The oxytocin antagonist cligosiban reduces human prostate contractility: Implications for the treatment of benign prostatic hyperplasia.

BACKGROUND AND PURPOSE: With increasing life expectancy, benign prostatic hyperplasia (BPH) consequently affects more ageing men, illustrating the urgent need for advancements in BPH therapy. One emerging possibility may be the use of oxytocin antagonists to relax smooth muscle cells in the prostate, similar to the currently used (although often associated with side effects) α1-adrenoceptor blockers. EXPERIMENTAL APPROACH: For the first time we used live-imaging, combined with a novel image analysis method, to investigate the multidirectional contractions of the human prostate and determine their changes in response to oxytocin and the oxytocin antagonists atosiban and cligosiban. Human prostate samples were obtained and compared from patients undergoing prostatectomy due to prostate cancer as well as from patients with transurethral resection of prostate tissue due to severe BPH. KEY RESULTS: The two cohorts of tissue samples showed spontaneous multidirectional contractions, which significantly increased after the addition of oxytocin. Different to atosiban, which showed ambiguous effects of short duration, only long-acting cligosiban reliably prevented, as well as counteracted, any contractile oxytocin effect. Furthermore, cligosiban visibly reduced not only oxytocin-induced contractions, but also showed intrinsic activity to relax prostatic tissue. CONCLUSION AND IMPLICATIONS: Thus, the oxytocin antagonist cligosiban could be an interesting candidate in the search for novel BPH treatment options.

Age-Dependent Effects of Oxytocin and Oxytocin Receptor Antagonists on Bladder Contractions: Implications for the Treatment of Overactive Bladder Syndrome.

Overactive bladder (OAB) is an age-related disorder characterised by unstable bladder contractions resulting in disruptive lower urinary tract symptoms (LUTS), thus creating a profound impact on an individual's quality of life. The development of LUTS may be linked to the overexpression of oxytocin receptors (OXTRs) within the bladder detrusor muscle, resulting in increased baseline myogenic tone. Thus, it is hypothesised that targeting OXTRs within the bladder using oxytocin antagonists may attenuate myogenic tone within the bladder, thereby providing a new therapeutic avenue for treating OAB. Organ bath contractility and immunohistochemistry techniques were conducted on bladder tissue sourced from young rats (7-8 weeks and 10-12 weeks) and older rats (4-5 months and 7-9 months). Organ bath studies revealed that oxytocin (OT) significantly increased bladder contractions, which were significantly attenuated by [ß-Mercapto-ß,ß-cyclopentamethylenepropionyl1, O-Me-Tyr2, Orn8]-Oxytocin) (1 µM) (**** p < 0.0001) and atosiban (10 µM) in both young and older rats (** p < 0.01); in contrast, cligosiban (1 µM and 10 µM) did not inhibit OT-induced contractions in both young and older rats (p ≥ 0.05). Interestingly, cligosiban (1 µM and 10 µM) significantly reduced the frequency of spontaneous contractions within the bladder of both young (*** p < 0.001) and older rats (**** p < 0.0001), while atosiban (10 µM) only demonstrated this effect in older rats (** p < 0.01). Furthermore, immunohistochemistry (IHC) analysis revealed significant colocalization of nuclear-specific oxytocin receptors (OXTRs) in the contractile (smooth muscle) cells within young (** p < 0.01) and older rats (* p < 0.05), indicating OT may be a key modulator of bladder contractility.

Teamwork baseline assessment tool: Sparking teamwork dialogues in health professions training.

WHAT WAS THE EDUCATIONAL CHALLENGE?: A major challenge in health professions education is to equip graduates with essential teamwork skills, addressing cognitive, motivational, and emotional barriers that hinder effective collaboration among students from diverse backgrounds. WHAT WAS THE SOLUTION AND HOW WAS THIS IMPLEMENTED?: The Teamwork Baseline Assessment Tool (TBAT) was developed as an innovative solution to teach collaboration and teamwork, focusing on growth mindsets, reactions to challenging scenarios, and ideal team player attributes. Implemented during the orientation for new first-year students, TBAT facilitated early engagement in teamwork discussions, with students receiving personalised reports to aid in self-reflection and development. WHAT LESSONS WERE LEARNED?: Key lessons included the importance of initiating teamwork conversations early, the value of personalised feedback in promoting self-awareness and peer understanding, and the effectiveness of TBAT in providing instructors with insights into students' teamwork aptitudes. WHAT ARE THE NEXT STEPS?: Expanding TBAT across various student populations and integrating it into the curriculum aims to provide continuous opportunities for applying and reinforcing teamwork and collaboration skills. This strategy will support the development of targeted instructional approaches, fostering a collaborative learning environment and preparing students for the teamwork challenges in healthcare settings.

The Effects of Age on Prostatic Responses to Oxytocin and the Effects of Antagonists.

Benign prostatic hyperplasia (BPH) is an age-related enlargement of the prostate with urethral obstruction that predominantly affects the middle-aged and older male population, resulting in disruptive lower urinary tract symptoms (LUTS), thus creating a profound impact on an individual's quality of life. The development of LUTS may be linked to overexpression of oxytocin receptors (OXTR), resulting in increased baseline myogenic tone within the prostate. Thus, it is hypothesised that targeting OXTR using oxytocin receptor antagonists (atosiban, cligosiban, and ß-Mercapto-ß,ß-cyclopentamethylenepropionyl1, O-Me-Tyr2, Orn8]-Oxytocin (ßMßßC)), may attenuate myogenic tone within the prostate. Organ bath and immunohistochemistry techniques were conducted on prostate tissue from young and older rats. Our contractility studies demonstrated that atosiban significantly decreased the frequency of spontaneous contractions within the prostate of young rats (**** p < 0.0001), and cligosiban (* p < 0.05), and ßMßßC (**** p < 0.0001) in older rats. Additionally, immunohistochemistry findings revealed that nuclear-specific OXTR was predominantly expressed within the epithelium of the prostate of both young (*** p < 0.001) and older rats (**** p < 0.0001). In conclusion, our findings indicate that oxytocin is a key modulator of prostate contractility, and targeting OXTR is a promising avenue in the development of novel BPH drugs.

Reference Gene U2 Enables Direct Comparison between Relative Gene Expression Levels of Vascular Smooth Muscle Cells in Tissue and Culture Using Real-Time Quantitative PCR.

In nearly every lab, real-time quantitative polymerase chain reaction (qPCR) is used to quantify gene expression. However, a comparison of different samples requires the careful selection of suitable reference genes (RGs), sometimes referred to as housekeeping genes. In the case of vascular smooth muscle cells (vSMCs), it is important to know under which conditions gene expression in isolated and cultured vSMCs can be compared with vSMCs in a healthy blood vessel. We isolated the vSMC-containing layer of the rat aorta (tunica media) and used one (longitudinal) half for direct RNA extraction, while the other half served to isolate and culture vSMCs prior to RNA extraction. First, the expression of the routinely used RGs beta-actin (Actb) and Glyceraldehyde-3-phosphate dehydrogenase (Gapdh) is investigated in intact media and corresponding cultured vSMCs. Significant differences in their Ct values show that these RGs could not be used for such direct comparisons; therefore, we select 15 different RGs. Only the gene expression of the small ribonuclear protein (snRNP) U2 shows no significant differences between the absolute Ct values of cultured vSMCs and the intact media; moreover, no differences were found between male and female rats in our experimental setup. In conclusion, U2 was shown to be an appropriate (sex-independent) RG to compare relative expression levels of vSMCs in culture to those vSMCs within their physiological tissue environment.

Identifying the core concepts of pharmacology education: A global initiative.

BACKGROUND AND PURPOSE: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts. EXPERIMENTAL APPROACH: We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two-part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents. KEY RESULTS: The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology. CONCLUSION AND IMPLICATIONS: This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts.

Treatment of benign prostatic hyperplasia and abnormal ejaculation: live imaging reveals tamsulosin - but not tadalafil - induced dysfunction of prostate, seminal vesicles and epididymis.

In brief: One of the most commonly prescribed benign prostatic hyperplasia (BPH) pharmacotherapies, the alpha1-adrenergic blocker tamsulosin, is frequently discontinued, especially by younger patients due to ejaculatory disorders, often without feedback to the attending physician. Using a newly developed ex vivo system simulating sympathetic effects on the most relevant structures for the emission phase of ejaculation, that is seminal vesicles, prostate and the most distal part of the cauda epididymidis, we elucidated that tamsulosin fundamentally disturbed the obligatory noradrenaline-induced contractions in each of these structures which differed to an alternative pharmacotherapy, the PDE5 inhibitor tadalafil. Abstract: 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. 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 smooth muscle cell-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 lead 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 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 do not apply to tadalafil treatment. This new knowledge translates directly to clinical medicine.

Development of a Vertically Integrated Pharmacy Degree.

Whilst curriculum revision is commonplace, whole degree transformation is less so. In this paper we discuss the rationale, design and implementation of a unique pharmacy program by a research-intensive faculty. The new Monash pharmacy curriculum, which had its first intake in 2017, was built using a range of key innovations that aimed to produce graduates that demonstrate key conceptual understanding and all the skills required to deliver world-best patient outcomes. The key elements of the re-design are outlined and include the process and principles developed, as well as key features such as a student-centred individualised program of development arranged around specific, authentic tasks for each skill and earlier enhanced experiential placements where students become proficient in entrustable professional activities. It is hoped the dissemination of this process, as well as the lessons learnt in the process, will be useful to others looking to transform a health curriculum.

Developing a Global Community of Practice for Pharmacy Workforce Resilience-Meet GRiT.

Workforce resilience in pharmacy is required to ensure the practice, education, and administrative systems remain viable and sustainable over time and when facing challenges. Whether it is addressing burnout of pharmacists or students, or the structure and policies/procedures of employment and professional organizations, working to increase resilience across all individuals and sectors is essential to relieve pressure and promote better well-being, especially during the recent pandemic. The purpose of this article is to describe the development of a community of practice global group focused on development of resilience within the pharmacy workforce that is inclusive of students, pharmacy interns/preregistration and registered pharmacists. The steering group meets monthly and has representation of 24 members across eight countries. Members meet to discuss pertinent issues they are facing in practice, as well as to share and progress ideas on education, research, and practice initiatives. To date, members have collectively implemented resilience training in pharmacy education, researched burnout and resilience in both students and pharmacists, and facilitated international collaborations both within and outside core group members. Future activities will focus on strengthening the community of practice in order to harness the power of the collective.

Physiological and pharmacological impact of oxytocin on epididymal propulsion during the ejaculatory process in rodents and men.

During the emission phase of ejaculation, the sperm is driven from the cauda epididymidis, where it is stored, through the vas deferens by strong contractions. These contractions are thought of as being mainly induced by the sympathetic nervous system and the neurotransmitter noradrenaline. In the present study, we investigated the effect of oxytocin (suggested to exert effects during ejaculation as well) on defined segments of the rat and human epididymis using live imaging. Our results indicate that it is the very last part of the epididymis, segment 19 (S19) in rat and likewise segment 9 in human, which responds in a uniquely strong and rapid manner to oxytocin (similar to noradrenaline). Because of the complex nature of this contractile response, we developed an imaging analysis method, which allowed us to quantify multidirectional contractions and to display them using heat maps. The reaction of S19 to oxytocin was concentration-dependent and could be inhibited by pretreatment with oxytocin antagonists (atosiban and cligosiban), but not with an arginine vasopressin 1A antagonist (SR49059). In both rat and human tissue, pretreatment with the alpha-1 adrenoreceptor antagonist tamsulosin inhibited the response to noradrenaline, whereas the effect of oxytocin was unimpaired. Our data (from men and rodents) strongly suggest that the hormone oxytocin is involved in the ejaculatory process. Thus, oxytocin-based medications might be a promising non-adrenergic treatment option for ejaculatory disorders. Additionally, we propose that S19 could be an advantageous model (detecting very low concentrations of oxytocin) to test the bioactivity of new oxytocin agonists and oxytocin antagonists.

Oxytocin receptor antagonists as a novel pharmacological agent for reducing smooth muscle tone in the human prostate.

Pharmacotherapies for the treatment of Benign Prostatic Hyperplasia (BPH) are targeted at reducing cellular proliferation (static component) or reducing smooth muscle tone (dynamic component), but response is unpredictable and many patients fail to respond. An impediment to identifying novel pharmacotherapies is the incomplete understanding of paracrine signalling. Oxytocin has been highlighted as a potential paracrine mediator of BPH. To better understand oxytocin signalling, we investigated the effects of exogenous oxytocin on both stromal cell proliferation, and inherent spontaneous prostate contractions using primary models derived from human prostate tissue. We show that the Oxytocin Receptor (OXTR) is widely expressed in the human prostate, and co-localises to contractile cells within the prostate stroma. Exogenous oxytocin did not modulate prostatic fibroblast proliferation, but did significantly (p < 0.05) upregulate the frequency of spontaneous contractions in prostate tissue, indicating a role in generating smooth muscle tone. Application of atosiban, an OXTR antagonist, significantly (p < 0.05) reduced spontaneous contractions. Individual tissue responsiveness to both exogenous oxytocin (R2 = 0.697, p < 0.01) and atosiban (R2 = 0.472, p < 0.05) was greater in tissue collected from older men. Overall, our data suggest that oxytocin is a key regulator of inherent spontaneous prostate contractions, and targeting of the OXTR and associated downstream signalling is an attractive prospect in the development of novel BPH pharmacotherapies.

Oxytocin in the Male Reproductive Tract; The Therapeutic Potential of Oxytocin-Agonists and-Antagonists.

In this review, the role of oxytocin and oxytocin-like agents (acting via the oxytocin receptor and belonging to the oxytocin-family) in the male reproductive tract is considered. Previous research (dating back over 60 years) is revised and connected with recently found aspects of the role oxytocin plays in male reproductive health. The local expression of oxytocin and its receptor in the male reproductive tract of different species is summarized. Colocalization and possible crosstalk to other agents and receptors and their resulting effects are discussed. The role of the newly reported oxytocin focused signaling pathways in the male reproductive tract, other than mediating contractility, is critically examined. The structure and effect of the most promising oxytocin-agonists and -antagonists are reviewed for their potential in treating male disorders with origins in the male reproductive tract such as prostate diseases and ejaculatory disorders.

Visualising functional 5-HT3 receptors containing A and C subunits at or near the cell surface.

Five different subunits of the human serotonin 3 (5-hydroxytrptamine 3; 5-HT3) receptor exist and these are present in both central and peripheral systems. Different subunits alter the efficacy of 5-HT3 receptor antagonists used to treat diarrhoea predominant-irritable bowel syndrome, chemotherapy induced nausea and vomiting and depression. Cell surface arrangement of 5-HT3 receptor complexes and the contribution of C, D and E subunits to receptor function is poorly understood. Here, we examine interactions of A and C subunits using 5-HT3 receptor subunits containing fluorescent protein inserts between the 3rd and 4th transmembrane spanning region. HEK293T cells that do not normally express 5-HT3 receptor subunits, were transiently transfected with A or C or both subunits. Patch clamp experiments show that cells transfected with either fluorescent protein tagged A or A and C subunits generate whole cell currents in response to 5-HT. These findings correlate with the apparent distribution of fluorescent protein tagged A and C subunits at or near cell surfaces detected using TIRF microscopy. In co-transfected cells, the A and C subunits are associated forming AC heteromer complexes at or near the cell surface and a proportion can also form A or C homomers. In conclusion, it is likely that both A homomers and AC heteromers contribute to whole cell currents in response to 5-HT with minimal contribution from C homomers.

Generation and Regulation of Spontaneous Contractions in the Prostate.

Spontaneous myogenic contractions have been shown to be significantly upregulated in prostate tissue collected from men with Benign Prostatic Hyperplasia (BPH), an extremely common disorder of the ageing male. Although originally thought likely to be involved in 'housekeeping' functions, mixing prostatic secretions to prevent stagnation, these spontaneous myogenic contractions provide a novel opportunity to understand and treat BPH. This treatment potential differs from previous models, which focused exclusively on attenuating nerve-mediated neurogenic contractions. Previous studies in the rodent prostate have provided an insight into the mechanisms underlying the regulation of myogenic contractions. 'Prostatic Interstitial Cells' (PICs) within the prostate appear to generate pacemaker potentials, which arise from the summation of number of spontaneous transient depolarisations triggered by the spontaneous release of Ca2+ from internal stores and the opening of Ca2+-activated Cl- channels. Pacemaker potentials then conduct into neighbouring smooth muscle cells to generate spontaneous slow waves. These slow waves trigger the firing of 'spike-like' action potentials, Ca2+ entry and contraction, which are not attenuated by blockers of neurotransmission. However, these spontaneous prostatic contractions can be modulated by the autonomic nervous system. Here, we discuss the mechanisms underlying rodent and human prostate myogenic contractions and the actions of existing and novel pharmacotherapies for the treatment of BPH. Understanding the generation of human prostatic smooth muscle tone will confirm the mechanism of action of existing drugs, inform the identification and effectiveness of new pharmacotherapies, as well as predict patient outcomes.

Development of a self-report instrument for measuring in-class student engagement reveals that pretending to engage is a significant unrecognized problem.

Student engagement during classes includes behavioural, cognitive and emotional components, and is a pre-requisite for successful active learning environments. A novel approach to measuring student engagement was developed, involving triangulation of real-time student-self report, observation by trained observers and heart rate measurement. The self-report instrument was evaluated in four separate cohorts (n = 123) at Monash University and the University of North Carolina. The six item self-report demonstrated good reliability (Cronbach's alpha values ranged from 0.7-0.81). The self-report showed predictive validity in that small group activities were rated as significantly more engaging than didactic lecturing. Additionally, there was significant inter-instructor variability and within-class variability, indicating good discrimination between classroom activities. This self-report may prove useful to academic teaching staff in evaluating and refining their active learning activities. Independent observation was not found to correlate with student self-report, due in part to students who were pretending to engage being rated as engaged by an observer. Strikingly, students reported that they were pretending to engage for 23% of class time, even for highly regarded instructors. Individual participants were rated as engaged for 42 of the 46 intervals for which they reported that they had "pretended to engage", indicating that the two observers were unable to detect disengagement during periods in which students pretended to engage. Instructors should be aware that student cues such as eye contact and nodding may indicate pretending to engage. One particular self-report item; "I tried a new approach or way of thinking about the content", correlated positively with heart rates, and a controlled study reproduced this finding during two activities that required students to try a new approach to understanding a concept. Agreement with this item also correlated with superior performance on two in-class written assessment tasks (n = 101, p<0.01). Further use of this tool and related educational research may be useful to identify in-class activities that are engaging and likely to lead to improved student attainment of learning outcomes.

The C and E subunits of the serotonin 5-HT3 receptor subtly modulate electrical properties of the receptor.

Serotonin type 3 (5-hydroxytrptamine-3, 5-HT3) receptors are ligand-gated cation channels present in both central and peripheral nervous systems. In humans there are five different subunits (A, B, C, D and E) of 5-HT3 receptors which can form homomeric or heteromeric receptors that may account for discrepancies in patient responses to treatments. The present study commences characterisation of the profiles of human 5-HT3 receptors containing C and/or E subunits. Recombinant 5-HT3 receptors were expressed transiently in HEK293T cells and expression was checked via immunocytochemistry staining against each epitope-tagged subunits. Functional characterisation of different combinations of 5-HT3 receptor complexes was studied via patch clamp whole cell recordings. In this study, increased current was seen in cells containing A and C subunits but only subtle changes were seen in the electrical properties of cells expressing A, AE, or ACE subunits in response to the ligand, 5-HT. Both di- and tri-heteromeric 5-HT3 receptors were significantly inhibited by the antagonists, ondansetron and palonosetron. Notably, palonosetron exerted stronger and more rapid inhibition on the 5-HT3 receptor ACE tri-heteromer compared to homomeric and di-heteromeric counterparts. This study demonstrated that the C and E subunits when assembled as simple or complex heteromeric 5-HT3 receptors may alter efficacies of 5-HT and clinically used antagonists such as ondansetron and palonosetron, and this in turn may have implications for patient responses to therapies.

Novel imaging of the prostate reveals spontaneous gland contraction and excretory duct quiescence together with different drug effects.

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.

Age Related Differences in Responsiveness to Sildenafil and Tamsulosin are due to Myogenic Smooth Muscle Tone in the Human Prostate.

Lower urinary tract symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH) are highly prevalent in older men, having a profound impact on patient quality of life. Current therapeutics for BPH/LUTS target neurogenic smooth muscle tone, but response is unpredictable and many patients fail to respond. Spontaneous myogenic tone is another component of smooth muscle contractility that is uncharacterized in human prostate. To better understand and improve the predictability of patient response, we defined myogenic contractility using human prostate specimens and examined the effect of existing therapeutics. We show that myogenic activity is present in the human prostate with the frequency of contractions in transition zone (TZ) specimens from BPH diagnosed patients approximately 160% greater than matched controls. α1-adrenoreceptor antagonists (Tamsulosin) and PDE5 inhibitors (Sildenafil) both significantly reduced myogenic contractile parameters, including frequency, with notable interpatient variability. Tamsulosin was more effective in older patients (R2 = 0.36, p < 0.01) and men with larger prostate volumes (R2 = 0.41, p < 0.05), while Sildenafil was more effective in younger men (R2 = 0.45, p < 0.05). As myogenic tone is significantly increased in BPH, therapeutics targeting this mechanism used with reference to patient characteristics could improve clinical outcomes and better predict patient response.

Tamsulosin modulates, but does not abolish the spontaneous activity in the guinea pig prostate gland.

AIMS: To examine the effects of the α1A -adrenoceptor antagonist, tamsulosin, on spontaneous contractile and electrical activity in the guinea-pig prostate gland. METHODS: The effects of tamsulosin (0.1 and 0.3 nM) were investigated in adult and ageing male guinea pig prostate glands using conventional tension recording and electrophysiological intracellular microelectrode recording techniques. RESULTS: Tamsulosin reduced spontaneous activity, and had different age-dependent effects on adult and ageing guinea pigs at different concentrations. 0.1 nM tamsulosin caused a significantly greater reduction of spontaneous contractile and electrical activity in ageing guinea pigs in comparison to adult guinea pigs. In contrast, 0.3 nM tamsulosin had a significantly greater reduction of spontaneous contractile and electrical activity in adult guinea pigs in comparison to ageing guinea pigs. CONCLUSIONS: This study demonstrates that tamsulosin can modulate spontaneous myogenic stromal contractility and the underlying spontaneous electrical activity; tamsulosin does not block spontaneous activity. This reduction in spontaneous activity suggests that downstream cellular mechanisms underlying smooth muscle tone are being targeted, and these may represent novel therapeutic targets to better treat benign prostatic hyperplasia.

Male contraception via simultaneous knockout of α1A-adrenoceptors and P2X1-purinoceptors in mice.

Therapeutic targets for male contraception are associated with numerous problems due to their focus on disrupting spermatogenesis or hormonal mechanisms to produce dysfunctional sperm. Here we describe the dual genetic deletion of α1A-adrenergic G protein-coupled receptors (adrenoceptors) and P2X1-purinoceptor ligand gated ion channels in male mice, thereby blocking sympathetically mediated sperm transport through the vas deferens during the emission phase of ejaculation. This modification produced 100% infertility without effects on sexual behavior or function. Sperm taken from the cauda epididymides of double knockout mice were microscopically normal and motile. Furthermore, double knockout sperm were capable of producing normal offspring following intracytoplasmic sperm injection into wild-type ova and implantation of the fertilized eggs into foster mothers. Blood pressure and baroreflex function was reduced in double knockout mice, but no more than single knockout of α1A-adrenoceptors alone. These results suggest that this autonomic method of male contraception appears free of major physiological and behavioral side effects. In addition, they provide conclusive proof of concept that pharmacological antagonism of the P2X1-purinoceptor and α1A-adrenoceptor provides a safe and effective therapeutic target for a nonhormonal, readily reversible male contraceptive.