Abstract
Mixed lower urinary tract symptoms (LUTS) (voiding symptoms suggestive of benign prostatic hyperplasia plus storage symptoms, which can be caused by overactive bladder) are common in men. Unwanted contraction of prostate and/or bladder smooth muscle has been implied in the pathophysiology of male LUTS. Here, we examined effects of the serine/threonine kinase 16 (STK16) inhibitor STK16-IN-1 on contraction of human tissues from the prostate and male detrusor. Tissues were obtained from radical prostatectomy and radical cystectomy. Contractions were studied in an organ bath and STK16 expressions by Western blot analyses and fluorescence staining. In prostate tissues, STK16-IN-1 (1 μM) inhibited contractions induced by endothelin-1 and the thromboxane A2 analog U46619. Contractions of prostate tissues induced by noradrenaline, the α1-agonists phenylephrine and methoxamine, or electric field stimulation (EFS) were not changed by STK16-IN-1. In male detrusor tissues, STK16-IN-1 inhibited contractions induced by the cholinergic agonists carbachol and metacholine, and contractions induced by U46619. EFS-induced contractions of detrusor tissues were not changed by STK16-IN-1. Western blot analyses of prostate and detrusor tissues revealed bands matching the molecular weight of STK16. Fluorescence staining of prostate tissues using STK16 antibodies resulted in immunoreactivity in smooth muscle cells. STK16-IN-1 selectively inhibits non-adrenergic/non-neurogenic smooth muscle contractions in the male prostate and to limited extent in the bladder. Because non-adrenergic contractions in the male LUTS may account for limited efficacy of α1-blockers and for α1-blocker-resistant symptoms, studies assessing add-on of STK16-IN-1 to α1-blockers in mixed LUTS appear feasible.
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Acknowledgments
We thank Prof. Dr. E. Noessner and her coworkers (Institute of Molecular Immunology, Helmholtz Center, Munich) for their support with immunofluorescence microscopy and Prof. Dr. T. Kirchner (Institute of Pathology, Ludwig-Maximilians University, Munich) and his coworkers for the asservation of tissue samples from prostates.
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This work was supported by grants from the Deutsche Forschungsgemeinschaft (grant HE 5825/8-1) and the Chinese Scholarship Council (CSC).
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MH conceived and designed the study. BL, XW, BR, RW, AT, FS, RW, CGS, and MH performed research. MH and BL analyzed data. BL and MH wrote the paper. All authors read and approved the manuscript.
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Li, B., Wang, X., Rutz, B. et al. The STK16 inhibitor STK16-IN-1 inhibits non-adrenergic and non-neurogenic smooth muscle contractions in the human prostate and the human male detrusor. Naunyn-Schmiedeberg's Arch Pharmacol 393, 829–842 (2020). https://doi.org/10.1007/s00210-019-01797-x
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DOI: https://doi.org/10.1007/s00210-019-01797-x