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.

本研究使用激肽原缺乏的大鼠(Brown挪威-Katholiek(BN-KA)大鼠)，揭示了肾脏激肽释放酶作为体内过量钠或钠滞留的闸门，而肾脏激肽释放酶排泄减少在高血压的早期发展中起着关键作用。结论：1.与正常BN-Kitasato(KI)大鼠相比，BN-KA缺陷大鼠对食盐和2%的食盐敏感，尿量和尿钠排泄较正常BN-Kr大鼠少。对于BN-KA缺乏的大鼠，非升压剂量的血管紧张素II通过醛固酮释放在细胞内积聚钠而形成高血压。激肽通过定位于肾小管上皮细胞管腔一侧的B_2受体表现为利钠作用，如ebelacone B增加的利钠作用，它选择性地抑制尿液中的羧基肽酶Y样外肽酶。结论：1.自发性高血压大鼠(SHR)在高血压形成过程中尿激肽释放酶排泄量低于Wistar京都大鼠(WKY)。催产素诱导麻醉大鼠钠尿和排泄肾激肽释放酶。SHR与WKY大鼠肾脏激肽释放酶水平无明显差异，但催产素分泌的激肽释放酶显著低于WKY大鼠，提示SHR肾脏激肽释放酶分泌困难。单肾切除BN-KA缺陷型大鼠治疗2周后，DOCA-盐性高血压大鼠血压达到平台期。肾激肽释放酶释放物，如催产素，尿激肽酶抑制物，如依贝拉通B，可能是新的降压药物。

项目成果

M.Majima,et al.: "Hypertension induced by a non pressor dose of angiotensin 11 in kininogen‐deficient rats." Hypertension. 24. 111-119 (1994)

M. Majima 等人：“在缺乏激肽原的大鼠中使用非升压剂量的血管紧张素 11 诱发高血压。” 24. 111-119 (1994)

M.Majima, et al.: "Poststatin, a novel inhibitor of bradykinin-degrading enzymes in rat urine." Eru.J.Pharmacol. 232. 181-190 (1993)

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

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

M.Majima, et al.: "Failure of the oxytocin-indused increase in secretion of urinary kallikrein in yound spontaneously hypertensive rats." Jpn.J.Pharmacol. (in press). (1996)

M.Majima 等人：“年轻自发性高血压大鼠中催产素导致的尿激肽释放酶分泌增加失败。”

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。”