Dmitry Tsvetkov1,2, Mario Kaßmann1, Jean-Yves Tano1, Lan Chen1,3, Johanna Schleifenbaum1, Jakob Voelkl4, Florian Lang4, Yu Huang5, Maik Gollasch1,6. 1. 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. 2. 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. 3. Xiamen Zhongshan Hospital, Xiamen University, Xiamen, China. 4. Department of Cardiology, Vascular Medicine and Physiology, University of Tübingen, Tübingen, Germany. 5. School of Biomedical Sciences, 223A, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Chinese University of Hong Kong, Sha Tin, Hong Kong. 6. Medical Clinic for Nephrology and Internal Intensive Care, Campus Virchow, Charité University Medicine, Berlin, Germany.
Abstract
BACKGROUND AND PURPOSE: KV 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 (KV 7.1 channel opener), HMR1556, chromanol 293B (KV 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. EXPERIMENTAL APPROACH: We used Kcnq1-/- mice and pharmacological tools to determine whether KV 7.1 channels play a role in the regulation of arterial tone. KEY RESULTS: R-L3 produced similar concentration-dependent relaxations (EC50 ~ 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-KV 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 KV currents. The KV 7.2-5 channel opener retigabine caused similar relaxations in Kcnq1-/- and wild-type vessels. CONCLUSION AND IMPLICATIONS: We conclude that KV 7.1 channels were apparently not involved in the control of arterial tone by α1 -adrenoceptor agonists and PVAT. In addition, R-L3 is an inappropriate pharmacological tool for studying the function of native vascular KV 7.1 channels in mice.
BACKGROUND AND PURPOSE: KV 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 (KV 7.1 channel opener), HMR1556, chromanol 293B (KV 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. EXPERIMENTAL APPROACH: We used Kcnq1-/- mice and pharmacological tools to determine whether KV 7.1 channels play a role in the regulation of arterial tone. KEY RESULTS:R-L3 produced similar concentration-dependent relaxations (EC50 ~ 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-KV 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 KV currents. The KV 7.2-5 channel opener retigabine caused similar relaxations in Kcnq1-/- and wild-type vessels. CONCLUSION AND IMPLICATIONS: We conclude that KV 7.1 channels were apparently not involved in the control of arterial tone by α1 -adrenoceptor agonists and PVAT. In addition, R-L3 is an inappropriate pharmacological tool for studying the function of native vascular KV 7.1 channels in mice.
Authors: Fu Liang Ng; Alison J Davis; Thomas A Jepps; Maksym I Harhun; Shuk Yin Yeung; Andrew Wan; Marcus Reddy; David Melville; Antonio Nardi; Teck K Khong; Iain A Greenwood Journal: Br J Pharmacol Date: 2011-01 Impact factor: 8.739
Authors: Michael J Curtis; Richard A Bond; Domenico Spina; Amrita Ahluwalia; Stephen P A Alexander; Mark A Giembycz; Annette Gilchrist; Daniel Hoyer; Paul A Insel; Angelo A Izzo; Andrew J Lawrence; David J MacEwan; Lawrence D F Moon; Sue Wonnacott; Arthur H Weston; John C McGrath Journal: Br J Pharmacol Date: 2015-07 Impact factor: 8.739
Authors: M C Casimiro; B C Knollmann; S N Ebert; J C Vary; A E Greene; M R Franz; A Grinberg; S P Huang; K Pfeifer Journal: Proc Natl Acad Sci U S A Date: 2001-02-27 Impact factor: 11.205