Hinton Jane M, Langton Philip D
Department of Physiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
Br J Pharmacol. 2003 Mar;138(6):1031-5. doi: 10.1038/sj.bjp.0705171.
It is widely established that in rat mesenteric arteries, endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation evoked by acetylcholine is abolished by a combination of charybdotoxin plus apamin. 4-Aminopyridine, an inhibitor of voltage-gated (Kv) K(+)-channels, in combination with apamin had moderate effects on the EDHF-mediated relaxation. Maurotoxin (MTX), an inhibitor of Kv and intermediate-conductance Ca(2+)-activated K(+)-channels (IK), had no effect on EDHF-mediated relaxation. However, MTX in combination with apamin completely abolished EDHF-mediated relaxation and endothelial cell hyperpolarization. The selective IK inhibitor 2-(2-chlorophenyl)-2,2-diphenyl acetonitrile (TRAM-39) had no significant effect on EDHF-mediated relaxation. EDHF-mediated vasorelaxation and hyperpolarization was abolished by a combination of TRAM-39 and apamin. These data demonstrate two new combinations of K(+)-channel inhibitors for the investigation of EDHF. Furthermore, by using TRAM-39, a potent selective inhibitor of IK channels, we provide the first direct evidence that abolition of EDHF requires the simultaneous presence of intermediate- and small-conductance Ca(2+)-activated K(+)-channel inhibitors.
广泛证实，在大鼠肠系膜动脉中，由乙酰胆碱诱发的内皮源性超极化因子（EDHF）介导的舒张作用可被卡律蝎毒素加蜂毒明肽的组合所消除。4-氨基吡啶是一种电压门控（Kv）钾通道抑制剂，与蜂毒明肽联合使用对EDHF介导的舒张作用有中等程度的影响。毛蝎毒素（MTX）是一种Kv和中电导钙激活钾通道（IK）抑制剂，对EDHF介导的舒张作用无影响。然而，MTX与蜂毒明肽联合使用则完全消除了EDHF介导的舒张作用和内皮细胞超极化。选择性IK抑制剂2-（2-氯苯基）-2,2-二苯基乙腈（TRAM-39）对EDHF介导的舒张作用无显著影响。TRAM-39与蜂毒明肽联合使用可消除EDHF介导的血管舒张和超极化。这些数据证明了两种用于研究EDHF的钾通道抑制剂的新组合。此外，通过使用TRAM-39（一种有效的IK通道选择性抑制剂），我们首次提供了直接证据，即消除EDHF需要同时存在中电导和小电导钙激活钾通道抑制剂。
