Clinial Relevance of Novel Angiotensin II Generation Pathway within the Kidney

肾脏内新型血管紧张素 II 生成途径的临床相关性

基本信息

批准号：
10671004
负责人：
HAYASHI Koichi
金额：
$ 1.92万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Since the development of angiotensin receptor antagonists (AIIA), it has been a matter of controversy whether ACE-I is more effective than AIIA in retarding the progression of renal disease. The present study was conducted to elucidate whether the accumulation of bradykinin contributes to the ACE-I action, and whether non-ACE-mediated angiotensin II generation participates in the renal protection of these agents. Using intravital CCD camera technique, an angiotensin receptor antagonist (E4177) dilated different (AFF) and efferent arterioles (EFF), in superficial nephrons (SP) and juxtamedullary nephrons (JM). Subsequently, cilazaprilat caused further dilation of both AFF and EFF in JM, whereas in SP it dilated only EFF. These cilazaprilat-induced vasodilation and natriuresis were abolished by a bradykinin antagonist. In parallel with these results, cilazaprilat increased renal bradykinin contents, greater in the medulla than in the cortex. Next, angiotensin II generation via ACE-mediat … More ed 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ィイD111ィエD1, D-AlaィイD112ィエD1]-ANGI (S) (an ANGI 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 ANGI. S at a dose of 100 nmol caused 30% decrements in RBF, which was completely abolished by g ANG receptor antagonist, but was only 50% inhibited by chymostatin. Finally, the comparison of the efficacy of chronic ACE-I and AllA treatment was made. In contrast to the acute study, intrarenal bradykinin contents were nearly the same in renal tissues from ACE-I-and AIIA-treated dogs. In conclusion, zonal heterogeneity in renal bradykinin levels and segmental differences in reactivity to bradykinin contribute to the diverse responsiveness of renal afferent and efferent arterioles to acute administration of ACE-I; ACE-I-enhanced kinin action would participate in glomerular hemodynamic changes by ACE-I. Futhermore, 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. Chronic treatment, however, fails to demonstrate the benefit of ACE-I-induced intrarenal bradykinin accumulation in protecting renal injury. Less

自血管紧张素受体拮抗剂（AIIA）的发展以来，ACE-I是否比AIIA更有效地延迟了肾脏疾病的进展，这引起了争议。进行本研究的目的是阐明缓激肽的积累是否有助于ACE-I作用，以及非ACE介导的血管紧张素II生成参与这些药物的肾脏保护。使用浸润性CCD摄像头技术，在表面的肾肾素（SP）和并置肾上腺素（JM）中，血管紧张素受体拮抗剂（E4177）扩张了不同（AFF）和有效的小动脉（EFF）（EFF）。随后，cilazaprilat在JM中引起AFF和EFF的进一步扩张，而在SP中，它仅扩展了EFF。这些cilazaprilat诱导的血管舒张和纳特里雷氏菌被一个拮抗剂废除了。与这些结果同时，纤毛增加了肾肾上腺素含量，在髓质中比在皮质中更大。接下来，检查了血管紧张素II通过ACE - 中的产生……更多的ED和非ACE介导的途径。在狗肾皮质中，ACE/非ACE介导的ANG II产生的比率为8：2，而在心脏中，该值被证明为4：6。在肾脏中，与肾球内给药的影响和[PROII D111，D-Alaii D112] -Angi（S）（无法通过ACE转化为ANG II）对系统性血压（BP）（BP）和肾脏血流（RBF）的ANGI类似物（RBF）的影响，需要100倍的浓度以获得相同程度的较高范围和bpf compart bpf and bpf。使用内内针CCD摄像机显微镜进行进一步的研究表明，与ANGI相比，S的肾脏传入和有效的小动脉作用减少了。 S剂量为100 nmol会导致RBF降低30％，这完全被G Ang接收器拮抗剂完全废除，但仅被瓜莫斯汀抑制了50％。最后，进行了慢性ACE-I和Alla治疗的有效性的比较。与急性研究相反，在ACE-I-IIA和AIIA处理的狗的肾脏组织中，肾内心动激素含量几乎相同。总之，肾肾上腺素水平的纬向异质性和对松曲蛋白的反应性的分段差异有助于肾脏传入和有效的小动脉对ACE-I急性施用的反应性。 ACE-I-增强的Kinin作用将通过ACE-I参与肾小球血流动力学变化。与ACE活性相比，非ACE活性对肾ANG II产生的贡献较小，而Chimase介导的ANG II产生仅占非ACE介导的ANG II产生的一半。然而，慢性治疗未能证明ACE-I诱导的肾上腺内肾上腺素积累在保护肾脏损伤中的好处。较少的