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Kinetics of Rena1 Dispositon and Pharmacological Effect of Peptides

Rena1 处置动力学及肽的药理作用

基本信息

批准号：
04671326
负责人：
YASUHARA Masato
金额：
$ 1.34万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671326/
关键词：
Peptide drugs Natriuretic peptide Atrial natriuretic peptide Brain natriuretic Peptide Granulocyte-colony stimulating factor Isolated kidney perfusion C1earance Receptor 培養腎尿細管上皮細胞

项目摘要

Recent discovery of various bioactive peptides prompted their application to the treatment of dlseases, and the kidney is recognized as an important organ to regulate the disposition of peptide drugs. In the present study, we have investigated the renal disposition of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and granulocyte-colony stimulating factor (GCSF) in rats, and kinetically analyzed the pharmacologic effect of peptides.1. The isolated perfusion study of rat kidney has shown that the major elimination route of GCSF in the kidney is the glomerular filtration and the filtrated GCSF could be transferred into the renal tissue from the luminal side by the saturable process.2. The filtration fraction and the renal distribution of asialo-GCSF were greater than those of disialo- and monosialo-GCSF.A GCSF conjugate with poly-(stirene-co-maleic acid) was able to escape from glomerular filtration and showed a higher neutrophil-proliferating activity- after i.v.administration to rats compared to GCSF.3. The population analysis enabled quantification of net diuretic activities of ANP and BNP, and also assessment of the effects of hemodynamic change and an inhibitor of neutral endopeptidase.4. Utilizing LLC-PK_1 cell monolayrs cultured on permeable supports, the presence of natriuretic peptide receptors was indicated in both the apical and basolateral membranes in the kidney epithelial cells.

新近发现的各种生物活性多肽促进了它们在糖尿病治疗中的应用，肾脏被认为是调节多肽药物处置的重要器官。本实验研究了心钠素(ANP)、脑利钠肽(BNP)和粒细胞集落刺激因子(GCSF)在大鼠肾脏的分布，并对其药理作用进行了动力学分析。结论：1.大鼠肾脏离体灌注法研究表明，GCSF在肾脏中的主要清除途径是肾小球滤过，过滤后的GCSF可通过饱和过程从管腔侧进入肾组织。Assialo-GCSF的滤过分数和肾组织分布大于双唾液和单唾液GCSF。与GCSF相比，GCSF与聚(苯乙烯-马来酸)的结合物能够逃脱肾小球滤过，并显示出更高的中性粒细胞增殖活性。群体分析可以量化ANP和BNP的净利尿活性，也可以评估血流动力学变化和中性内肽酶抑制剂的影响。利用体外培养的LLC-PK_1细胞单层细胞，在肾上皮细胞的顶膜和基侧膜上均可见利钠肽受体的存在。