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Benign prostatic hyperplasia/obstruction ameliorated using a soluble guanylate cyclase activator

Zabbarova, Irina V. ; Ikeda, Youko ; Kozlowski, Mark G. ; Tyagi, Pradeep ; Birder, Lori A. ; Chakrabarty, Basu ; Perera, Subashan K.P.G. ; Dhir, Rajiv ; Straub, Adam C. and Sandner, Peter , et al. (2022) In Journal of Pathology 256(4). p.442-454
Abstract

Benign prostatic hyperplasia (BPH) is a feature of ageing males. Up to half demonstrate bladder outlet obstruction (BOO) with associated lower urinary tract symptoms (LUTS) including bladder overactivity. Current therapies to reduce obstruction, such as α1-adrenoceptor antagonists and 5α-reductase inhibitors, are not effective in all patients. The phosphodiesterase-5 inhibitor (PDE5I) tadalafil is also approved to treat BPH and LUTS, suggesting a role for nitric oxide (NO•), soluble guanylate cyclase (sGC), and cGMP signalling pathways. However, PDE5I refractoriness can develop for reasons including nitrergic nerve damage and decreased NO• production, or inflammation-related oxidation of the sGC haem group,... (More)

Benign prostatic hyperplasia (BPH) is a feature of ageing males. Up to half demonstrate bladder outlet obstruction (BOO) with associated lower urinary tract symptoms (LUTS) including bladder overactivity. Current therapies to reduce obstruction, such as α1-adrenoceptor antagonists and 5α-reductase inhibitors, are not effective in all patients. The phosphodiesterase-5 inhibitor (PDE5I) tadalafil is also approved to treat BPH and LUTS, suggesting a role for nitric oxide (NO•), soluble guanylate cyclase (sGC), and cGMP signalling pathways. However, PDE5I refractoriness can develop for reasons including nitrergic nerve damage and decreased NO• production, or inflammation-related oxidation of the sGC haem group, normally maintained in a reduced state by the cofactor cytochrome-b5-reductase 3 (CYB5R3). sGC activators, such as cinaciguat (BAY 58-2667), have been developed to enhance sGC activity in the absence of NO• or when sGC is oxidised. Accordingly, their effects on the prostate and LUT function of aged mice were evaluated. Aged mice (≥24 months) demonstrated a functional BPH/BOO phenotype, compared with adult animals (2–12 months), with low, delayed voiding responses and elevated intravesical pressures as measured by telemetric cystometry. This was consistent with outflow tract histological and molecular data that showed urethral constriction, increased prostate weight, greater collagen deposition, and cellular hyperplasia. All changes in aged animals were attenuated by daily oral treatment with cinaciguat for 2 weeks, without effect on serum testosterone levels. Cinaciguat had only transient (1 h) cardiovascular effects with oral gavage, suggesting a positive safety profile. The benefit of cinaciguat was suggested by its reversal of an overactive cystometric profile in CYB5R3 smooth muscle knockout mice that mirrors a profile of oxidative dysfunction where PDE5I may not be effective. Thus, the aged male mouse is a suitable model for BPH-induced BOO and cinaciguat has a demonstrated ability to reduce prostate-induced obstruction and consequent effects on bladder function.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ageing, benign prostatic hyperplasia, bladder outlet obstruction, cGMP, cinaciguat, CYB5R3, lower urinary tract symptoms, nitric oxide, PDE5 inhibitors, sGC activators
in
Journal of Pathology
volume
256
issue
4
pages
13 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:34936088
  • scopus:85124592921
ISSN
0022-3417
DOI
10.1002/path.5859
language
English
LU publication?
yes
id
f55ecf5f-bcb5-42e7-a91d-d3d4f108aeb4
date added to LUP
2022-04-12 09:01:22
date last changed
2024-06-17 00:00:24
@article{f55ecf5f-bcb5-42e7-a91d-d3d4f108aeb4,
  abstract     = {{<p>Benign prostatic hyperplasia (BPH) is a feature of ageing males. Up to half demonstrate bladder outlet obstruction (BOO) with associated lower urinary tract symptoms (LUTS) including bladder overactivity. Current therapies to reduce obstruction, such as α1-adrenoceptor antagonists and 5α-reductase inhibitors, are not effective in all patients. The phosphodiesterase-5 inhibitor (PDE5I) tadalafil is also approved to treat BPH and LUTS, suggesting a role for nitric oxide (NO<sup>•</sup>), soluble guanylate cyclase (sGC), and cGMP signalling pathways. However, PDE5I refractoriness can develop for reasons including nitrergic nerve damage and decreased NO<sup>•</sup> production, or inflammation-related oxidation of the sGC haem group, normally maintained in a reduced state by the cofactor cytochrome-b5-reductase 3 (CYB5R3). sGC activators, such as cinaciguat (BAY 58-2667), have been developed to enhance sGC activity in the absence of NO<sup>•</sup> or when sGC is oxidised. Accordingly, their effects on the prostate and LUT function of aged mice were evaluated. Aged mice (≥24 months) demonstrated a functional BPH/BOO phenotype, compared with adult animals (2–12 months), with low, delayed voiding responses and elevated intravesical pressures as measured by telemetric cystometry. This was consistent with outflow tract histological and molecular data that showed urethral constriction, increased prostate weight, greater collagen deposition, and cellular hyperplasia. All changes in aged animals were attenuated by daily oral treatment with cinaciguat for 2 weeks, without effect on serum testosterone levels. Cinaciguat had only transient (1 h) cardiovascular effects with oral gavage, suggesting a positive safety profile. The benefit of cinaciguat was suggested by its reversal of an overactive cystometric profile in CYB5R3 smooth muscle knockout mice that mirrors a profile of oxidative dysfunction where PDE5I may not be effective. Thus, the aged male mouse is a suitable model for BPH-induced BOO and cinaciguat has a demonstrated ability to reduce prostate-induced obstruction and consequent effects on bladder function.</p>}},
  author       = {{Zabbarova, Irina V. and Ikeda, Youko and Kozlowski, Mark G. and Tyagi, Pradeep and Birder, Lori A. and Chakrabarty, Basu and Perera, Subashan K.P.G. and Dhir, Rajiv and Straub, Adam C. and Sandner, Peter and Andersson, Karl Erik and Drake, Marcus J. and Fry, Christopher H. and Kanai, Anthony J.}},
  issn         = {{0022-3417}},
  keywords     = {{ageing; benign prostatic hyperplasia; bladder outlet obstruction; cGMP; cinaciguat; CYB5R3; lower urinary tract symptoms; nitric oxide; PDE5 inhibitors; sGC activators}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{442--454}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Journal of Pathology}},
  title        = {{Benign prostatic hyperplasia/obstruction ameliorated using a soluble guanylate cyclase activator}},
  url          = {{http://dx.doi.org/10.1002/path.5859}},
  doi          = {{10.1002/path.5859}},
  volume       = {{256}},
  year         = {{2022}},
}