Genetic background of development of hypertension and novel antipertensive drugs.

高血压发展的遗传背景和新型抗高血压药物。

• 批准号: 05454581
• 负责人: KATORI Makoto
• 金额: $ 4.8万
• 依托单位: Kitasato University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454581/
• 关键词: renal kallikrein; kininogen; kininase; carboxypeptidase Y; Brown Norway rats; DOCA-salt hypertension; spontaneously hypertensive rats; ebelactone B; DOCA-食塩高血圧; キニノゲン欠損ラット; 実験的高血圧; 尿キニナーゼ阻害薬; neutral endopeptidase; carboxypeptidase Y; oxytoc

The present works, using kininogen-deficient rats (Brown Norway-Katholiek (BN-Ka) rats), revealed that renal kallikrein act as a flood gate for excess sodium or sodium retention in the body and the reduced excretion of renal kallikrein plays a critical role in the early stage of the development of hypertension.I.A role of renal kallikrein-kinin system for sodium excretion1. Comparing with normal BN-Kitasato (Ki) rats, deficient BN-Ka rats were sensitive to NaCl and 2% NaCl in diet developed hypertension, by excretion of less urine volume and urinary sodium than normal BN-Kr rats.2. A non-pressor dose of angiotensin II to deficient BN-Ka rats developed hypertension by accumulating sodium in cells through aldosterone release.3. Kinin generated showed natriuresis through B_2 receptor localized on the luminal side of the tubular cells, as shown by increased natriuresis by ebelactone B,which selectively inhibited carboxypeptidase Y-like exopeptidase in urine.II.A role of renal kallikrein-kinin system in the development of hypertension1. Spontaneously hypertensive rats (SHR) excrete less urinary kallikrein during the development of hypertension than Wistar Kyoto rats (WKY).2. Oxytocin induced natriuresis in anesthetized rats and excreted renal kallikrein. The kallikrein level in kidney of SHR was not different from that in WKY,but the kallikrein excretion by oxytocin were much lower, suggesting that SHR showed difficulty in secretion of renal kallikrein.3. The blood pressure reached a plateau in DOCA-salt hypertension of uninephrectomized deficient BN-Ka rats 2 weeks after the onset of the treatment.4. Renal kallikrein releasers, such as oxytocin, and urine kininase inhibitors, such as ebelactone B,may be novel anti-hypertensive drugs.

目前的工作是使用缺乏动力学的大鼠（Brown Norway-Katholiek（BN-KA）大鼠），表明肾脏Kallikrein充当体内过量钠或钠保留过多的洪水大门，并且在肾脏肾脏中降低了Kallikrein的排泄，在Hypersemens of Hypertemension.a的早期Kallikrein扮演着重要的作用。排泄1。与正常的BN-KITASATO（KI）大鼠相比，不足的BN-KA大鼠对NaCl敏感，而在饮食中，与正常的BN-KR大鼠相比，饮食中的NaCl敏感为2％NaCl。非压力剂量的血管紧张素II对不足的BN-KA大鼠通过通过醛固酮释放在细胞中积聚钠来形成高血压。3。产生的Kinin通过B_2受体局部位于肾小管细胞的腔侧，如ebelactone b的纳地二硫硫酮所示，它们在尿液中有选择地抑制尿液中的羧肽酶y型外肽酶。高血压发育过程中自发性高血压大鼠（SHR）排泄物比Wistar Kyoto大鼠（WKY）。2。催产素在麻醉大鼠中诱导纳特里雷SIS，并排出肾脏Kallikrein。 SHR肾脏中的Kallikrein水平与WKY中的Kallikrein水平没有什么不同，但是催产素的Kallikrein排泄率要低得多，这表明SHR在肾脏Kallikrein的分泌方面表现出难度。3。血压在治疗发作后2周，在单次化缺陷BN-KA大鼠的DOCA盐高压中达到了高原。4。肾脏Kallikrein释放蛋白（例如催产素和尿激酶抑制剂，例如ebelactone b）可能是新型的抗高血压药物。

项目成果

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T.Oda 等人：“通过活体显微镜分析仓鼠颊囊微循环中的中性粒细胞外渗。”

M.Hashimoto,et al.: "Immediate inhibitory effect of methylprednisolone suleptanate (U-67590A)on antigen-induced cutaneous and airway anaphylactic in guinea-pigs." Br.J.Phamacol.108. 604-612 (1993)

M.Hashimoto 等人：“甲基泼尼松龙磺酯 (U-67590A) 对豚鼠抗原诱导的皮肤和气道过敏的立即抑制作用。”

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M.Majima 等人：“Poststatin，一种新型大鼠尿液中缓激肽降解酶抑制剂。”

M.Katori,et al.: "Induction of prostaglandin H synthase-2 in rat carrageenin-induced pleurisy and effect of A selection cox-2 inhibitor." Adv.PG.TX.LT.Res.(in press).

M.Katori 等人：“大鼠角叉胶诱导的胸膜炎中前列腺素 H 合酶 2 的诱导以及 A 选择 cox-2 抑制剂的作用。”

M.Majima, et al.: "Failure of endogenous blood kinin levels elevated by captopril to induce hypotesion in normotensive and hypertensive rats. --- A study using a newly developed ELISA for kinin ---" Biomed.Res.17 (in press). (1995)

M.Majima 等人：“卡托普利无法提高内源性血液激肽水平，从而诱导正常血压和高血压大鼠的低血压。 --- 使用新开发的激肽 ELISA 进行的研究 ---”Biomed.Res.17（载于