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

自血管紧张素受体拮抗剂（AIIA）问世以来，ACE-I在延缓肾脏疾病进展方面是否比AIIA更有效一直存在争议。本研究旨在阐明缓激肽的积累是否参与了ACE-I的作用，以及非ace介导的血管紧张素II的产生是否参与了这些药物的肾保护作用。利用活体CCD摄像技术，血管紧张素受体拮抗剂（E4177）在浅浅肾单位（SP）和髓旁肾单位（JM）中扩张不同（AFF）和输出小动脉（EFF）。随后，西拉普利拉在JM中使AFF和EFF进一步扩张，而在SP中仅使EFF扩张。这些西拉普利引起的血管舒张和尿钠被缓激肽拮抗剂所消除。与这些结果平行，西拉普利拉增加肾缓激肽含量，髓质大于皮质。接下来，通过ace介导的血管紧张素II的产生…更多的ed和非ace介导的途径被检查。在狗肾皮质中，ACE/非ACE介导的ANG II生成的比例为8:2，而在心脏中，这一比例为4:6。在肾脏,当与intrarenally管理的影响和我和(箴ィイD111ィエD1, D-AlaィイD112ィエD1)安吉人(S)(一个安吉人模拟,不能转化为ANG II ACE)在系统性血压(BP)和肾血流量(RBF),需要100倍浓度更高获得同等程度的BP和RBF的变化。进一步的活体针式CCD相机显微镜研究表明，与ANGI相比，S的肾传入和传出小动脉作用减弱。100 nmol S可使RBF减少30%，g ANG受体拮抗剂可完全消除RBF，而凝乳抑素仅能抑制RBF的50%。最后比较慢性ACE-I与真主安拉治疗的疗效。与急性研究相反，ace - i和aiia治疗犬的肾组织中肾内缓激素含量几乎相同。总之，肾缓激素水平的区域异质性和对缓激素反应性的节段性差异导致肾传入和传出小动脉对急性给药ACE-I的不同反应性；ACE-I增强的激肽作用可参与肾小球血流动力学的改变。此外，与ACE活性相比，非ACE活性对肾脏ANG II生成的贡献较小，而乳糜介导的ANG II生成仅占非ACE介导的ANG II生成的一半。然而，慢性治疗未能证明ace -i诱导的肾内缓激素积累在保护肾损伤方面的益处。少

项目成果

林晃一: "腎微小循環におけるアンジオテンシンII作用の新知見"診断と新薬. 36(3). 205-208 (1999)

Koichi Hayashi：“血管紧张素 II 在肾脏微循环中的作用的新发现”《诊断与新药》36(3) (1999)。

Matsuda H: "Potential role of endothelium-derived hyperpolarizing factor(EDHF)induced by ACE-I in renal microcirculation in vivo." Journal of American Society of Nephrology. 9. 342 (1998)

Matsuda H：“ACE-I 诱导的内皮源性超极化因子 (EDHF) 在体内肾微循环中的潜在作用。”

Murakami M, et al.: "Role ofangiotensin II generated by an ACE independent pathway in canine kidney"Nephrology. 3. S53 (1997)

Murakami M 等人：“犬肾中 ACE 独立途径产生的血管紧张素 II 的作用”肾脏病学。

Ozawa Y,et al.: "Renal afferent and efferent arteriolar dilation by nilvadipine : studies in the isolated perfused hydronephrotic kidney." J Cardiovasc Pharmacol. 33. 243-247 (1999)

Ozawa Y 等人：“尼伐地平的肾传入和传出小动脉扩张：离体灌注肾积水肾的研究”。

Hayashi K, et al.: "Potential role of angiotensin receptor antagonists in renal protection."Nippon Rinsho. 57(5). 1164-1167 (1999)

Hayashi K 等人：“血管紧张素受体拮抗剂在肾脏保护中的潜在作用。”Nippon Rinsho。