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Aims: To test specific mono-agonists to the glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR) and glucose-dependent insulinotropic peptide receptor (GIPR), individually and in combination, in a mouse model of diet-induced non-alcoholic steatohepatitis (NASH) and fibrosis in order to decipher the contribution of their activities and potential additive effects to improving systemic and hepatic metabolism., Materials and Methods: We induced NASH by pre-feeding C57BL/6J mice a diet rich in fat, fructose and cholesterol for 36 weeks. This was followed by 8 weeks of treatment with the receptor-specific agonists 1-GCG (20 μg/kg twice daily), 2-GLP1 (3 μg/kg twice daily) or 3-GIP (30 μg/kg twice daily), or the dual (1 + 2) or triple (1 + 2 + 3) combinations thereof. A dual GLP-1R/GCGR agonistic peptide, 4-dual-GLP1/GCGR (30 μg/kg twice daily), and liraglutide (100 μg/kg twice daily) were included as references., Results: Whereas low-dose 1-GCG or 3-GIP alone did not influence body weight, liver lipids and histology, their combination with 2-GLP1 provided additional weight loss, reduction in liver triglycerides and improvement in histological disease activity score. Notably, 4-dual-GLP-1R/GCGR and the triple combination of selective mono-agonists led to a significantly stronger reduction in the histological non-alcoholic fatty liver disease activity score compared to high-dose liraglutide, at the same extent of body weight loss., Conclusions: GCGR and GIPR agonism provide additional, body weight-independent improvements on top of GLP-1R agonism in a murine model of manifest NASH with fibrosis., (© 2020 John Wiley & Sons Ltd.)

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.)