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Background and Purpose: BK channels play important roles in various physiological and pathophysiological processes and thus have been the target of several drug development programmes focused on creating new efficacious BK channel openers, such as the GoSlo-SR compounds. However, the effect of GoSlo-SR compounds on vascular smooth muscle has not been studied. Therefore, we tested the hypothesis that GoSlo-SR compounds dilate arteries exclusively by activating BK channels., Experimental Approach: Experiments were performed on rat Gracilis muscle, saphenous, mesenteric and tail arteries using isobaric and isometric myography, sharp microelectrodes, digital droplet PCR and the patch-clamp technique., Key Results: GoSlo-SR compounds dilated isobaric and relaxed and hyperpolarised isometric vessel preparations and their effects were abolished after (a) functionally eliminating K + channels by pre-constriction with 50 mM KCl or (b) blocking all K + channels known to be expressed in vascular smooth muscle. However, these effects were not blocked when BK channels were inhibited. Surprisingly, the K v 7 channel inhibitor XE991 reduced their effects considerably, but neither K v 1 nor K v 2 channel blockers altered the inhibitory effects of GoSlo-SR. However, the combined blockade of BK and K v 7 channels abolished the GoSlo-SR-induced relaxation. GoSlo-SR compounds also activated K v 7.4 and K v 7.5 channels expressed in HEK 293 cells., Conclusion and Implications: This study shows that GoSlo-SR compounds are effective relaxants in vascular smooth muscle and mediate their effects by a combined activation of BK and K v 7.4/K v 7.5 channels. Activation of K v 1, K v 2 or K v 7.1 channels or other vasodilator pathways seems not to be involved., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background and Purpose: K V 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 V 7.1 channel opener), HMR1556, chromanol 293B (K V 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 K V 7.1 channels play a role in the regulation of arterial tone., Key Results: R-L3 produced similar concentration-dependent relaxations (EC 50  ~ 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 V 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 V currents. The K V 7.2-5 channel opener retigabine caused similar relaxations in Kcnq1 -/- and wild-type vessels., Conclusion and Implications: We conclude that K V 7.1 channels were apparently not involved in the control of arterial tone by α 1 -adrenoceptor agonists and PVAT. In addition, R-L3 is an inappropriate pharmacological tool for studying the function of native vascular K V 7.1 channels in mice., (© 2016 The British Pharmacological Society.)