Treatment with the soluble guanylate cyclase activator BAY 60–2770 normalizes bladder function in an in vivo rat model of chronic prostatitis

Aydoğdu, Özgü; Perez, Fernando; Aronsson, Patrik; Göçün, Pınar Uyar; Carlsson, Thomas; Sandner, Peter; Patel, Bhavik Anil; Winder, Michael

doi:10.1016/j.ejphar.2022.175052

Cited by 7 publications

(6 citation statements)

References 44 publications

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“…However, the amounts of NO used in the current study to induce detrusor relaxation may be greater than what is produced in vivo . Considering that several previous studies have demonstrated that impairment of the NO-sGC-cGMP pathway is strongly associated with lower urinary tract symptoms, and that restoring this pathway ameliorates symptoms ( Monica and Antunes, 2018 ; Aydogdu et al, 2022 ), the current data should be interpreted with this in mind. It should also be noted that levels of cGMP were not measured in the current study.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the considerable number of studies that have been conducted to outline the functional roles of NO in the lower urinary tract, there are still missing pieces to the puzzle, for instance, an accurate description of which intracellular pathways that are involved in nitrergic signaling. Nevertheless, the involvement of the NO-sGC-cGMP pathway (Figure 1) has repeatedly been demonstrated in basic and clinical studies on various lower urinary tract pathologies (Logadottir et al, 2004;Kedia et al, 2008;Cho et al, 2017;Monica and Antunes, 2018;Zabbarova et al, 2021;Aydogdu et al, 2022). The effects of NO on detrusor contractility have been extensively examined using a wide range of experimental designs.…”

Section: Introductionmentioning

confidence: 99%

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Soluble guanylate cyclase mediates the relaxation of healthy and inflamed bladder smooth muscle by aqueous nitric oxide

Aronsson,

Stenqvist,

Ferizovic

et al. 2023

Front. Physiol.

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Introduction: Due to its chemical properties, functional responses to nitric oxide (NO) are often difficult to examine. In the present study, we established a method to produce NO in an aqueous solution and validated its capacity to evoke functional responses in isolated rat bladders. Furthermore, we compared the NO responses to the commonly used NO donor sodium nitroprusside (SNP). We also investigated the impact of ongoing inflammation on the involvement of soluble guanylate cyclase (sGC) dependent signaling in NO relaxation.Methods: A setup to produce an aqueous NO solution was established, allowing the production of an aqueous solution containing a calculated NO concentration of 2 mM. Sixty male Sprague-Dawley rats received either no treatment (controls) or cyclophosphamide (CYP; 100 mg*kg−1 i.p., 60 h prior to the experiment) to induce experimental cystitis. Bladder strip preparations were mounted in organ baths and studied at basal tension or pre-contracted with methacholine (3 μM). Aqueous NO solution (40–400 μL; 2 mM corresponding to 4–40 μM) or SNP (1–1,000 μM) was added cumulatively in increasing concentrations. Relaxation to aqueous NO was also studied in the presence of the sGC inhibitor ODQ (0.25–25 μM). The expression of sGC was investigated by immunohistochemical analysis.Results: The NO solution caused functional relaxations in both controls and inflamed bladder preparations. NO-induced relaxations were significantly greater in inflamed bladder strips at basal tension, whereas no differences were seen in methacholine pre-contracted strips. In the presence of the sGC inhibitor ODQ in a high concentration, the NO-evoked relaxations were abolished in both control and inflamed preparations. At a lower concentration of ODQ, only NO relaxations in inflamed preparations were attenuated. Immunohistochemical analysis showed that sGC was expressed in the detrusor and mucosa, with a significantly lower expression in the inflamed detrusor.Conclusion: In the present study, we found that aqueous NO solution induces relaxation of the rat detrusor by activating soluble guanylate cyclase in both control and inflamed bladder strips. Induction of inflammation conceivably leads to decreased sGC expression in the detrusor, which may explain the different susceptibility towards inhibition of sGC in inflamed versus control tissue. The use of an aqueous NO solution should be further considered as a valuable complement to the pharmacological tools currently used.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Soluble guanylate cyclase mediates the relaxation of healthy and inflamed bladder smooth muscle by aqueous nitric oxide

Aronsson,

Stenqvist,

Ferizovic

et al. 2023

Front. Physiol.

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“…The authors suggested this may be due to cross‐organ senitization whereby afferent senitization activity of one organ, in this case the prostate, triggers increased efferent signaling to the bladder. A further study demonstrated how treatment with an sGC activator, BAY 60‐2770, normalized bladder parameters in animals with prostatitis‐induced bladder overactivity 34 . Thus, several studies show promising results when aiming to alleviate inflammation‐induced bladder dysfunction by treatment with sGC activators.…”

Section: No• Signaling and Lut Inflammationmentioning

confidence: 96%

“…A further study demonstrated how treatment with an sGC activator, BAY 60-2770, normalized bladder parameters in animals with prostatitis-induced bladder overactivity. 34 Thus, several studies show promising results when aiming to alleviate inflammation-induced bladder dysfunction by treatment with sGC activators.…”

Section: No• Signaling and Lut Inflammationmentioning

confidence: 99%

Nitric oxide signaling pathways in the normal and pathological bladder: Do they provide new pharmacological pathways?—ICI‐RS 2023

Chakrabarty,

Winder,

Kanai

et al. 2023

Neurourology and Urodynamics

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AimsThe nitric oxide (NO•)/soluble guanylate cyclase/cyclic‐GMP (cGMP) signaling pathway is ubiquitous and regulates several functions in physiological systems as diverse as the vascular, nervous, and renal systems. However, its roles in determining normal and abnormal lower urinary tract functions are unclear. The aim was to identify potential therapeutic targets associated with this pathway to manage lower urinary tract functional disorders.MethodsThis review summarizes a workshop held under the auspices of ICI‐RS with a view to address these questions.ResultsFour areas were addressed: NO• signaling to regulate neurotransmitter release to detrusor smooth muscle; its potential dual roles in alleviating and exacerbating inflammatory pathways; its ability to act as an antifibrotic mediator; and the control by nitrergic nerves of lower urinary tract vascular dynamics and the contractile performance of muscular regions of the bladder wall. Central to much of the discussion was the role of the NO• receptor, soluble guanylate cyclase (sGC) in regulating the generation of the enzyme product, the second messenger cGMP. The redox state of sGC is crucial in determining its enzymic activity and the role of a class of novel agents, sGC activators, to optimize activity and to potentially alleviate the consequences of lower urinary tract disorders was highlighted. In addition, the consequences of a functional relationship between nitrergic and sympathetic nerves to regulate vascular dynamics was discussed.ConclusionsSeveral potential NO•‐dependent drug targets in the lower urinary tract were identified that provide the basis for future research and translation to clinical trials.

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“…In a recent intervention study in rats, prostatic inflammation was induced by intraprostatic injection with zymosan, which acts via toll-like receptor 2. 46 Bladder function was assessed in metabolic cages and by cystometry, displaying clear signs of bladder dysfunction, most notably bladder overactivity. Treatment with the sGC activator BAY 60-2770, either alone or in combination with the cyclooxygenase-2 inhibitor, celecoxib, led to normalization of bladder function and simultaneous abolishment of prostatic inflammation.…”

Section: New Therapeutic Targets What They Treat and Their Advantage ...mentioning

confidence: 99%

New therapeutic targets to prevent benign prostatic enlargement and symptomatic progression to benign prostatic obstruction—ICI‐RS 2023

Kanai,

Chakrabarty,

Winder

et al. 2023

Neurourology and Urodynamics

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AimsBenign prostatic enlargement (BPE) can impact lower urinary tract function due to its potential progression to benign prostatic obstruction (BPO). Treatment options include removal of the obstruction by surgery or through use of therapeutics designed to slow growth or reduce tissue stress imposed by muscular stromal components. Inflammation and development of fibrosis can also raise intrinsic tissue stress within the gland, further impacting obstruction. Outflow tract obstruction can also impact emission and ejaculation if the obstruction persists.MethodsThis review summarizes an ICI‐RS think tank considering novel drug treatments that might address BPO caused by progressive development of BPE, as well as manage decompensation changes to bladder function.ResultsTopics included recent advances in our understanding of pathological changes occurring to the prostate and other lower urinary tract tissues during progressive development of BPE, and how prevention or reversal might benefit from the identification of novel drug targets. These included contractile properties of prostatic tissues, the impact of BPE and its effects on bladder function, the deposition of intramural fibrotic tissue with protracted BPO, the role of inflammation in the development of BPE and its progression to BPO. In particular, we discussed current therapeutic options for treating BPE/BPO, and new therapeutic targets, what they treat and their advantage over current medications.ConclusionSeveral new drug targets were identified, including soluble guanylate cyclase (sGC), the receptor for nitric oxide (NO•), and sGC activators that promotes sGC‐mediated cGMP production when sGC is inactivated and unresponsive to NO•.

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Treatment with the soluble guanylate cyclase activator BAY 60–2770 normalizes bladder function in an in vivo rat model of chronic prostatitis

Cited by 7 publications

References 44 publications

Soluble guanylate cyclase mediates the relaxation of healthy and inflamed bladder smooth muscle by aqueous nitric oxide

Soluble guanylate cyclase mediates the relaxation of healthy and inflamed bladder smooth muscle by aqueous nitric oxide

Nitric oxide signaling pathways in the normal and pathological bladder: Do they provide new pharmacological pathways?—ICI‐RS 2023

New therapeutic targets to prevent benign prostatic enlargement and symptomatic progression to benign prostatic obstruction—ICI‐RS 2023

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