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）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。本研究的目的是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的产生是否参与这些药物的肾脏保护。应用活体CCD摄像技术，观察血管紧张素受体拮抗剂（E4177）扩张浅肾单位（SP）和髓质肾单位（JM）的不同小动脉（AFF）和输出小动脉（EFF）。随后，cilazaprilat引起JM的AFF和EFF进一步扩张，而SP仅扩张EFF。这些西拉普利诱导的血管舒张和钠尿排泄被缓激肽拮抗剂消除。与这些结果平行，西拉普利拉增加肾缓激肽含量，在髓质比在皮质更大。接下来，通过ACE介导的血管紧张素II的产生， ...更多信息 检测了艾德和非ACE介导的途径。在狗肾皮质中，ACE/非ACE介导的ANG II生成比例为8：2，而在心脏中，该值为4：6。在肾脏中，当与肾内给予ANG I和[脯氨酸D111脯氨酸D1，D-Ala脯氨酸D112脯氨酸D1]-ANG I（S）（一种不能被ACE转化为ANG II的ANG I类似物）对全身血压（BP）和肾血流量（RBF）的影响相比时，S需要高100倍的浓度才能获得相同程度的BP和RBF变化。使用活体针型CCD摄像显微镜的进一步研究表明，与ANGI相比，S的肾传入和传出小动脉作用减弱。100 nmol的S使RBF下降30%，g ANG受体拮抗剂可完全阻断S的作用，而糜蛋白酶抑制剂仅抑制50%。最后，对ACE-I和AllA慢性治疗的疗效进行了比较。与急性研究相反，ACE-I和AIIA治疗犬肾组织中的缓激肽含量几乎相同。总之，肾缓激肽水平的区域异质性和对缓激肽的反应性的节段差异有助于肾传入和传出小动脉对ACE-I急性给药的不同反应; 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。与ACE活性相比，非ACE活性的Fuglycine对肾脏ANG II生成的贡献较小，并且糜酶介导的ANG II生成仅占非ACE介导的ANG II生成的一半。然而，慢性治疗未能证明ACE-I诱导的肾内缓激肽蓄积在保护肾损伤中的益处。少

项目成果

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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。