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Modulation of lower urinary tract smooth muscle contraction and relaxation by the urothelium

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Abstract

The epithelial inner layer of the lower urinary tract, i.e., the urothelium, and other parts of the mucosa are not just a passive barrier but play an active role in the sensing of stretching, neurotransmitters, paracrine mediators, hormones, and growth factors and of changes in the extracellular environment. We review the molecular and cellular mechanisms enabling the urothelium to sense such inputs and how this leads to modulation of smooth muscle contraction and relaxation. The urothelium releases various mediators including ATP, acetylcholine, prostaglandins, nitric oxide, and nerve growth factor. These may affect function and growth of smooth muscle cells and afferent nerves. However, the molecular identity of the urothelium-derived mediator directly modulating contractile and relaxant responses of isolated bladder strips has remained elusive. The morphology and function of the urothelium undergo changes with aging and in many pathophysiological conditions. Therefore, the urothelium may contribute to the therapeutic effects of established drugs to treat lower urinary tract dysfunction and may also serve as a target for novel therapeutics. However, therapeutics may also change urothelial function, and it is not always easy to determine whether such changes are part of the therapeutic response or reflect secondary alterations.

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Abbreviations

Ach:

Acetylcholine

CBS:

Cystathionine-β-synthase

CSE:

Cystathionine-γ-lyase

EFS:

Electrical field stimulation

H2S:

Hydrogen sulfide

LUT:

Lower urinary tract

NGF:

Nerve growth factor

NO:

Nitric oxide

NOS:

NO synthase

OAB:

Overactive bladder syndrome

ÜG:

Prostaglandin

TRP:

Transient receptor potential channel

UDIF:

Urothelium-derived inhibitor factor

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Acknowledgements

Work in the authors’ labs is being or has been funded by the Australian National Health and Medical Research Council, Cancer Council Queensland, Australian Bladder Foundation and Deutsche Forschungsgemeinschaft (Mi 294/8-1).

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Authors and Affiliations

  1. Centre for Urology Research, Faculty of Health Sciences & Medicine, Bond University, Robina, QLD, Australia

    Donna Sellers & Russ Chess-Williams

  2. Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Str. 67, 55131, Mainz, Germany

    Martin C. Michel

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  1. Donna Sellers
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  2. Russ Chess-Williams
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  3. Martin C. Michel
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Contributions

DS, RCW, and MCM conceived the outline of this review, retrieved and extracted the references, and contributed to write sections of the manuscript. All authors read, critically revised for content, and approved the manuscript.

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Correspondence to Martin C. Michel.

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DS and RCW do not declare a conflict of interest. In the field of urology, MCM is a consultant to and shareholder of Velicept Therapeutics, a former employee (2011–2016) and present consultant of Boehringer Ingelheim, and a consultant of Apogepha and Dr. Wilmar Schwabe.

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Sellers, D., Chess-Williams, R. & Michel, M.C. Modulation of lower urinary tract smooth muscle contraction and relaxation by the urothelium. Naunyn-Schmiedeberg's Arch Pharmacol 391, 675–694 (2018). https://doi.org/10.1007/s00210-018-1510-8

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  • DOI: https://doi.org/10.1007/s00210-018-1510-8

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