No abstract

Bradykinin (BK) has been proposed to modulate urinary bladder functions and implicated in the pathophysiology of detrusor overactivity. The present study aims to elucidate the signaling pathways of BK-induced detrusor muscle contraction, with the goal of better understanding the molecular regulation of micturition and identifying potential novel therapeutic targets of its disorders. Experiments have been carried out on bladders isolated from wild-type or genetically modified [smooth muscle-specific knockout (KO): Gαq/11-KO, Gα12/13-KO and constitutive KO: thromboxane prostanoid (TP) receptor-KO, cyclooxygenase-1 (COX-1)-KO] mice and on human bladder samples. Contractions of detrusor strips were measured by myography. Bradykinin induced concentration-dependent contractions in both murine and human bladders, which were independent of secondary release of acetylcholine, ATP, or prostanoid mediators. B2 receptor antagonist HOE-140 markedly diminished contractile responses in both species, whereas B1 receptor antagonist R-715 did not alter BK's effect. Consistently with these findings, pharmacological stimulation of B2 but not B1 receptors resembled the effect of BK. Interestingly, both Gαq/11- and Gα12/13-KO murine bladders showed reduced response to BK, indicating that simultaneous activation of both pathways is required for the contraction. Furthermore, the Rho-kinase (ROCK) inhibitor Y-27632 markedly decreased contractions in both murine and human bladders. Our results indicate that BK evokes contractions in murine and human bladders, acting primarily on B2 receptors. Gαq/11-coupled and Gα12/13-RhoA-ROCK signaling appear to mediate these contractions simultaneously. Inhibition of ROCK enzyme reduces the contractions in both species, identifying this enzyme, together with B2 receptor, as potential targets for treating voiding disorders.

Összefoglaló. Bevezetés: A hiperaktív húgyhólyag szindróma népbetegség mértékű probléma, mely jelentősen rontja az érintettek életminőségét. A konzervatív, gyógyszeres kezelés eredménytelensége esetén másodvonalbeli terápiaként a minimálisan invazív botulinumtoxin intradetrusor injekció javasolható. Célkitűzés: A nem neurogén eredetű hiperaktív (túlműködő) hólyag szindróma miatt végzett botulinumtoxin intradetrusor injekciós kezelés hatékonyságának, biztonságosságának felmérése saját beteganyagunkon, és annak vizsgálata, hogy az eredményességet befolyásolják-e a vizsgált preoperatív paraméterek. Módszer: Egy retrospektív vizsgálat során összegyűjtöttük 33, intradetrusor BOTOX® injekción átesett betegünk perioperatív adatait (életkor, testtömegindex, kísérő betegségek, anatómiai eltérések, korábbi műtétek, panaszok, urodinámiás leletek). Az eredményesség és a posztoperatív komplikációk felmérése a betegdokumentáció, telefoninterjúk, kérdőívek segítségével történt. A statisztikai analízis során kapott eredményeket p<0,05 esetén tekintettük szignifikánsnak. Eredmények: Műtét után jelentős szövődményt nem tapasztaltunk (p>0,05), 6 betegnél észleltünk hólyagkatéterezést nem igénylő residuumot (p = 0,024). Az urgencia, ’urge’ incontinentia, pollakisuria, nycturia előfordulása és mértéke, a vizeletincontinentia miatti betéthasználat szignifikánsan csökkent (p<0,01), az életminőség, az általános egészségi állapot mutatói szignifikánsan javultak a műtét után (p<0,001). A perioperatív faktorok és a posztoperatív eredményesség (72,7%) között szignifikáns kapcsolat nem igazolódott (p>0,05). Megbeszélés: A tüneti javulás eredményei megegyeznek az irodalmi adatokkal, a nemzetközi publikációkban közölt eredményekhez képest is jobb mellékhatásprofil pedig az óvatosabb betegszelekcióval és részletesebb kivizsgálással magyarázható. Következtetés: A botulinumtoxin-A-terápia hatékony, biztonságos, minimálisan invazív kezelése a terápiarefrakter hiperaktív hólyag szindrómának. Nem sikerült olyan preoperatív faktort azonosítanunk, mely szignifikáns hatással bírna a kezelés eredményességének előrejelzésére. Orv Hetil. 2021; 162(36): 1459–1465. Summary. Introduction: Overactive bladder syndrome is an endemic phenomenon, which has a significant impact on the quality of life. In cases where conservative treatment fails, intradetrusor onabotulinumtoxinA injection can be used as second-line therapy. Objective: To assess the safety and efficacy of onabotulinumtoxinA treatment in the management of non-neurogenic detrusor overactivity among our patients. Also, to examine the influence of perioperative factors on the effects of the efficacy. Method: We have retrospectively collected the perioperative data of 33 patients treated with intradetrusor BOTOX®. The assessment of the efficacy and complications was done by the examination of patient files and questionnaires. The results obtained during the statistical analysis were considered significant for p<0.05. Results: We have not experienced notable complications after the procedures. Only 6 patients had residual urine (p = 0.024), none of them needed to be catheterized. We have observed significant decrease in the incidence of frequency, nocturia, urgency and incontinence, just as in the number of pads needed daily (p<0.01). Quality of life and general health were significantly improved (p<0.001). We have not found any significant connection between preoperative factors and efficacy (72.7%). Discussion: Our results considering the relief of symptoms are well in line with international data. The fact that our rate of complications is – in international comparison – outstanding can be explained by a more careful patient selection and thorough preoperative assessment. Conclusion: OnabotulinumtoxinA therapy is a safe and effective solution of therapy-refractory overactive bladder. We could not identify any perioperative factor to predict postoperative efficacy of therapy. Orv Hetil. 2021; 162(36): 1459–1465.

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BackgroundIn animal studies, the inhibition of VEGF activity results in high mortality and impaired renal and glomerular development. Mechanical stimuli, like mechanical stretch in respiratory and circulatory systems, results in an elevated expression of VEGF. In animal models, the experimental urinary obstruction is associated with stretching of tubular cells and activations of the renin-angiotensin system. This results in the upregulation of vascular endothelial growth factor (VEGF) and TNF-alfa.Material/MethodsTissue samples from urinary tract obstruction were collected and immunohistochemistry was performed in 14 patients (average age: 7.1±4.1 years). The control histology group consisted of ureteropelvic junction tissue from 10 fetuses after midtrimester artificial abortion. The fetuses did not have any failure at ultrasound screening and pathological examination. The mean gestational age was 20.6 weeks of gestation (±2.2SD). Expression of VEGF was detected with immunohistochemistry method.ResultsExpression of VEGF was found in varying intensity in the submucosa and subserosa layers, but only in the test tissue (placental tissue). The tissue of the patients with urinary obstruction and the tissue of the fetal ureteropelvic junction without urinary obstruction were negative for expression of VEGF. The repeated examination showed negative cells and no color staining.ConclusionsThe pressure due to congenital urogenital obstruction resulting in mechanical stress in cells did not increase the expression of VEGF in young children in our study. To find a correlation between urogenital tract obstruction and increased expression of VEGF, we need to perform more examinations because the connection may be of therapeutic significance.