Effekte von Inhibitoren der p21-aktivierten Kinase auf die glattmuskuläre Kontraktion der humanen Prostata

Jährlich werden weltweit 4,2 Milliarden USD für die Behandlung des BPS ausgegeben. Es wird vermutet, dass ca. 847 Millionen Männer weltweit an LUTS sekundär zu BPH leiden. Die BPH zählt mit einer Prävalenz von über 70 % bei über 70-Jährigen zu einer der häufigsten geriatrischen Erkrankungen des Mannes, bei der vor allem das Alter als der entscheidende Faktor anzusehen ist. Die leitliniengerechte Therapie sieht vor allem α1-Adrenozeptorblocker als Goldstandard vor. Diese können den IPSS um 30-50 % und Qmax um 15-40 % verbessern. Hier muss allerdings angemerkt werden, dass deren Wirksamkeit in der Symptomenreduktion den Placebos nahezu gleicht. So verbessern Placebos den IPSS um 10-34 % und Qmax sogar um bis zu 27 %. Nicht zu vernachlässigen sind auch die Nebenwirkungen der α1-Blocker, wie etwa Schwindel, Hypotension, Abgeschlagenheit, Kopfschmerzen, Diarrhoe und Ejakulationsstörungen. Die Ergebnisse der hier vorliegenden Arbeit konnten zeigen, dass Inhibitoren der p21-aktivierten Kinase nicht nur die neurogene über α1-Adrenozeptoren vermittelte, sondern auch die Endothelin induzierte glattmuskuläre Kontraktion der humanen Prostata signifikant herabsetzen. Daher wäre zu erwarten, dass PAK-Inhibitoren im Hinblick auf ihre urodynamische Wirksamkeit effektiver sind als die bisher zur Anwendung kommenden α1-Adrenozeptorblocker

Effekte von Inhibitoren der p21-aktivierten Kinase auf die glattmuskuläre Kontraktion der humanen Prostata

Jährlich werden weltweit 4,2 Milliarden USD für die Behandlung des BPS ausgegeben. Es wird vermutet, dass ca. 847 Millionen Männer weltweit an LUTS sekundär zu BPH leiden. Die BPH zählt mit einer Prävalenz von über 70 % bei über 70-Jährigen zu einer der häufigsten geriatrischen Erkrankungen des Mannes, bei der vor allem das Alter als der entscheidende Faktor anzusehen ist. Die leitliniengerechte Therapie sieht vor allem α1-Adrenozeptorblocker als Goldstandard vor. Diese können den IPSS um 30-50 % und Qmax um 15-40 % verbessern. Hier muss allerdings angemerkt werden, dass deren Wirksamkeit in der Symptomenreduktion den Placebos nahezu gleicht. So verbessern Placebos den IPSS um 10-34 % und Qmax sogar um bis zu 27 %. Nicht zu vernachlässigen sind auch die Nebenwirkungen der α1-Blocker, wie etwa Schwindel, Hypotension, Abgeschlagenheit, Kopfschmerzen, Diarrhoe und Ejakulationsstörungen. Die Ergebnisse der hier vorliegenden Arbeit konnten zeigen, dass Inhibitoren der p21-aktivierten Kinase nicht nur die neurogene über α1-Adrenozeptoren vermittelte, sondern auch die Endothelin induzierte glattmuskuläre Kontraktion der humanen Prostata signifikant herabsetzen. Daher wäre zu erwarten, dass PAK-Inhibitoren im Hinblick auf ihre urodynamische Wirksamkeit effektiver sind als die bisher zur Anwendung kommenden α1-Adrenozeptorblocker

Concentration-dependent alpha(1)-Adrenoceptor Antagonism and Inhibition of Neurogenic Smooth Muscle Contraction by Mirabegron in the Human Prostate

Introduction: Mirabegron is available for treatment of storage symptoms in overactive bladder, which may be improved by β3-adrenoceptor-induced bladder smooth muscle relaxation. In addition to storage symptoms, lower urinary tract symptoms in men include obstructive symptoms attributed to benign prostatic hyperplasia, caused by increased prostate smooth muscle tone and prostate enlargement. In contrast to the bladder and storage symptoms, effects of mirabegron on prostate smooth muscle contraction and obstructive symptoms are poorly understood. Evidence from non-human smooth muscle suggested antagonism of α1-adrenoceptors as an important off-target effect of mirabegron. As α1-adrenergic contraction is crucial in pathophysiology and medical treatment of obstructive symptoms, we here examined effects of mirabegron on contractions of human prostate tissues and on proliferation of prostate stromal cells. Methods: Contractions were induced in an organ bath. Effects of mirabegron on proliferation, viability, and cAMP levels in cultured stromal cells were examined by EdU assays, CCK-8 assays and enzyme-linked immunosorbent assay. Results: Mirabegron in concentrations of 5 and 10 μM, but not 1 µM inhibited electric field stimulation-induced contractions of human prostate tissues. Mirabegron in concentrations of 5 and 10 µM shifted concentration response curves for noradrenaline-, methoxamine- and phenylephrine-induced contractions to the right, including recovery of contractions at high concentrations of α1-adrenergic agonists, increased EC50 values, but unchanged Emax values. Rightshifts of noradrenaline concentration response curves and inhibition of EFS-induced contractions were resistant to L-748,337, l-NAME, and BPIPP. 1 µM mirabegron was without effect on α1-adrenergic contractions. Endothelin-1- and U46619-induced contractions were not affected or only inhibited to neglectable extent. Effects of mirabegron (0.5–10 µM) on proliferation and viability of stromal cells were neglectable or small, reaching maximum decreases of 8% in proliferation assays and 17% in viability assays. Mirabegron did not induce detectable increases of cAMP levels in cultured stromal cells. Conclusion: Mirabegron inhibits neurogenic and α1-adrenergic human prostate smooth muscle contractions. This inhibition may be based on antagonism of α1-adrenoceptors by mirabegron, and does not include activation of β3-adrenoceptors and requires concentrations ranging 50-100fold higher than plasma concentrations reported from normal dosing. Non-adrenergic contractions and proliferation of prostate stromal cells are not inhibited by mirabegron

Selective inhibition of neurogenic, but not agonist‐induced contractions by phospholipase A2 inhibitors points to presynaptic phospholipase A2 functions in contractile neurotransmission to human prostate smooth muscle

Background Phospholipases A2 (PLA2) may be involved in α1-adrenergic contraction by formation of thromboxane A2 in different smooth muscle types. However, whether this mechanism occurs with α1-adrenergic contractions of the prostate, is still unknown. While α1-adrenoceptor antagonists are the first line option for medical treatment of voiding symptoms in benign prostatic hyperplasia (BPH), improvements are limited, probably by nonadrenergic contractions including thromboxane A2. Here, we examined effects of PLA2 inhibitors on contractions of human prostate tissues. Methods Prostate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS) and by α1-adrenergic agonists in an organ bath, after application of the cytosolic PLA2 inhibitors ASB14780 and AACOCF3, the secretory PLA2 inhibitor YM26734, the leukotriene receptor antagonist montelukast, or of solvent to controls. Results Frequency-dependent contractions of human prostate tissues induced by EFS were inhibited by 25% at 8 Hz, 38% at 16 Hz and 37% at 32 Hz by ASB14780 (1 µM), and by 32% at 16 Hz and 22% at 32 Hz by AACOCF3 (10 µM). None of both inhibitors affected contractions induced by noradrenaline, phenylephrine or methoxamine. YM26734 (3 µM) and montelukast (0.3 and 1 µM) neither affected EFS-induced contractions, nor contractions by α1-adrenergic agonists, while all contractions were substantially inhibited by silodosin (100 nM). Conclusions Our findings suggest presynaptic PLA2 functions in prostate smooth muscle contraction, while contractions induced by α1-adrenergic agonists occur PLA2-independent. Lacking sensitivity to montelukast excludes an involvement of PLA2-derived leukotrienes in promotion of contractile neurotransmission

Gender Bias in Urology: How Do Patients Really Choose Their Urologist?

Purpose: The present study aimed to investigate the influence of patients’ and urologists’ gender when choosing a urologist. With rising population diversity through immigration and generational differences, patient-centered healthcare has recently moved to the focus of European healthcare systems. As healthcare in urology often concentrates on sensitive topics, and often involves gender-specific diseases, research on the influence of gender on decision-making processes is of high importance. Understanding influence of gender on patients’ choices in real life would provide patients, and physicians alike, with the means to provide better resources to achieve greater satisfaction from visits to a urologist. Patients and Methods: A questionnaire was prepared, and patients at our tertiary referral center were given the opportunity to voluntarily participate in our survey. We collected questionnaires from 1012 patients during their visits from June 2021 to October 2021. Results: Patients were divided into groups according to their gender: male (n=763), female (n=246), and non-binary (n=3). Our patient cohort consisted of more men than women (75% vs 24%), with only three patients identifying as non-binary. Irrespective of the patients’ own gender, patients preferred a male urologist when problems were considered embarrassing, limiting daily activities, or when worrisome. When problems were considered painful, all patients preferred a female urologist. When patients had had a previous positive experience with a female or male urologist, they preferred to be treated by a female or male urologist, respectively. Overall, 65% of patients stated a gender preference for at least one given situation, or consultation scenario. Conclusion: As the majority of our patients stated a gender preference, urological departments should be considerate of potential patients’ preferences for urologist gender that may be based on the individual patient’s history, taking a comprehensive approach to fulfill the patients’ need for same gender urologists in educational hospitals and health care services

Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766

Introduction: Lower urinary tract symptoms (LUTS) due to overactive bladder (OAB) are caused by spontaneous detrusor contractions. Medical treatment with muscarinic receptor antagonists or β3-adrenoceptor agonists aims to inhibit detrusor contractions, but overall results are unsatisfactory. Consequently, improved understanding of bladder smooth muscle contraction and identification of novel compounds for its inhibition are needed to develop alternative options. A role of the GTPase Rac1 for smooth muscle contraction has been reported from the prostate, but is unknown in the human detrusor. Here, we examined effects of the Rac inhibitors NSC23766, which may also antagonize muscarinic receptors, and EHT1864 on contraction of human detrusor tissues. Methods: Female and male human detrusor tissues were obtained from radical cystectomy. Effects of NSC23766 (100 µM) and EHT1864 (100 µM) on detrusor contractions were studied in an organ bath. Results: Electric field stimulation induced frequency-dependent contractions of detrusor tissues, which were inhibited by NSC23766 and EHT1864. Carbachol induced concentration-dependent contractions. Concentration response curves for carbachol were shifted to the right by NSC23766, reflected by increased EC50 values, but unchanged Emax values. EHT1864 reduced carbachol-induced contractions, resulting in reduced Emax values for carbachol. The thromboxane analog U46619 induced concentration-dependent contractions, which remained unchanged by NSC23766, but were reduced by EHT1864. Conclusions: NSC23766 and EHT1864 inhibit female and male human detrusor contractions. NSC23766, but not EHT1864 competitively antagonizes muscarinic receptors. In addition to neurogenic and cholinergic contractions, EHT1864 inhibits thromboxane A2-induced detrusor contractions. The latter may be promising, as the origin of spontaneous detrusor contractions in OAB is noncholinergic. In vivo, both compounds may improve OAB-related LUTS

Ghrelin Aggravates Prostate Enlargement in Rats with Testosterone-Induced Benign Prostatic Hyperplasia, Stromal Cell Proliferation, and Smooth Muscle Contraction in Human Prostate Tissues

Epidemiologic studies revealed a context between lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and metabolic syndrome. However, molecular mechanisms underlying this relationship are largely unknown. Prostate enlargement and increased prostate smooth muscle tone are important factors in the pathophysiology of LUTS suggestive of BPH. In the present study, we studied effects of the metabolic hormone ghrelin on prostate enlargement in rats with experimentally induced BPH, growth of cultured stromal cells from human prostate (WPMY-1), and smooth muscle contraction of human prostate tissues. Ghrelin (20 nmol/kg daily, p.o., 2 weeks) increased prostate size in rats with testosterone-induced BPH. Microarray identified 114 ghrelin-upregulated genes (2-fold or more) in these prostates, with possible roles in growth, smooth muscle contraction, or metabolism. 12 genes were selected for further analyses. In human prostate tissues, mRNA levels of 11 of them correlated positively with ghrelin receptor (GHSR) expression, but only two with the degree of BPH. Accordingly, no correlation was evident between GHSR expression level and BPH in human prostate tissues. In WPMY-1 cells, the GHRS agonist MK0677 upregulated 11 of the selected genes. MK0677 induced proliferation of WPMY-1 cells, shown by EdU assay, colony formation, proliferation markers, flow cytometry, and viability. In myographic measurements, GHSR agonists enhanced contractions of human prostate strips. Together, ghrelin may aggravate prostate enlargement, stromal cell growth, and prostate smooth muscle contraction in BPH. Ghrelin may deteriorate urethral obstruction independently from BPH, qualifying the ghrelin system as an attractive new target to be tested for LUTS treatment in BPH

Propensity Score-Matched Analysis of Single Fraction Robotic Radiosurgery Versus Open Partial Nephrectomy in Renal Cell Carcinoma: Oncological Outcomes

Introduction High-dose local stereotactic robotic radiosurgery (RRS) is a non-invasive alternative to surgery in renal masses and selected patients. We have, so far, limited its use to the elderly and patients at high risk from surgery. In this study, we matched patients with renal tumors who were treated with single fraction RRS to patients who underwent open partial nephrectomy (OPN). Methods Between January 2009 and December 2017, we included 571 consecutive patients undergoing OPN and 99 patients who underwent RRS in this retrospective analysis. Patients had to have a follow-up of at least six months and we were able to match 35 with a propensity score. Matching criteria were Eastern Cooperative Oncology Group (ECOG) status, age, clinical tumor, nodes, and metastases (TNM), and tumor diameter. Tumor response, renal function, survival, and adverse events were evaluated every three months until progression or death. Results Median age was 65 years for RRS (range 58-75) and 71 (range 56-76) for OPN (p=0.131). Median diameter of renal tumors was 2.8 cm (range 2.4-3.9) for RRS and 3.5 cm (2.8-4.5) for OPN, p=0.104. Median follow-up was 28.1 months (range 6.0-78.3 months). Local tumor control nine months after RRS and OPN was 98% (95% CI: 89-99%). Renal function remained stable with a median creatinine clearance (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) at baseline of 76.8mlmin/1.73m(2) (range 25.3-126.3) and 70.3ml/min/1.73m(2)(range 18.6-127.3) at follow-up (p=0.89). Median overall survival was not reached. No difference in overall survival (OS) was seen in RRS compared to OPN (p=0.459). Conclusions Single fraction RRS is an alternative to OPN in patients unfit for surgery. Oncological and functional results are comparable to those of OPN. Further studies are needed to determine long-term results and limits of RRS in this setting and in younger patients