Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response

Oliveira, Mariana Gonçalves de; Rojas-Moscoso, Julio Alejandro; Bertollotto, Gabriela Maria; Candido, Tuany Z.; Kiguti, Luiz Ricardo de Almeida; Pupo, André S.; Antunes, Edson; Nucci, Gilberto De; Mónica, Fabíola Z.

doi:10.1016/j.ejphar.2019.172447

Cited by 11 publications

(6 citation statements)

References 49 publications

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“…Rats in both groups were administered saline orally for 7 days. Ulcerated animals in groups 3 and 4 received carvedilol (CR; Selleckchem, TX, USA) at doses of 15 and 30 mg/kg ( Fatani et al, 2015 ), whereas rats in group 5 were treated with mirabegron (MA; 30 mg/kg; Selleckchem, TX, USA) based on a pilot study testing 3 ( Hatanaka et al, 2013 ), 10 ( Sawada et al, 2013 ), and 30 mg/kg ( de Oliveira et al, 2019 ; Supplementary Figures S1, S2 ). In the last group, ulcerated rats received a combination of mirabegron with the low dose of carvedilol (MA+CR15).…”

Section: Methodsmentioning

confidence: 99%

The novel anti-colitic effect of β-adrenergic receptors via modulation of PS1/BACE-1/Aβ axis and NOTCH signaling in an ulcerative colitis model

et al. 2022

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Although dysautonomia was documented in inflammatory bowel disease, with activation of the stress-related sympathetic system, the role of agonists/antagonists of the adrenergic receptors is not conclusive. Moreover, ulcerative colitis was recently linked to dementia, but the potential role of the presenilin 1(PS1)/BACE-1/beta-amyloid (Aβ) axis has not been evaluated. Hence, we investigated the impact of mirabegron (β3-agonist) and/or carvedilol (β1/β2 antagonist) on iodoacetamide-induced ulcerative colitis with emphasis on the novel pathomechanism of the PS1/BACE-1/Aβ axis in ulcerative colitis, and its relation to the inflammatory cascade, fibrotic processes, and the gut barrier dysfunction. Ulcerated rats were either left untreated or treated for 8 days with mirabegron and/or carvedilol. Besides minimizing colon edema and weight loss, and improving colon structure, mirabegron and/or carvedilol abated colonic PS1/BACE-1/Aβ axis and the NOTCH1/NICD/HES1 hub besides the inflammatory cascade GSK3-β/NF-κΒ/TNF-α, and the oxidative stress marker malondialdehyde. The anti-fibrotic effect was verified by boosting SMAD-7 and inhibiting TGF-β1, α-SMA immunoexpression, and MTC staining. Moreover, the drugs improved the gut barrier function, attested by the increased goblet cells and expression of E-cadherin, and the inhibited expression of p(Y654)-β-catenin to preserve the E-cadherin/β-catenin adherens junction (AJ). These signaling pathways may be orchestrated by the replenished PPAR-γ, a transcription factor known for its anti-colitic effect.Conclusion: Besides maintaining the gut barrier, mirabegron and/or carvedilol mediated their anti-colitic effect by their anti-oxidant, anti-inflammatory, and anti-fibrotic capacities. The therapeutic effect of these drugs depends partly on suppressing the harmful signaling pathways PS1/BACE-1/Aβ, NOTCH1/NICD/HES1, GSK3-β/NF-κΒ/TNF-α, and TGF-1β/α-SMA while enhancing PPAR-γ, SMAD-7, mucus, and AJ.

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Section: Methodsmentioning

confidence: 99%

The novel anti-colitic effect of β-adrenergic receptors via modulation of PS1/BACE-1/Aβ axis and NOTCH signaling in an ulcerative colitis model

et al. 2022

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“…5 Although there is limited information on the dosage of vibegron in animal studies, a recent study showed that vibegron at 10 to 100 mg/kg reduced NVCs dose-dependently in a rat model of bladder outlet obstruction. 6 Thus, the dosage (30 mg/kg) of vibegron was selected according to this study as well as other reports using another β3-adrenoceptor agonist, mirabegron, in rodent models, 7,8 and confirmed to show the therapeutic efficacy for DO in SCI mice in preliminary experiments.…”

Section: Vibegron Administrationmentioning

confidence: 99%

Effects of a new β3‐adrenoceptor agonist, vibegron, on neurogenic bladder dysfunction and remodeling in mice with spinal cord injury

Gotoh

Shimizu

Wada

et al. 2020

Neurourology and Urodynamics

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Aims: To examine vibegron effects on lower urinary tract dysfunction (LUTD) in mice with spinal cord injury (SCI). Methods: Female mice underwent Th8-9 spinal cord transection and were orally administered vehicle or vibegron after SCI. We evaluated urodynamic parameters at 4 weeks after SCI with or without vibegron. Fibrosis-and ischemia-related messenger RNA (mRNA) and protein levels of collagen and elastin were measured in bladders of vehicle-and vibegron-treated SCI mice, and spinal intact mice. Results: Non-voiding contractions (NVCs) were significantly fewer (15.3 ± 8.9 vs 29.7 ± 11.4 contractions; P < .05) and the time to the first NVC was significantly longer (1488.0 ± 409.5 vs 782.7 ± 399.7 seconds; P < .01) in vibegrontreated SCI mice vs vehicle-treated SCI mice. mRNAs levels of collagen types 1 and 3, transforming growth factor-β1 (TGF-β1), and hypoxia-inducible factor-1α (HIF-1α) were significantly upregulated in vehicle-treated SCI mice compared with spinal intact and vibegron-treated SCI mice (Col 1: 3.5 vs 1.0 and 2.0-fold; P < .01 and P < .05, Col 3: 2.1 vs 1.0 and 1.2-fold; P < .01 and P < .05, TGF-β1: 1.2 vs 1.0 and 0.9-fold; P < .05 and P < .05, HIF-1α: 1.4 vs 1.0 and 1.0-fold; P < .05 and P < .01). Total collagen and elastin protein levels in vehicle-and vibegron-treated SCI mice did not differ. Conclusions: Vibegron reduced NVCs, delayed the first NVC, and improved collagen types 1 and 3, TGF-β1, and HIF-1α mRNA expression in SCI mice. Vibegron might be effective for SCI-induced LUTD.

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“…Experimental studies demonstrated that mirabegron, which is used in the treatment of OAB, led to the relaxation of the corpus cavernosum by alpha-1 adrenoceptor blockade and that avanafil, which is a type 5 PDH inhibitor, inhibited the activation of detrusor activated by potassium chloride [14,15]. Both experimental studies and the relationship of ED with LUTS suggest that these two urological diseases may be each other's risk factors or comorbid conditions.…”

Section: Introductionmentioning

confidence: 99%

Is overactive bladder a risk factor for erectile dysfunction? A cross-sectional study

Başer¹,

Baykam²

2020

Journal of Surgery and Medicine

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Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response

Cited by 11 publications

References 49 publications

The novel anti-colitic effect of β-adrenergic receptors via modulation of PS1/BACE-1/Aβ axis and NOTCH signaling in an ulcerative colitis model

The novel anti-colitic effect of β-adrenergic receptors via modulation of PS1/BACE-1/Aβ axis and NOTCH signaling in an ulcerative colitis model

Effects of a new β3‐adrenoceptor agonist, vibegron, on neurogenic bladder dysfunction and remodeling in mice with spinal cord injury

Is overactive bladder a risk factor for erectile dysfunction? A cross-sectional study

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