Prostate carcinoma and benign prostate hyperplasia (BPH) with associated lower urinary tract symptoms (LUTS) are among the most prevalent and clinically relevant diseases in men. BPH is characterized by an enlargement of prostate tissue associated with increased tone of smooth muscle cells (SMCs) which surround the single glands composing the prostate. Secretions of the glands leave the prostate through local excretory ducts during the emission phase of ejaculation. Pharmacological treatment of BPH suggests different local drug targets based on reduction of prostate smooth muscle tone as the main effect and disturbed ejaculation as a common side effect. This highlights the need for detailed investigation of single prostate glands and ducts. We combined structural and functional imaging techniques-notably, clear lipid-exchanged, acrylamide-hybridized rigid imaging/immunostaining/ in situ hybridization-compatible tissue-hydrogel (CLARITY) and time-lapse imaging-and defined glands and ducts as distinct SMC compartments in human and rat prostate tissue. The single glands of the prostate (comprising the secretory part) are characterized by spontaneous contractions mediated by the surrounding SMCs, whereas the ducts (excretory part) are quiescent. In both SMC compartments, phosphodiesterase (PDE)-5 is expressed. PDE5 inhibitors have recently emerged as alternative treatment options for BPH. We directly visualized that the PDE5 inhibitors sildenafil and tadalafil act by reducing spontaneous contractility of the glands, thereby reducing the muscle tone of the organ. In contrast, the ductal (excretory) system and thus the prostate's contribution to ejaculation is unaffected by PDE5 inhibitors. Our differentiated imaging approach reveals new details about prostate function and local drug actions and thus may support clinical management of BPH.-Kügler, R., Mietens, A., Seidensticker, M., Tasch, S., Wagenlehner, F. M., Kaschtanow, A., Tjahjono, Y., Tomczyk, C. U., Beyer, D., Risbridger, G. P., Exintaris, B., Ellem, S. J., Middendorff, R. Novel imaging of the prostate reveals spontaneous gland contraction and excretory duct quiescence together with different drug effects.

Structures responsible for the emission phase of ejaculation are the seminal vesicles, the most distal part of the cauda epididymidis and the newly characterized prostate excretory ducts. The emission phase is mainly regulated by the sympathetic nervous system through alpha1-adrenergic receptor activation by noradrenaline at the targeted organs. Benign prostatic hyperplasia (BPH) treatment with alpha1A-adrenergic antagonists such as tamsulosin is known to result in ejaculation dysfunction, often leading to discontinuation of therapy. Mechanisms of this disturbance remain unclear. We established a rodent model system to predict drug responses in tissues involved in the emission phase of ejaculation. Imitating the therapeutic situation, prostate ducts, seminal vesicles and the distal cauda epididymal duct were pre-incubated with the SMC-relaxing BPH drugs tadalafil, a novel BPH treatment option and tamsulosin in an ex vivo-time-lapse imaging approach. Afterwards, noradrenergic responses in the relevant structures were investigated to simulate sympathetic activation. Noradrenaline induced strong contractions ultimately leading to secretion in structures without pre-treatment. Contractions were abolished by tamsulosin in prostate ducts and seminal vesicles and significantly decreased in the epididymal duct. Such effects were not observed with tadalafil pre-treatment. Data visualized a serious dysfunction of each organ involved in emission by affecting alpha1-adrenoceptors localized at the relevant structures, but not by targeting of smooth muscle cell-localized PDE5 by tadalafil. Our model system reveals the mechanism of tamsulosin resulting in adverse effects during ejaculation in patients treated for BPH. These adverse effects on contractility don’t apply to tadalafil treatment. This new knowledge translates directly to clinical medicine.

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