Tsvetkov Dmitry, Kaßmann Mario, Tano Jean-Yves, Chen Lan, Schleifenbaum Johanna, Voelkl Jakob, Lang Florian, Huang Yu, Gollasch Maik
Experimental and Clinical Research Center (ECRC), A Joint Cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany.
Br J Pharmacol. 2017 Jan;174(2):150-162. doi: 10.1111/bph.13665. Epub 2016 Dec 20.
K 7.1 voltage-gated potassium channels are expressed in vascular smooth muscle cells (VSMC) of diverse arteries, including mesenteric arteries. Based on pharmacological evidence using R-L3 (K 7.1 channel opener), HMR1556, chromanol 293B (K 7.1 channel blockers), stimulation of these channels has been suggested to evoke profound relaxation in various vascular beds of rats. However, the specificity of these drugs in vivo is uncertain.
We used Kcnq1 mice and pharmacological tools to determine whether K 7.1 channels play a role in the regulation of arterial tone.
R-L3 produced similar concentration-dependent relaxations (EC ~ 1.4 μM) of arteries from wild-type (Kcnq1 ) and Kcnq1 mice, pre-contracted with either phenylephrine or 60 mM KCl. This relaxation was not affected by 10 μM chromanol 293B, 10 μM HMR1556 or 30 μM XE991 (pan-K 7 channel blocker). The anti-contractile effects of the perivascular adipose tissue (PVAT) were normal in Kcnq1 arteries. Chromanol 293B and HMR1556 did not affect the anti-contractile effects of (PVAT). Isolated VSMCs from Kcnq1 mice exhibited normal peak K currents. The K 7.2-5 channel opener retigabine caused similar relaxations in Kcnq1 and wild-type vessels.
We conclude that K 7.1 channels were apparently not involved in the control of arterial tone by α -adrenoceptor agonists and PVAT. In addition, R-L3 is an inappropriate pharmacological tool for studying the function of native vascular K 7.1 channels in mice.
K7.1电压门控钾通道在包括肠系膜动脉在内的多种动脉的血管平滑肌细胞（VSMC）中表达。基于使用R-L3（K7.1通道开放剂）、HMR1556、色满醇293B（K7.1通道阻滞剂）的药理学证据，有人提出刺激这些通道可引起大鼠各种血管床的深度舒张。然而，这些药物在体内的特异性尚不确定。
我们使用Kcnq1基因敲除小鼠和药理学工具来确定K7.1通道是否在动脉张力调节中起作用。
R-L3对预先用去氧肾上腺素或60mM氯化钾预收缩的野生型（Kcnq1 +/+）和Kcnq1基因敲除小鼠的动脉产生了相似的浓度依赖性舒张作用（EC50约为1.4μM）。这种舒张不受10μM色满醇293B、10μM HMR1556或30μM XE991（泛Kv7通道阻滞剂）的影响。Kcnq1基因敲除动脉中血管周围脂肪组织（PVAT）的抗收缩作用正常。色满醇293B和HMR1556不影响PVAT的抗收缩作用。来自Kcnq1基因敲除小鼠的分离VSMC表现出正常的钾电流峰值。K7.2 - 5通道开放剂瑞替加滨在Kcnq1基因敲除和野生型血管中引起相似的舒张作用。
我们得出结论，K7.1通道显然不参与α-肾上腺素能激动剂和PVAT对动脉张力的控制。此外，R-L3是研究小鼠天然血管K7.1通道功能的不合适的药理学工具。
