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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671004/
• 关键词: angiotensin converting enzyme inhibitors; angiotensin receptor antagonists; kidney; afferent arterioles; efferent arterioles; renal hemodynamics; アンジオテンシン変換酵素阻害薬

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

自从血管紧张素受体拮抗剂（AIIA）开发以来，ACE-I是否比AIIA更有效地延缓肾脏疾病的进展一直存在争议。本研究旨在阐明缓激肽的积累是否有助于 ACE-I 的作用，以及非 ACE 介导的血管紧张素 II 的生成是否参与这些药物的肾脏保护。使用活体 CCD 摄像技术，血管紧张素受体拮抗剂 (E4177) 扩张浅表肾单位 (SP) 和近髓肾单位 (JM) 中的不同 (AFF) 和传出小动脉 (EFF)。随后，西拉普利拉导致 JM 中 AFF 和 EFF 进一步扩张，而 SP 中仅扩张 EFF。这些西拉普利拉诱导的血管舒张和尿钠排泄被缓激肽拮抗剂消除。与这些结果平行，西拉普利拉增加了肾缓激肽含量，髓质中的缓激肽含量高于皮质中的缓激肽含量。接下来，检查了通过 ACE 介导和非 ACE 介导的途径生成血管紧张素 II。狗肾皮质中 ACE/非 ACE 介导的 ANG II 生成比例为 8:2，而在心脏中该比例被证明为 4:6。在肾脏中，与肾内给予ANG I和[ProィイD111ィエD1，D-AlaィイD112ィエD1]-ANGI (S)（一种ANGI类似物，不能被ACE转化为ANG II）对全身血压（BP）和肾血流量（RBF）的影响相比，S需要高100倍的浓度才能获得相同程度的变化。 BP 和 RBF。使用活体针型 CCD 相机显微镜进行的进一步研究表明，与 ANGI 相比，S 的肾传入和传出小动脉活动减弱。 100 nmol 剂量的 S 引起 RBF 减少 30%，g ANG 受体拮抗剂可完全消除 RBF，但糜抑素仅抑制 50%。最后对长期ACE-I和AllA治疗的疗效进行比较。与急性研究相反，ACE-I 和 AIIA 治疗狗的肾组织中肾内缓激肽含量几乎相同。总之，肾缓激肽水平的区域异质性和缓激肽反应性的节段差异导致肾传入和传出小动脉对急性施用ACE-I的不同反应性； ACE-I增强的激肽作用将参与ACE-I引起的肾小球血流动力学变化。此外，与 ACE 活性相比，非 ACE 活性对肾脏 ANG II 生成的贡献较小，并且食糜酶介导的 ANG II 生成仅占非 ACE 介导的 ANG II 生成的一半。然而，长期治疗未能证明ACE-I诱导的缓激肽肾内积累在保护肾损伤方面的益处。较少的

项目成果

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