Vasodilation of rat skeletal muscle arteries by the novel BK channel opener GoSlo is mediated by the simultaneous activation of BK and K_v7 channels

Abstract

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 Kv7 channel inhibitor XE991 reduced their effects considerably, but neither Kv1 nor Kv2 channel blockers altered the inhibitory effects of GoSlo‐SR. However, the combined blockade of BK and Kv7 channels abolished the GoSlo‐SR‐induced relaxation. GoSlo‐SR compounds also activated Kv7.4 and Kv7.5 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 Kv7.4/Kv7.5 channels. Activation of Kv1, Kv2 or Kv7.1 channels or other vasodilator pathways seems not to be involved.

Electrophysiological characterization of the activating action of a novel liposomal nitric oxide carrier on Maxi-K channels in pulmonary artery smooth muscle cells

“…GoSlo (Webb et al, 2015). However, the introduction of such drugs into clinical practice has been much less spectacular, not in the least because they show multiple off target effects including inhibition of voltage-gated Ca 2+ channels (Bentzen et al, 2014) and activation of other types of K + channels (Zavaritskaya et al, 2020). Therefore, in clinical practice nitroglycerin and sodium nitroprusside are still widely used as NO donors that affect among other molecular targets activity of Maxi-K channels.…”

The Functional Availability of Arterial Kv7 Channels Is Suppressed Considerably by Large-Conductance Calcium-Activated Potassium Channels in 2- to 3-Month Old but Not in 10- to 15-Day Old Rats

“…In summary, due to the smaller driving force and the decreased membrane resistance after activating BK channels, changes in Kv7 channel activity, induced by either blockers or openers, will result in a smaller change in membrane potential and vessel tension. Of note, this reasoning has been successfully applied to explain the differential effects of dual Kv7 and BK channel opener substances, GoSlo compounds (Zavaritskaya et al, 2020).…”

“…Taking into account the considerable differences in experimental conditions between patch-clamp studies on channels or currents and myography experiments on intact vessels, this IC 50 value was used as a first orientation. Additionally, recent data were considered where we found that in an intact vessel preparation the effect of a Kv7 channel opener was inhibited by 3 * 10 −6 M XE991 and 10 −5 M XE991 to the same degree (Zavaritskaya et al, 2020). In addition, unpublished data on gracilis arteries showed that the effect of 3 * 10 −5 M XE991 on spontaneous myogenic tone was smaller compared to 3 * 10 −6 M XE991 and 10 −5 M XE991 pointing to an unspecific effect at this high concentration.…”

“…Of note, whereas XE991, IBTX and retigabine have been used at the reported concentrations in intact vessels as selective tools to study the function of Kv7 and BK channels previously (Galvez et al, 1990;Wickenden et al, 2000;Yeung and Greenwood, 2005;Ng et al, 2011;Hannigan et al, 2016;Gollasch et al, 2018;Shvetsova et al, 2019;Zavaritskaya et al, 2020), the BK channel opener NS19504 has not been explored on intact vessels before. The data of the present study show, that effects not related to BK channels, i.e., not blocked by IBTX, are observed at higher concentrations of NS19504 (10 −5 M).…”

Detrusor Smooth Muscle KV7 Channels: Emerging New Regulators of Urinary Bladder Function

“…A number of prior reviews describe in detail K V 7 channels in smooth muscle and other cell types including regulatory mechanisms under normal and pathophysiological conditions ( Stott et al, 2014 ; Barrese et al, 2018b ; Byron and Brueggemann, 2018 ; Nappi et al, 2020 ). For non-bladder smooth muscle, transcript and protein expressions of K V 7 channels as well as functional roles (patch-clamp electrophysiology and contractility) have been revealed in arteries (cerebral, basal, mesenteric, renal, gracilis, penile, and visceral adipose), portal vein, airway, gastrointestinal tract, uterus, and corpus cavernosum ( Yeung and Greenwood, 2005 ; Yeung et al, 2008 ; Jepps et al, 2009 ; McCallum et al, 2009 ; Zhong et al, 2010 ; Ipavec et al, 2011 ; Mani et al, 2011 , 2013 ; McCallum et al, 2011 ; Ng et al, 2011 ; Brueggemann et al, 2012a , 2014 , 2018 ; Evseev et al, 2013 ; Chadha et al, 2014 ; Jepps et al, 2016 ; Barrese et al, 2018a ; Stott et al, 2018 ; Zavaritskaya et al, 2020 ). The expression profiles of K V 7 channel subtypes differ substantially based on smooth muscle cell (SMC) type.…”