| Co-Investigator(Kenkyū-buntansha) |
HONDA Masanori Keio University, School of Medicine, Assistant, 医学部, 助手 (20270514)
KUBOTA Eiji Keio University, School of Medicine, Assistant, 医学部, 助手 (40255451)
MATSUDA Hiroto Keio University, School of Medicine, Assistant, 医学部, 助手 (80245498)
HAYASHI Koichi Keio University, School of Medicine, Assist.Prof., 医学部, 講師 (80164937)
藤原 啓二 慶應義塾大学, 医学部, 助手 (80255463)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 1998: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1997: ¥3,900,000 (Direct Cost: ¥3,900,000)
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| Research Abstract |
Although angiotensin converting enzyme (ACE) inhibitors retard the progression of renal diseases, it remains undetermined whether a non-ACE-mediated pathway contributes to the angiotensin (ANG) ii generation within the kidney This study attempted to clarify the role of ACE and non-ACE pathway, including chymase, for ANG II generation within the kidney. ANG II generation via ACE-mediated and non-ACE-mediated pathways was examined. The ratio of ACE/non-ACE-mediated ANG II generation was 8 : 2 in dog renal cortex, whereas in the heart this value proved to be 4 : 6. In the kidney, when compared with the effects of intrarenally administered ANG I and [Pro^<11>, D-Ala^<12>]-ANG I (S) (an ANG I analog that cannot be converted to ANG II by ACE) on systemic blood pressure (BP) and renal blood flow (RBF), S required 100-fold higher concentrations to obtain the same degree of changes in BP and RBF.Further studies using intravital needle-type CCD camera microscopy demonstrated that renal afferent and efferent arteriolar actions of S were diminished, compared with those of ANG I.S at a dose of 100 nmol caused 30% decrements in RBF, which was completely abolished by an ANG receptor antagonist, but was only 50% inhibited by chymostatin. Finally, unlike systemic vascular beds, dexamethasone dilates the renal vasculature, which is associated with a decrease in renal interstitial ANG II formation and the paralleled inhibition of renal ACE activity, suggesting glucocorticoid does not affect non-ACE-mediated ANG II generation. Collectively, non-ACE activity, compared with ACE activity, contributes less to the renal ANG II generation, and chymase-mediated ANG II generation shares only half of the non-ACE-mediated ANG II production. Furthermore, non-ACE pathway does not play an important role in ANG II formation in glucocorticoid-treated kidneys Nevertheless, further studies are required to establish the role of non-ACE-mediated renal ANG II formation under a variety of renal diseases.
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