Development of a novel anti-hypertensive agent acting through the inhibition of urinary kininase.

开发一种通过抑制尿激酶发挥作用的新型抗高血压药。

基本信息

批准号：
05671904
负责人：
MAJIMA Masataka
金额：
$ 0.96万
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 (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05671904/
关键词：
KININ KININASE DOCA-SALT HYPERTENSION KININOGEN KININ ANTAGONIST POSTSTATIN EBELACTONE B エベラクトンB Kinin Kininogen Kininase Kinin antagoniot DOCA-salt hypertension angio tensin Salt induced hypertension

项目摘要

The degradation pathway of bradykinin in urine, collected from the rat ureter, was quite different from that in rat or human plasma. Kininases in rat urine were neutral endopeptidase and carboxypeptidase Y (CPY) -like kininase, whereas those in rat and human plasma were kininase I (carboxypeptidase N) and kininase II (angiotensin I-converting enzyme, ACE) . Ebelactone B,isolated from Actinomycetes, was originally reported to inhibit some enzymes such as esterase, lipase and N-formylmethionine aminopeptidase. We found that ebelactone B selectively inhibited not only CPY from yeast, but also the CPY-like kininase in rat urine without inhibiting other kininases in plasma and urine. Ebelactone B enhanced kinin-dependent diuretic and natriuretic effects in saline-infused anesthetized rats. Kininogen-deficient Brown Norway Katholiek (BN-Ka) rats excreted little urinary kinin, compared with normal rats from the same strain (BN Kitasato (BN-Ki) rats) . DOCA-salt treatment increased systolic blood pressure (SBP) in both strain rats, but the development of hypertension was much faster in deficient BN-Ka rats than in normal BN-Ki rats. Daily subcutaneous administration of ebelactone B (5,15 mg/kg/day) significantly reduced SBP in normal BN-Ki rats, but not in deficient BN-Ka rats. This treatment significantly increased urinary sodium excretion and reduced sodium concentration in the erythrocytes in normal BN-Ki rats, but not in deficient BN-Ka rats. An ACE inhibitor, lisinopril (5 mg/kg/day, s.c.) , did not reduce the SBP in either normal BN-Ki rats or deficient BN-Ka rats. These results suggested that ebelactone B may be promising as an antihypertensive agent acting through the inhibition of urinary kinin degradation.

从大鼠输尿管中收集的尿液中尿中的尿中的降解途径与大鼠或人血浆中的降解途径大不相同。大鼠尿液中的激酶是中性内肽酶和羧肽酶Y（CPY）类似激酶，而大鼠和人血浆中的激酶是差异酶I（羧肽酶N）和激酶II（血管紧张素I -Converting酶，ACE，ACE，ACE）。据报道，从放线菌分离的Ebelactone B最初抑制某些酶，例如酯酶，脂肪酶和N-甲基硫代氨酸氨基肽酶。我们发现，ebelactone B不仅有选择地抑制大鼠尿液中的CPY样激酶，而不会抑制血浆和尿液中的其他动力酶。 Ebelactone B增强了盐水注入麻醉大鼠的基因蛋白依赖性的利尿剂和纳地氧化作用。与来自相同菌株（BN Kitasato（BN-KI）大鼠）的正常大鼠相比，缺乏动力学的棕色挪威凯瑟利克（BN-KA）大鼠尿素少量尿。 DOCA盐处理增加了两种菌株大鼠的收缩压（SBP），但是高血压的发育率不足BN-KA大鼠的速度要比正常的BN-KI大鼠快得多。每日皮下给药ebelactone b（5,15 mg/kg/day）显着降低了正常BN-KI大鼠的SBP，但bn-ka大鼠不足。这种治疗可显着增加尿钠排泄，并降低正常BN-KI大鼠红细胞的钠浓度，但并非BN-KA大鼠不足。 ACE抑制剂Lisinopril（5 mg/kg/day，S.C。）在正常的BN-KI大鼠或不足的BN-KA大鼠中均未降低SBP。这些结果表明，ebelactone b可能是通过抑制尿中的基因蛋白降解作用的抗高血压剂。