正常血压大鼠中缓激肽和一氧化氮诱导的低血压中的信号通路；钾通道的作用

Signalling pathways in bradykinin- and nitric oxide-induced hypotension in the normotensive rat; role of K+-channels.

作者信息

Berg T, Koteng O

机构信息

Department of Physiology, Institute for Basic Medical Sciences, The Medical Faculty, University of Oslo, Norway.

出版信息

Br J Pharmacol. 1997 Jul;121(6):1113-20. doi: 10.1038/sj.bjp.0701246.

DOI:10.1038/sj.bjp.0701246

PMID:9249246

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1564804/

Abstract

Bradykinin and nitric oxide (NO) are potent hypotensive agents. In the present study, the role of K+-channels in the signalling pathways responsible for their hypotensive action was investigated in normotensive, anaesthetized rats. The rats were treated with ion-channel inhibitors before administration of bradykinin (2.8, 5.6, 28 and 56 nmol kg(-1), i.v.) followed in some of the protocols by nitroprusside (1.1, 3.5, 7, 14, and 28 nmol kg(-1), i.v.). 2. No attenuation of the hypotensive response to bradykinin was detected for inhibitors of the Na-K-Cl-cotransporter (30 micromol kg(-1) furosemide), the ATP-sensitive K+-channel (40 micromol kg(-1) glibenclamide), high conductance Ca2+-activated K+-channel (180 micromol kg(-1) tetraethylammonium, 54 micromol kg(-1) tetrabutylammonium, 35 nmol kg(-1) iberiotoxin, 35 nmol kg(-1) charybdotoxin) or the low conductance Ca2+-activated K+-channel (74 nmol kg(-1) apamin). 3. However, the voltage-sensitive K+-channel (I(A)) inhibitor 4-aminopyridine (4.05-40.5 micromol kg(-1)) induced a concentration-dependent (P<0.0001) attenuation of the hypotensive response (P<0.0001). Bradykinin had no effect on heart rate in anaesthetized rats and this observation was not altered by pretreatment with 4-aminopyridine. 4. 4-Aminopyridine (53 micromol kg(-1)) also significantly attenuated the hypotensive response to nitroprusside (P<0.0003) without altering the heart rate concentration-response curve. Of the two Ca2+-activated K+-channel inhibitors tested on nitroprusside-induced hypotension, tetrabutylammonium induced a slight attenuation (P<0.0101), whereas iberiotoxin had no effect. 5. We therefore concluded that, although the acute hypotensive response to bradykinin in the normotensive rat is not mediated through nitric oxide synthesis, the hypotensive response to both agents was mediated through opening of voltage-sensitive K+-channels (I(A)), resulting in a decrease in peripheral vascular resistance.

摘要

缓激肽和一氧化氮（NO）是强效降压剂。在本研究中，我们在正常血压、麻醉的大鼠中研究了钾通道在其降压作用相关信号通路中的作用。在静脉注射缓激肽（2.8、5.6、28和56 nmol kg⁻¹）之前，用离子通道抑制剂处理大鼠，在某些实验方案中随后静脉注射硝普钠（1.1、3.5、7、14和28 nmol kg⁻¹）。2. 未检测到钠 - 钾 - 氯共转运体抑制剂（30 μmol kg⁻¹ 呋塞米）、ATP敏感性钾通道抑制剂（40 μmol kg⁻¹ 格列本脲）、高电导钙激活钾通道抑制剂（180 μmol kg⁻¹ 四乙铵、54 μmol kg⁻¹ 四丁铵、35 nmol kg⁻¹ iberiotoxin、35 nmol kg⁻¹ 蝎毒素）或低电导钙激活钾通道抑制剂（74 nmol kg⁻¹ 蜂毒明肽）对缓激肽降压反应的减弱作用。3. 然而，电压敏感性钾通道（I(A)）抑制剂4 - 氨基吡啶（4.05 - 40.5 μmol kg⁻¹）诱导了降压反应的浓度依赖性（P<0.0001）减弱（P<0.0001）。缓激肽对麻醉大鼠的心率无影响，且该观察结果不受4 - 氨基吡啶预处理的改变。4. 4 - 氨基吡啶（53 μmol kg⁻¹）也显著减弱了对硝普钠的降压反应（P<0.0003），而不改变心率浓度 - 反应曲线。在测试的两种钙激活钾通道抑制剂对硝普钠诱导的低血压作用中，四丁铵诱导了轻微减弱（P<0.0101），而iberiotoxin无作用。5. 因此我们得出结论，尽管正常血压大鼠对缓激肽的急性降压反应不是通过一氧化氮合成介导的，但对这两种药物的降压反应都是通过电压敏感性钾通道（I(A)）的开放介导的，导致外周血管阻力降低。