An increase in smooth muscle tone and enlargement of the human prostate gland are major components of benign prostatic hyperplasia (BPH) and the associated pathophysiology of lower urinary tract symptoms (LUTS). BPH is an extremely common disorder of the aging male population and the development can be categorized into two components; the dynamic and static component. An increase of the dynamic component is composed of the neurogenic tone and the myogenic tone of the prostate and leads to an increase in smooth muscle contractility and tone. The static component comprises the stromal proliferation of prostatic tissue and leads to an increase in prostate size and occurs due to age-dependent changes in hormone levels. Therefore, current pharmacological treatment options target to reduce either smooth muscle tone (dynamic component) or to decrease the prostate size (static component). Pharmacotherapies used to reduce the prostate size include 5alpha-reductase (5AR) inhibitors. Classical treatment options to reduce smooth muscle tone and contractility are performed with alpha1-adrenoceptor antagonists like tamsulosin but often result in adverse effects like abnormal ejaculation, having an impact on the quality of life and thus potentially leading to discontinuation of therapy. The exact causes and mechanisms of action leading to ejaculation disorders due to treatment with tamsulosin are still a matter of debate. Although inhibitors of the cyclic guanosine monophosphate (cGMP)-hydrolyzing enzyme phosphodiesterase type 5 (PDE5) are now regularly used for the treatment of BPH, detailed information about their cellular site of action and function within the prostate is missing. Another key component regulating levels of cGMP within smooth muscle cells (SMCs) is nitric oxide (NO), a free radical gas that promotes SMC relaxation by causing an increase of cGMP levels within the cells.In prostate tissue of rat and man, PDE5 was shown to be highly expressed in interstitial and vascular SMCs but not in epithelial cells of the gland. Investigation of the effects of various PDE5 inhibitors (tadalafil and sildenafil) on the smooth muscle tissue of the prostate was performed for rat and human tissue utilizing a novel time-lapse imaging approach.Moreover, the structural and functional architecture of rat prostate tissue was defined which allowed separate investigations of the single glands, producing prostatic fluid, and the excretory ducts, transporting prostatic fluid to the urethra during ejaculation. In rat prostate, spontaneous contractility was only observed in terminal prostatic glands but not in proximal ducts. Recordings showed that PDE5 inhibitors reduced the myogenic tone (spontaneous contractions) of prostate tissue in rat and man. Analysis of adverse effects of the alpha1-adrenoceptor antagonist tamsulosin on contractile tissues responsible for ejaculation, specifically the excretory prostate ducts, seminal vesicles and the sperm-storing part of the cauda epididymal duct, was performed utilizing the novel time-lapse imaging approach. This model system visualized and revealed adverse effects of tamsulosin on different tissues involved in ejaculation and showed that these adverse effects were not present under the influence of the PDE5 inhibitor tadalafil.Aside from already approved pharmacotherapies to treat BPH, research for novel pharmacological options to relax smooth muscle tissue is crucial. S-nitrosoglutathione (GSNO), a NO donor, was tested (i) as its common construct and (ii) conjugated to the core of a cross-linked star polymer in tension recording experiments as well as in vitro experiments of primary human prostate SMCs. Experiments showed an upregulation of cGMP pathway components on RNA and protein levels as well as relaxing effects on contractility, especially reduction of basal tension of tissues following incubation with either variant. Nevertheless, further studies are necessary to confirm the observed results due to differences in patient parameters like age, previous medication, and individual lifestyles.
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