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

从大鼠输尿管收集的尿液中缓激肽的降解途径与大鼠或人血浆中的降解途径完全不同。大鼠尿中的激酶为中性内肽酶和羧肽酶Y（CPY）样激酶，而大鼠和人血浆中的激酶为激酶I（羧肽酶N）和激酶II（血管紧张素I转换酶，ACE）。依贝内酯B最初是从放线菌中分离得到的，对酯酶、脂肪酶和N-甲酰甲硫氨酸氨基肽酶有抑制作用。我们发现依贝内酯B不仅选择性地抑制酵母CPY，而且对大鼠尿中CPY样激肽酶也有抑制作用，而对血浆和尿中其他激肽酶无抑制作用。依贝内酯B增强了生理盐水灌注麻醉大鼠的激肽依赖性利尿和利钠作用。Kininogen-deficient Brown Norway Katholiek（BN-Ka）大鼠与来自相同品系的正常大鼠（BN Kitasato（BN-Ki）大鼠）相比，排出很少的尿激肽。DOCA-盐处理增加了两种品系大鼠的收缩压（SBP），但BN-Ka缺陷大鼠的高血压发展速度比正常BN-Ki大鼠快得多。每日皮下注射依贝内酯B（5、15 mg/kg/天）可显著降低正常BN-Ki大鼠的SBP，但对缺乏BN-Ka的大鼠无显著影响。这种治疗显着增加尿钠排泄和降低钠浓度的红细胞在正常的BN-Ki大鼠，但不缺乏BN-Ka大鼠。ACE抑制剂赖诺普利（5 mg/kg/天，s.c.）在正常BN-Ki大鼠和BN-Ka缺陷大鼠中，均不能降低SBP。这些结果表明，依贝内酯B可能是通过抑制尿激肽降解而起作用的有希望的抗高血压药物。

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.