、Noboru Toda、Tomio Okamura：“NO 能神经和勃起功能障碍。NO 病理生理学综述 - 药物发现的发展”日本药理学会杂志 119. 21-28 (2002)。

Ayajiki, K., Ozaki, M., Shiomi, M., Okamura, T., Toda, N: "Comparison of endothelium-dependent relaxation in carotid arteries from Japanese white and Watanabe heritable hyperlipidemic rebbits"Journal of Cardiovascular Pharmacology. 36(5). 662-630 (2000)

Ayajiki, K.、Ozaki, M.、Shiomi, M.、Okamura, T.、Toda, N：“日本白种人和渡边遗传性高脂血症患者颈动脉内皮依赖性松弛的比较”心血管药理学杂志。

Ayajiki, K., Fujioka, H., Okamura, T.: "Mechanisms underlying endothelium-dependent, nitric oxide/prostacyclin-independent, acetylcholine-induced relaxation in canine corpus cavernosum"Naunyn-Schmiedeberg's Archives of Pharmacology. 362. 448-451 (2000)

Ayajiki, K.、Fujioka, H.、Okamura, T.：“犬海绵体中内皮依赖性、一氧化氮/前列环素独立、乙酰胆碱诱导的松弛的机制”Naunyn-Schmiedeberg 的药理学档案。

Ayajiki K., Fujioka H. and Okamura T.: "Mechanisms underlying endothelium dependent, nitric oxide/prostacyclin independent, acetylcholine-induced relaxation in canine corpus cavernosum"Naunyn-Schmiedeberg's Archives of Pharmacology. 362. 448-451 (2000)

Ayajiki K.、Fujioka H. 和 Okamura T.：“犬海绵体中内皮依赖性、一氧化氮/前列环素独立、乙酰胆碱诱导的松弛的机制”Naunyn-Schmiedeberg 的药理学档案。