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，使用激肽原缺陷的大鼠（棕色挪威-卡托利克（BN-Ka）大鼠），揭示肾激肽释放酶充当体内过量钠或钠潴留的闸门，肾激肽释放酶排泄减少起着关键作用。在高血压发展的早期阶段的作用。I.肾激肽释放酶-激肽系统对钠排泄的作用1。与正常BN-Kitasato(Ki)大鼠相比，缺陷BN-Ka大鼠对饮食中的氯化钠和2%氯化钠敏感，表现为高血压，尿量和尿钠排泄量均低于正常BN-Kr大鼠。 2．对BN-Ka缺陷大鼠给予非升压剂量的血管紧张素II可通过醛固酮释放在细胞内积聚钠而产生高血压。3．产生的激肽通过位于肾小管细胞管腔侧的 B_2 受体表现出排钠作用，如 ebelactone B 增加排钠作用所示，它选择性地抑制尿液中的羧肽酶 Y 样外肽酶。 二、肾激肽释放酶-激肽系统在发育中的作用高血压1.自发性高血压大鼠(SHR)在高血压发生过程中尿激肽释放酶的分泌量比Wistar京都大鼠(WKY)少。2．催产素在麻醉大鼠中诱导尿钠排泄并排出肾激肽释放酶。 SHR肾中激肽释放酶水平与WKY无差异，但催产素排泄的激肽释放酶要低得多，提示SHR肾激肽释放酶分泌困难。 3．治疗开始后2周，未切除肾的BN-Ka缺陷大鼠的血压达到DOCA-盐高血压的平台。4．肾激肽释放酶释放剂（例如催产素）和尿激酶抑制剂（例如 ebelactone B）可能是新型抗高血压药物。

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.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.: "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 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。”

T.Oda,et al.: "Analyses of neutrophil extravasation in microcirculation of hamster cheek pouch by intravital microscopy." Progress in Microcirculation Research(eds.H.Niimi,M.Oda,T.Sawada and R.J.Xiu). 263-266 (1994)

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。”