激肽原缺乏大鼠与正常大鼠内毒素诱导低血压的比较研究。

Comparative study of endotoxin-induced hypotension in kininogen-deficient rats with that in normal rats.

作者信息

Ueno A, Ishida H, Oh-ishi S

机构信息

Department of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.

出版信息

Br J Pharmacol. 1995 Mar;114(6):1250-6. doi: 10.1111/j.1476-5381.1995.tb13340.x.

DOI:10.1111/j.1476-5381.1995.tb13340.x

PMID:7620716

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1510346/

Abstract

The aim of this study was to clarify the role of endogenous bradykinin (BK) in the hypotensive response induced by lipopolysaccharide (LPS) by comparing the degree of hypotension caused by LPS in a strain of specific pathogen-free (SPF) Brown Norway (B/N), kininogen-deficient mutant Katholiek rats with that of B/N normal Kitasato rats. 2. The dose-dependent hypotensive responses caused by intravenous injection of BK (1-100 nmol kg-1) or platelet-activating factor (PAF, 0.003-1 microgram kg-1), were not different in the two strains of rats used. However, there was a strong difference in the hypotensive response induced by LPS in kininogen-deficient and normal rats; in normal rats the hypotensive response was composed of two phases (15 min and 70-80 min after LPS injection), but in kininogen-deficient rats LPS caused a delayed (second phase), but not an acute (first phase) hypotension. 3. We demonstrate that Hoe 140 (1 mg kg-1, i.v.) is a potent, selective, and long-lasting antagonist of the hypotensive effects of BK. Hoe 140 diminished the hypotension caused by LPS in normal rats to the level observed in kininogen-deficient rats, but had no effect on the hypotension caused by LPS in kininogen-deficient rats. 4. TCV309 (0.1 mg kg-1, i.v.) selectively inhibited the hypotension caused by repetitive injection of PAF for up to 180 min. Pretreatment with TCV309 caused a near complete inhibition of the LPS-induced hypotension in kininogen-deficient and normal B/N rats. 5. In the normal rats, dexamethasone (0.5 mg kg-1, i.p.) inhibited the second phase of the hypotension induced by LPS, but not the first phase of the hypotension. 6. A small amount of BK (0.1 nmol kg-1) potentiated the hypotensive action of PAF (0.01 microg kg-1),when they were injected simultaneously.7. In conclusion, we demonstrate that formation of endogenous BK contributes primarily to the acute,but not to the delayed hypotension afforded by endotoxin in the rat. In contrast, formation of endogenous PAF contributes to both the acute and the delayed hypotension afforded by endotoxin in vivo.

摘要

本研究旨在通过比较脂多糖（LPS）在特定病原体-free（SPF）棕色挪威（B/N）品系、激肽原缺陷突变体Katholiek大鼠与B/N正常北里大鼠中引起的低血压程度，阐明内源性缓激肽（BK）在LPS诱导的低血压反应中的作用。2. 静脉注射BK（1 - 100 nmol kg-1）或血小板活化因子（PAF，0.003 - 1微克 kg-1）引起的剂量依赖性低血压反应在所用的两种品系大鼠中并无差异。然而，LPS在激肽原缺陷和正常大鼠中诱导的低血压反应存在强烈差异；在正常大鼠中，低血压反应由两个阶段组成（LPS注射后15分钟和70 - 80分钟），但在激肽原缺陷大鼠中，LPS引起延迟性（第二阶段）而非急性（第一阶段）低血压。3. 我们证明Hoe 140（1 mg kg-1，静脉注射）是BK降压作用的一种强效、选择性且长效的拮抗剂。Hoe 140将正常大鼠中LPS引起的低血压降低至激肽原缺陷大鼠中观察到的水平，但对激肽原缺陷大鼠中LPS引起的低血压无影响。4. TCV309（0.1 mg kg-1，静脉注射）选择性抑制重复注射PAF长达180分钟所引起的低血压。用TCV309预处理可使激肽原缺陷和正常B/N大鼠中LPS诱导的低血压几乎完全受到抑制。5. 在正常大鼠中，地塞米松（0.5 mg kg-1，腹腔注射）抑制LPS诱导的低血压的第二阶段，但不抑制第一阶段。6. 当同时注射少量BK（0.1 nmol kg-1）和PAF（0.01微克 kg-1）时，BK增强了PAF的降压作用。7. 总之，我们证明内源性BK的形成主要导致大鼠体内内毒素引起急性低血压，而非延迟性低血压。相反，内源性PAF的形成对体内内毒素引起的急性和延迟性低血压均有作用。