The Soluble Guanylyl Cyclase Activator BAY 60-2770 Ameliorates Overactive Bladder in Obese Mice

Leiria, Luiz O.; Silva, Fábio H.; Davel, Ana Paula; Alexandre, Eduardo C.; Calixto, Marina C.; Nucci, Gilberto De; Mónica, Fabíola Z.; Antunes, Edson

doi:10.1016/j.juro.2013.09.020

Cited by 38 publications

(34 citation statements)

References 29 publications

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“…It is interesting that a recent study showed that the heme domain of sGC contains an S-nitrosylation site (b 1 C122) involved in enzyme desensitization, and BAY 60-2770 facilitates the displacement of heme from ferric sGC or alternatively binds to the vacant heme pocket of apo sGC (Kumar et al, 2013). Adiposity markedly increases ROS levels in the bladder (Leiria et al, 2013) and in urethral tissues (present study). Two-week therapy with BAY 60-2770 did not significantly affect ROS levels in the bladder but rather normalized ROS levels in the urethra.…”

mentioning

confidence: 53%

“…Given that sGC activators reactivate the heme-oxidized enzyme in vascular diseases (Stasch et al, 2006) and ameliorate obesity-associated OAB (Leiria et al, 2013), we next examined Relaxations were calculated relative to the maximal changes from the contraction produced by phenylephrine (10 mM) in each urethral ring, which was taken as 100%. Data are presented as mean 6 S.E.M.…”

Section: Resultsmentioning

confidence: 99%

“…To achieve this, lean and obese mice were orally treated with BAY 60-2770 (1 mg/kg per day, given as daily gavage from the 10th to 12th week) or its vehicle (Transcutol/Cremophor/water, 1:2:7, v/v/v), according to our previous experience (Leiria et al, 2013). Thereafter, concentration-response curves to NaNO 2 , protein expression of b 1 -subunit of sGC and ROS levels were evaluated in the urethral tissues in all groups.…”

Section: Obesity-associated Impairment Of Urethral Relaxationsmentioning

confidence: 99%

“…Direct sGC stimulation causes cGMP-dependent urethral relaxations (Costa et al, 2001) in a synergistic fashion with NO (Toque et al, 2008 . These compounds are reported to protect sGC from heme oxidation in smooth muscle tissues (Stasch et al, 2006;Meurer et al, 2009;Jones et al, 2010;Lasker et al, 2013), ameliorating OAB in obese mice (Leiria et al, 2013). Additionally, long-term sGC stimulation counteracts the voiding dysfunction in chronically NO-deficient rats (Mónica et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Given that sGC activators can reactivate heme-oxidized sGC (Stasch et al, 2006) and ameliorate obesity-associated overactive bladder (Leiria et al, 2013), we next investigated the effects of prolonged BAY 60-2770 administration on the functional and molecular alterations of USM and its association with obesity. Two-week oral treatment with BAY 60-2770 fully restored the impaired NO-mediated urethral relaxations in obese mice without affecting the responses in the lean group.…”

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confidence: 99%

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Soluble Guanylyl Cyclase (sGC) Degradation and Impairment of Nitric Oxide-Mediated Responses in Urethra from Obese Mice: Reversal by the sGC Activator BAY 60-2770

Alexandre

Leiria

Silva

et al. 2014

J Pharmacol Exp Ther

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Obesity has emerged as a major contributing risk factor for overactive bladder (OAB), but no study examined urethral smooth muscle (USM) dysfunction as a predisposing factor to obesityinduced OAB. This study investigated the USM relaxant machinery in obese mice and whether soluble guanylyl cyclase ( Long-term oral BAY 60-2770 administration fully prevented the impairment of USM relaxations in obese mice. Reactiveoxygen species (ROS) production was enhanced, but protein expression of b1 second guanylate cyclase subunit was reduced in USM from obese mice, both of which were restored by BAY 60-2770 treatment. In conclusion, impaired USM relaxation in obese mice is associated with ROS generation and down-regulation of sGC-cGMP signaling. Prevention of sGC degradation by BAY 60-2770 ameliorates the impairment of urethral relaxations in obese mice.

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mentioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Section: Obesity-associated Impairment Of Urethral Relaxationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Soluble Guanylyl Cyclase (sGC) Degradation and Impairment of Nitric Oxide-Mediated Responses in Urethra from Obese Mice: Reversal by the sGC Activator BAY 60-2770

Alexandre

Leiria

Silva

et al. 2014

J Pharmacol Exp Ther

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Implication of Rho‐kinase and soluble guanylyl cyclase enzymes in prostate smooth muscle dysfunction in middle‐aged rats

Calmasini

Silva

Alexandre

et al. 2016

Neurourology and Urodynamics

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Chronic high‐fat diet decreased detrusor mitochondrial respiration and increased nerve‐mediated contractions

Powers

Ryan

Pak

et al. 2019

Neurourology and Urodynamics

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Aims To assess the impact of chronic high‐fat diet (HFD) on behavioral voiding patterns, detrusor contractility, and smooth muscle mitochondrial function in male mice. Materials and Methods Male C57BL/6J mice (6 weeks) were fed a control or HFD for 20 weeks. Bladder function was assessed by void spot assays. Bladders were collected and detrusor contractility to carbachol (10−9‐10−5 M), and electrical field stimulation (EFS, 0.5–32 Hz) in the presence and absence of atropine was measured. Homogenized detrusor samples were placed in oxygraphs to assess the rate of oxygen consumption of the mitochondria within the detrusor in the presence of different substrates. Mitochondrial hydrogen peroxide (H2O2) emission was measured fluorometrically. Detrusor citrate synthase activity was measured via enzyme activity kit and Western blots assessed the electron transport chain (ETC) protein content. Results HFD significantly increased body weight, adiposity, and blood glucose levels. HFD mice demonstrated increased voiding frequency and increased EFS‐induced detrusor contractility. There were no changes in detrusor relaxation or cholinergic‐medicated contraction. Mitochondrial respiration was decreased with HFD and H2O 2 emission was increased. The relative amount of mitochondria in the detrusor was similar between groups. However, ETC complexes V and III were increased following HFD. Conclusions Chronic HFD increased adiposity, lead to more frequent voiding, and enhanced EFS‐mediated detrusor contractions. Mitochondrial respiration was decreased and H2O 2 emission increased following HFD. Further research is required to determine if alterations in mitochondrial function could play a role in the development of HFD‐induced bladder dysfunction.

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The Soluble Guanylyl Cyclase Activator BAY 60-2770 Ameliorates Overactive Bladder in Obese Mice

Abstract: Two-week BAY 60-2770 therapy increased cyclic guanosine monophosphate and rescued expression of the soluble guanylyl cyclase α1 and β1 subunits in bladder tissue, resulting in great amelioration of bladder dysfunction.

Cited by 38 publications

References 29 publications

Soluble Guanylyl Cyclase (sGC) Degradation and Impairment of Nitric Oxide-Mediated Responses in Urethra from Obese Mice: Reversal by the sGC Activator BAY 60-2770

Soluble Guanylyl Cyclase (sGC) Degradation and Impairment of Nitric Oxide-Mediated Responses in Urethra from Obese Mice: Reversal by the sGC Activator BAY 60-2770

Implication of Rho‐kinase and soluble guanylyl cyclase enzymes in prostate smooth muscle dysfunction in middle‐aged rats

Chronic high‐fat diet decreased detrusor mitochondrial respiration and increased nerve‐mediated contractions

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