| Budget Amount *help |
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1994: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1993: ¥800,000 (Direct Cost: ¥800,000)
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| Research Abstract |
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.
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