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Stimulators and activators of soluble guanylate cyclase for urogenital disorders

Nature Reviews Urology volume 15, pages 42–54 (2018)Cite this article

Subjects

Key Points

  • The nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic GMP (cGMP) signalling pathway is present in the smooth muscle of the lower urinary tract (bladder and urethra), prostate, and corpus cavernosum

  • Impairment of NO–sGC–cGMP signalling in bladder, urethra, prostate, and corpus cavernosum smooth muscles can result in urogenital diseases such as overactive bladder, prostate hypercontractility, and erectile dysfunction

  • Stimulators (BAY 41–2272, BAY 41–8543, and BAY 60–4552) and activators (BAY 58–2667 and BAY 60–2770) of sGC can enhance cGMP levels by directly acting on sGC independently of NO

  • Both sGC stimulators and activators have a potent relaxation effect on bladder, ureter, urethra, prostate, and corpus cavernosum smooth muscle in nonpathological and pathological conditions

  • sGC activators are highly effective at restoring sGC expression and activity in disorders associated with increased oxidative stress involving urogenital smooth muscle. sGC activators are more efficacious than sGC stimulators

  • sGC stimulators and activators are promising molecules that enable urogenital smooth muscle relaxation in pathological conditions. However, clinical studies are required to corroborate the efficacy of these drugs

Abstract

Lower urinary tract symptoms (LUTS), comprising storage (such as urinary incontinence and urinary frequency), voiding, and postmicturition symptoms, are highly prevalent conditions that affect millions of people worldwide. LUTS have a profound effect on quality of life and are a considerable cost to health care systems. In men specifically, BPH commonly leads to LUTS. Clinical studies also show an association of LUTS with erectile dysfunction (ED). Nitric oxide (NO) has long been recognized as an important nonadrenergic, noncholinergic (NANC) transmitter in bladder, urethra, prostate, and corpus cavernosum smooth muscle. Data from clinical and basic research show that oxidation and degradation of soluble guanylate cyclase (sGC; also known as GCS) and reduced cyclic GMP (cGMP) levels are involved in the physiopathology of genitourinary diseases. The NO–sGC–cGMP signalling pathway has a role in disease pathophysiology of the bladder, urethra, prostate, and corpus cavernosum in animal models and humans. Advances in targeting sGC directly to enhance cGMP production independently of endogenous NO have been made using NO-independent stimulators and activators of sGC. These molecules are potential therapeutics in the treatment of LUTS and ED.

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Figure 1: Effects of nitric oxide in nonpathological and pathological conditions.
Figure 2: Role of reactive oxygen species in urogenital tract disorders.

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Acknowledgements

F.Z.M. and E.A. acknowledge FAPESP, CAPES, CNPq, and UNICAMP for research support.

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  1. Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Alexander Fleming, 13083–881, São Paulo, Brazil

    Fabiola Z. Mónica & Edson Antunes

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Both authors researched data for the manuscript, made substantial contributions to discussion of content, wrote the article, and reviewed and edited the manuscript before submission.

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Mónica, F., Antunes, E. Stimulators and activators of soluble guanylate cyclase for urogenital disorders. Nat Rev Urol 15, 42–54 (2018). https://doi.org/10.1038/nrurol.2017.181

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