Inhibitory effects of openers of large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channels on agonist-induced phasic contractions in rabbit and mouse bronchial smooth muscle

Bradley, Eamonn; Large, Roddy J.; Bihun, Viktoriia Volodymyrivna; Mullins, Nicolas D.; Hollywood, Mark A.; Sergeant, Gerard P.; Thornbury, Keith D.

doi:10.1152/ajpcell.00068.2018

Cited by 7 publications

(4 citation statements)

References 47 publications

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“…The efficacy of some of them has been reported to depend on the presence of BK channel regulatory β and γ‐subunits (Kshatri et al, ; Large et al, ; Webb et al, ). These compounds, in particular GoSlo‐SR‐5‐130 and GoSlo‐SR‐5‐6,activated BK channels in freshly isolated smooth muscle cells from rabbit bladder (Large et al, ), rabbit corpus cavernosum (Hannigan et al, ), and bronchial smooth muscle (Bradley et al, ). Furthermore, Webb et al () demonstrated that the effects of GoSlo‐SR‐5‐6 were reduced by >80%, when a triplet of mutations were introduced on the S4/S5 linker and S6 helix.…”

Section: Introductionmentioning

confidence: 99%

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

Zavaritskaya

Dudem

et al. 2020

British J Pharmacology

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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 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.

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Section: Introductionmentioning

confidence: 99%

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

Zavaritskaya

Dudem

et al. 2020

British J Pharmacology

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“…42) But it has also been reported that Ca 2+ signaling can relax artery smooth muscle and ASMCs by activation of BK channels. 43,44,45) In ASMCs, Ca 2+ signaling induced by the activation of bitter taste receptors opens BK channels and thus induces membrane hyperpolarization and the relaxation of ASMCs. 21) Besides the opening of BK channels, the inhibition of voltage-dependent L-type Ca 2+ channels and non-selective cation channels have also been suggested to be involved in TAS2Rs-triggered relaxation of ASMCs.…”

Section: Discussionmentioning

confidence: 99%

Chemical Activation of Piezo1 Alters Biomechanical Behaviors toward Relaxation of Cultured Airway Smooth Muscle Cells

Luo

et al. 2023

Biological & Pharmaceutical Bulletin

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Inspired by the well-known phenomenon of stretch-induced airway dilation in normal lungs and the emerging stretch-responsive Piezo1 channels that can be chemically activated by specific agonists such as Yoda1, we attempted to investigate whether chemical activation of Piezo1 by Yoda1 can modulate the biomechanical behaviors of airway smooth muscle cells (ASMCs) so that it may be exploited as a novel approach for bronchodilation. Thus, we treated in vitro cultured rat ASMCs with Yoda1, and examined the cells for calcium signaling, cell stiffness, traction force, cell migration, and the mRNA expression and distribution of molecules relevant to cell biomechanics. The data show that ASMCs expressed abundant mRNA of Piezo1. ASMCs exposed to 1 µM Yoda1 exhibited a potent but transient Ca 2 signaling, and treatment with 1 µM Yoda1 for 24 h led to decreased cell stiffness and traction force, all of which were partially reversed by Piezo1 inhibitor GsMTx4 and Piezo1 knockdown, respectively. In addition, ASMCs treated with 1 µM Yoda1 for 24 h exhibited impaired horizontal but enhanced vertical cell migration, as well as significant changes in key components of cells' contractile machinery including the structure and distribution of stress fibers and alphasmooth muscle actin (α-SMA) fibrils, the mRNA expression of molecules associated with cell biomechanics. These results provide the first evidence that chemical activation of Piezo1 by Yoda1 resulted in marked prorelaxation alterations of biomechanical behaviors and contractile machinery of the ASMCs. These findings suggest that Piezo1-specific agonists may indeed have great potential as alternative drug agents for relaxing ASMCs.

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“…The bronchial tree was exposed by sharp dissection under a microscope to remove surrounding blood vessels and lung tissue. 22 The left and right bronchi were removed and cut into rings and placed in Krebs solution.…”

Section: Methodsmentioning

confidence: 99%

M2 Muscarinic Receptor-Dependent Contractions of Airway Smooth Muscle are Inhibited by Activation of β-Adrenoceptors

et al. 2022

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Beta-adrenoceptor (β-AR) agonists inhibit cholinergic contractions of airway smooth muscle (ASM), but the underlying mechanisms are unclear. ASM cells express M3 and M2 muscarinic receptors, but the bronchoconstrictor effects of acetylcholine are believed to result from activation of M3Rs, while the role of the M2Rs confined to offsetting β-AR-dependent relaxations. However, a profound M2R-mediated hypersensitization of M3R-dependent contractions of ASM was recently reported, indicating an important role for M2Rs in cholinergic contractions of ASM. Here we investigated if M2R-dependent contractions of murine bronchial rings were inhibited by activation of β-ARs. M2R-dependent contractions of murine ASM were apparent at low frequency (2Hz) electric field stimulation (EFS) and when the stimulus interval was reduced from 100 to 10s. The β1-AR agonist, denopamine inhibited EFS-evoked contractions of ASM induced by reduction in stimulus interval from 100 to 10s and was more effective at inhibiting contractions evoked by EFS at 2Hz than 20Hz. Denopamine also abolished carbachol-evoked contractions that were resistant to the M3R antagonist 4-DAMP, similar to the effects of the M2R antagonists, methoctramine and AFDX-116. The inhibitory effects of denopamine on EFS-evoked contractions of ASM were smaller in preparations taken from M2R−/− mice, compared to wild-type controls. In contrast, inhibitory effects of the β3-AR agonist, BRL-37344, on EFS-evoked contractions of detrusor strips taken from M2R−/− mice were greater than wild-type controls. These data suggest that M2R-dependent contractions of ASM were inhibited by activation of β1-ARs and that genetic ablation of M2Rs decreased the efficacy of β-AR agonists on cholinergic contractions.

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Inhibitory effects of openers of large-conductance Ca²⁺-activated K⁺ channels on agonist-induced phasic contractions in rabbit and mouse bronchial smooth muscle

Cited by 7 publications

References 47 publications

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

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

Chemical Activation of Piezo1 Alters Biomechanical Behaviors toward Relaxation of Cultured Airway Smooth Muscle Cells

M2 Muscarinic Receptor-Dependent Contractions of Airway Smooth Muscle are Inhibited by Activation of β-Adrenoceptors

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Inhibitory effects of openers of large-conductance Ca2+-activated K+ channels on agonist-induced phasic contractions in rabbit and mouse bronchial smooth muscle

Cited by 7 publications

References 47 publications

Vasodilation of rat skeletal muscle arteries by the novel BK channel opener GoSlo is mediated by the simultaneous activation of BK and Kv7 channels

Vasodilation of rat skeletal muscle arteries by the novel BK channel opener GoSlo is mediated by the simultaneous activation of BK and Kv7 channels

Chemical Activation of Piezo1 Alters Biomechanical Behaviors toward Relaxation of Cultured Airway Smooth Muscle Cells

M2 Muscarinic Receptor-Dependent Contractions of Airway Smooth Muscle are Inhibited by Activation of β-Adrenoceptors

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Inhibitory effects of openers of large-conductance Ca²⁺-activated K⁺ channels on agonist-induced phasic contractions in rabbit and mouse bronchial smooth muscle

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

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