参与脑动脉中内皮衍生超极化因子介导舒张作用的钾通道的特性研究

Characterization of the potassium channels involved in EDHF-mediated relaxation in cerebral arteries.

作者信息

Petersson J, Zygmunt P M, Högestätt E D

机构信息

Department of Clinical Pharmacology, Lund University Hospital, Sweden.

出版信息

Br J Pharmacol. 1997 Apr;120(7):1344-50. doi: 10.1038/sj.bjp.0701032.

DOI:10.1038/sj.bjp.0701032

PMID:9105711

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1564595/

Abstract

In the presence of NG-nitro-L-arginine (L-NOARG, 0.3 mM) and indomethacin (10 microM), the relaxations induced by acetylcholine and the calcium (Ca) ionophore A23187 are considered to be mediated by endothelium-derived hyperpolarizing factor (EDHF) in the guinea-pig basilar artery. 2. Inhibitors of adenosine 5'-triphosphate (ATP)-sensitive potassium (K)-channels (KATP; glibenclamide, 10 microM), voltage-sensitive K-channels (Kv; dendrotoxin-1, 0.1 microM or 4-aminopyridine, 1 mM), small (SKCa; apamin, 0.1 microM) and large (BKCa; iberiotoxin, 0.1 microM) conductance Ca-sensitive K-channels did not affect the L-NOARG/indomethacin-resistant relaxation induced by acetylcholine. 3. Synthetic charybdotoxin (0.1 microM), an inhibitor of BKCa and Kv, caused a rightward shift of the concentration-response curve for acetylcholine and reduced the maximal relaxation in the presence of L-NOARG and indomethacin, whereas the relaxation induced by A23187 was not significantly inhibited. 4. A combination of charybdotoxin (0.1 microM) and apamin (0.1 microM) abolished the L-NOARG/ indomethacin-resistant relaxations induced by acetylcholine and A23187. However, the acetylcholine-induced relaxation was not affected by a combination of iberiotoxin (0.1 microM) and apamin (0.1 microM). 5. Ciclazindol (10 microM), an inhibitor of Kv in rat portal vein smooth muscle, inhibited the L-NOARG/ indomethacin-resistant relaxations induced by acetylcholine and A23187, and the relaxations were abolished when ciclazindol (10 microM) was combined with apamin (0.1 microM). 6. Human pial arteries from two out of four patients displayed an L-NOARG/indomethacin-resistant relaxation in response to substance P. This relaxation was abolished in both cases by pretreatment with the combination of charybdotoxin (0.1 microM) and apamin (0.1 microM), whereas each toxin had little effect alone. 7. The results suggest that Kv, but not KATP and BKCa, is involved in the EDHF-mediated relaxation in the guinea-pig basilar artery. The synergistic action of apamin and charybdotoxin (or ciclazindol) could indicate that both Kv and SKCa are activated by EDHF. However, a single type of K-channel, which may be structurally related to Kv and allosterically regulated by apamin, could also be the target for EDHF.

摘要

在存在NG-硝基-L-精氨酸（L-NOARG，0.3 mM）和吲哚美辛（10 microM）的情况下，乙酰胆碱和钙离子载体A23187诱导的豚鼠基底动脉舒张被认为是由内皮衍生超极化因子（EDHF）介导的。2. 三磷酸腺苷（ATP）敏感性钾（K）通道（KATP；格列本脲，10 microM）、电压敏感性钾通道（Kv；树突毒素-1，0.1 microM或4-氨基吡啶，1 mM）、小电导钙敏感性钾通道（SKCa；蜂毒明肽，0.1 microM）和大电导钙敏感性钾通道（BKCa；iberiotoxin，0.1 microM）的抑制剂均不影响乙酰胆碱诱导的对L-NOARG/吲哚美辛耐药的舒张。3. 合成的蝎毒素（0.1 microM），一种BKCa和Kv的抑制剂，使乙酰胆碱的浓度-反应曲线向右移动，并在存在L-NOARG和吲哚美辛的情况下降低最大舒张，而A23187诱导的舒张未被显著抑制。4. 蝎毒素（0.1 microM）和蜂毒明肽（0.1 microM）的组合消除了乙酰胆碱和A23187诱导的对L-NOARG/吲哚美辛耐药的舒张。然而，乙酰胆碱诱导的舒张不受iberiotoxin（0.1 microM）和蜂毒明肽（0.1 microM）组合的影响。5. 西氯他宁（10 microM），大鼠门静脉平滑肌中Kv的抑制剂，抑制了乙酰胆碱和A23187诱导的对L-NOARG/吲哚美辛耐药的舒张，当西氯他宁（10 microM）与蜂毒明肽（0.1 microM）联合使用时，舒张被消除。6. 四名患者中有两名患者的人脑膜动脉对P物质表现出对L-NOARG/吲哚美辛耐药的舒张。在这两种情况下，用蝎毒素（0.1 microM）和蜂毒明肽（0.1 microM）的组合预处理后，这种舒张被消除，而每种毒素单独作用时影响很小。7. 结果表明，Kv而非KATP和BKCa参与了豚鼠基底动脉中EDHF介导的舒张。蜂毒明肽和蝎毒素（或西氯他宁）的协同作用可能表明Kv和SKCa均被EDHF激活。然而，一种可能在结构上与Kv相关并受蜂毒明肽变构调节的单一类型钾通道也可能是EDHF的作用靶点。