Effects of oral administration of nonselective Trk inhibitor on bladder overactivity in rodent models of prostatic inflammation.

BACKGROUND: Our research focused on the assessment of the impact of systemic inhibition of Trk receptors, which bind to nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), on bladder hypersensitivity in two distinct rodent models of prostatic inflammation (PI). METHODS: Male Sprague-Dawley rats were divided into three groups (n = 6 each): the control group (no PI, vehicle administration), the untreated group (PI, vehicle administration), and the treated group (PI, nonselective Trk inhibitor, GNF 5837, administration). PI in rats was induced by a intraprostatic injection of 5% formalin. Posttreatment, we carried out conscious cystometry and a range of histological and molecular analyses. Moreover, the study additionally evaluated the effects of a nonselective Trk inhibitor on bladder overactivity in a mouse model of PI, which was induced by prostate epithelium-specific conditional deletion of E-cadherin. RESULTS: The rat model of PI showed upregulations of NGF and BDNF in both bladder and prostate tissues in association with bladder overactivity and inflammation in the ventral lobes of the prostate. GNF 5837 treatment effectively mitigated these PI-induced changes, along with reductions in TrkA, TrkB, TrkC, and TRPV1 mRNA expressions in L6-S1 dorsal root ganglia. Also, in the mouse PI model, GNF 5837 treatment similarly improved bladder overactivity. CONCLUSIONS: The findings of our study suggest that Trk receptor inhibition, which reduced bladder hypersensitivity and inflammatory responses in the prostate, along with a decrease in overexpression of Trk and TRPV1 receptors in sensory pathways, could be an effective treatment strategy for male lower urinary tract symptoms associated with PI and bladder overactivity.

Autonomic nervous system dysregulation in children with monosymptomatic nocturnal enuresis.

AIM: To investigate the role of autonomic nervous system in subpopulations of children with enuresis. METHODS: We included 35 children with enuresis, divided in children with (17) and without nocturnal polyuria (18) and 43 healthy controls. For all participants hormones and neurotransmitters were measured. Patients and controls wore a sleep tracker device and children with enuresis underwent a 24 h blood pressure monitoring, nocturnal urine output measurement and uroflowmetry. RESULTS: Children with enuresis had lower than controls copeptin and aldosterone, with the latter being more prominent in patients without nocturnal polyuria. Dopamine was lower in patients without nocturnal polyuria compared with patients with nocturnal polyuria. Children without polyuria experienced episodes only during NREM sleep, whereas in children with polyuria episodes occurred in both REM and NREM sleep. Children with enuresis experienced a non-dipping phenomenon during sleep which was more prominent in the group without polyuria. CONCLUSION: In patients with nocturnal polyuria, nocturnal enuresis is associated with sympathetic hyperactivity which results in pressure polyuria and significantly lower systolic dipping during sleep. On the contrary, in children without nocturnal polyuria, it is mostly associated with bladder overactivity due to parasympathetic overstimulation as demonstrated by the NREM-related enuretic episodes and the lower aldosterone and dopamine levels.

Local Injection of Stem Cells Can Be a Potential Strategy to Improve Bladder Dysfunction after Outlet Obstruction in Rats.

This study investigates whether hAFSCs can improve bladder function in partial bladder outlet obstruction (pBOO) rats by targeting specific cellular pathways. Thirty-six female rats were divided into sham and pBOO groups with and without hAFSCs single injection into the bladder wall. Cystometry, inflammation/hypoxia, collagen/fibrosis/gap junction proteins, and smooth muscle myosin/muscarinic receptors were examined at 2 and 6 weeks after pBOO or sham operation. In pBOO bladders, significant increases in peak voiding pressure and residual volume stimulated a significant upregulation of inflammatory and hypoxic factors, TGF-ß1 and Smad2/3. Collagen deposition proteins, collagen 1 and 3, were significantly increased, but bladder fibrosis markers, caveolin 1 and 3, were significantly decreased. Gap junction intercellular communication protein, connexin 43, was significantly increased, but the number of caveolae was significantly decreased. Markers for the smooth muscle phenotype, myosin heavy chain 11 and guanylate-dependent protein kinase, as well as M2 muscarinic receptors, were significantly increased in cultured detrusor cells. However, hAFSCs treatment could significantly ameliorate bladder dysfunction by inactivating the TGFß-Smad signaling pathway, reducing collagen deposition, disrupting gap junctional intercellular communication, and modifying the expressions of smooth muscle myosin and caveolae/caveolin proteins. The results support the potential value of hAFSCs-based treatment of bladder dysfunction in BOO patients.

Efficacy of KPR-5714, a selective transient receptor potential melastatin 8 antagonist, on chronic psychological stress-induced bladder overactivity in male rats.

AIMS: Chronic psychological stress aggravates lower urinary tract symptoms. Among others, water avoidance stress is a chronic psychological stressor that plays a causal role in the exacerbation and development of bladder dysfunction in rats. In this report, the effects of KPR-5714, which is a selective transient receptor potential melastatin 8 (TRPM8) antagonist, on bladder overactivity induced by water avoidance stress were examined. METHODS: Male rats were subjected to water avoidance stress for 2 h per day for 10 consecutive days. The effects of water avoidance stress on voiding behavior using metabolic cages and histological bladder changes were investigated in rats. The involvement of bladder C-fiber afferent on voiding frequency in rats exposed to water avoidance stress was assessed using capsaicin. The effects of KPR-5714 on storage dysfunction in rats subjected to water avoidance stress were examined. RESULTS: In voiding behavior measurements, water avoidance stress-induced storage dysfunction, causing a decrease in the mean voided volume and increasing voiding frequency. A comparison of bladders from normal rats and rats exposed to water avoidance stress showed no histological differences. Water avoidance stress-induced bladder overactivity was completely inhibited by pretreatment with capsaicin. KPR-5714 showed a tendency to increase the mean voided volume and significantly decreased the voiding frequency without affecting the total voided volume in these rats. CONCLUSION: The results suggest that KPR-5714 is a promising option for treating chronic psychological stress-induced bladder overactivity.

Uroprotective Potential of Campesterol in Cyclophosphamide Induced Interstitial Cystitis; Molecular Docking Studies.

Cyclophosphamide (CYP) is commonly used to treat cancer of the ovaries, breast, lymph, and blood system and produces interstitial cystitis (IC) via its urotoxic metabolite: i. e., acrolein. The present study was aimed to investigate the uroprotective effect of campesterol (a steroidal phytochemical) in cyclophosphamide induced IC. IC was induced by CYP (150 mg/kg, i. p.) in rats. The Enzyme linked immunosorbent assays for oxidative stress markers and Polymerase Chain Reaction (PCR) for inflammatory cytokines were carried out. The Tissue Organ Bath Technique was used for the evaluation of the spasmolytic effect of campesterol. Different pharmacological antagonists have been used to explore the mechanism of action of campesterol. Treatment with campesterol (70 mg/kg) reduced nociception (55 %), edema (67 %), hemorrhage (67 %), and protein leakage significantly (94 %). The antioxidant activity of campesterol was exhibited by a fall in MDA, NO, and an elevation in SOD, CAT, and GPX levels. Campesterol presented anti-inflammatory potential by decreasing IL-1, TNF-α, and TGF-ß expression levels. Histologically, it preserved urothelium from the deleterious effect of CYP. Campesterol showed a spasmolytic effect by reducing bladder overactivity that was dependent on muscarinic receptors, voltage-gated calcium and KATP channels, and cyclo-oxygenase pathways. In silico studies confirmed the biochemical findings. The findings suggest that campesterol could be valorized as a possible therapeutic agent against cyclophosphamide-induced interstitial cystitis.

KPR-5714, a selective transient receptor potential melastatin 8 antagonist, improves voiding dysfunction in rats with bladder overactivity but does not affect voiding behavior in normal rats.

AIMS: Transient receptor potential melastatin 8 (TRPM8) has a role in the abnormal sensory transduction of the bladder and is involved in the pathophysiology of hyperactivity bladder disorders. The aim of this study is to examine the effects of KPR-5714, a novel and selective TRPM8 antagonist, on voiding dysfunction induced by bladder afferent hyperactivity via mechanosensitive C-fibers in rats. METHODS: The effects of intragastric administration of KPR-5714 on bladder overactivity induced by intravesical instillation of 10 mM ATP were investigated using cystometry in conscious female rats. We examined the effects of oral administration of KPR-5714 on voiding behavior using a metabolic cage in normal male rats and rats with an intratesticular injection of 3% acetic acid. RESULTS: In cystometry measurements, the intercontraction interval was decreased by intravesical ATP instillation. KPR-5714 (0.1, 0.3, and 1 mg/kg) dose-dependently prolonged the shortened intercontraction interval provoked by ATP. In voiding behavior measurements, intratesticular injection of acetic acid decreased the mean voided volume and increased voiding frequency. KPR-5714 (0.1 and 0.3 mg/kg) dose-dependently increased the mean voided volume and decreased voiding frequency without affecting the total voided volume in these rats. However, KPR-5714 (1 and 10 mg/kg) did not influence the voiding behavior in normal rats. CONCLUSION: The present results suggest that KPR-5714 improves voiding dysfunction by inhibiting the enhanced activity of mechanosensitive bladder C-fibers in rats with bladder overactivity and shows no significant change in voiding behavior in normal rats.

Estrogen inhibits bladder overactivity in rats with cyclophosphamide-induced cystitis via downregulating the expression of P2X3 receptors in bladder epithelium cells.

AIMS: The therapeutic effect of estrogen on interstitial cystitis/bladder pain syndrome is unclear. We aim to explore the effect of estrogen on bladder overactivity in rats with cyclophosphamide-induced cystitis and its underlying mechanism. METHODS: In vivo cystometry was used to determine the effect of estrogen on bladder excitability. The effect of estrogen on the expression of P2X3 receptors in bladder epithelium was detected by real-time polymerase chain reaction and western blot. Effect of P2X3 receptors in bladder urothelium on stretch-released adenosine triphosphate was performed by a Flexcell FX5000 Compression system and an Enzyme-Linked Immunosorbent Assay Kit. RESULTS: Estrogen deprivation significantly increased the urinary frequency, while supplementation with diarylpropionitrile (DPN), an estrogen receptor ß (ERß) agonist, alleviated the urinary frequency. 17ß-Estradiol and DPN decreased the expression of P2X3 receptors in urothelium cells which was partially inhibited by ERß antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol. Meanwhile, inhibiting the expression of P2X3 receptors by ERß agonist or antagonizing the function of P2X3 receptors by selective P2X3 receptor antagonist AF-353 or A-317491 significantly reduced the stretch-released ATP from urothelium cells. CONCLUSIONS: Estrogen has a direct effect on the regulation of bladder overactivity in rats with cyclophosphamide-induced cystitis by downregulating the expression of bladder epithelial P2X3 receptors through ERß and reducing the adenosine triphosphate released from urothelium during bladder filling, thereby inhibiting the generation of the micturition reflex.

Re: Safety and short-term efficacy of mirabegron in children with valve bladder: a pilot study.

Overactive bladder (OAB) is a common lower urinary tract dysfunction syndrome. A stepwise approach is a prudent choice. Urotherapy is recommended by the International Children's Continence Society (ICCS) as the first-line treatment for OAB.

Safety and short-term efficacy of mirabegron in children with valve bladder: a pilot study.

AIMS: This pilot study aims to assess the short-term efficacy and safety of mirabegron in valve bladder, an important cause of persistent hydronephrosis after successful treatment of posterior urethral valves (PUV). METHODS: Twenty-two patients with early valve bladder (no residual PUV; persistent hydronephrosis, wetting and urodynamic evidence of detrusor overactivity) were included. Three subjective parameters: frequency, wetting episodes; patient perception of bladder condition score (PPBC) and four objective parameters: uroflow index (UI = Qave/Qmax), voided volume (VV = voided volume/ expected bladder capacity), maximum filling pressure (P det-max) and society of fetal urology (SFU) hydronephrosis grading were analysed pre- and post-3-month treatment with mirabegron (0.5-1 mg/kg/day). All patients were observed for heart rate, BP, ECG changes during therapy. RESULTS: There was significant reduction (p = 0.001) in mean frequency (pre 15; post 10), wetting episodes (pre 5; post 2) and PPBC (pre 4; post 3). There was significant improvement (p = 0.01) in mean UI (pre 0.3; post 0.5), VV (pre 0.54; post 0.72), Pdet-max (pre 42; post 25) and hydronephrosis grade (pre 3.5; post 2.2). There were no significant side effects. CONCLUSION: This pilot study establishes short-term efficacy and safety of mirabegron in valve bladder with overactivity. Further larger long-term studies are warranted.

Therapeutic effects of nerve growth factor-targeting therapy on bladder overactivity in rats with prostatic inflammation.

BACKGROUND: The present study examined the effect of liposomes conjugated with antisense oligonucleotide of nerve growth factor (NGF-OND) on local overexpression of NGF and bladder overactivity using rats with prostatic inflammation (PI). METHODS: Male Sprague-Dawley rats were divided into three groups: (1) Control group; intact rats, (2) PI-NS group; rats with PI and intravesical instillation of normal saline (NS), (3) PI-OND group; rats with PI and intravesical instillation of NGF-OND. On Day 0, PI was induced by intraprostatic 5%-formalin injection. On Day 14, NGF-OND or NS was instilled directly into the bladder after laparotomy. On Day 28, therapeutic effects of NGF-OND were evaluated by awake cystometry and histological analysis as well as reverse-transcription polymerase chain reaction measurements of messenger RNA (mRNA) levels of NGF in the bladder and prostate, inflammatory markers in the prostate, C-fiber afferent markers, and an A-type K+ channel α-subunit (Kv 1.4) in L6-S1 dorsal root ganglia (DRG). RESULTS: Intravesical NFG-OND treatment reduced PI-induced overexpression of NGF in both bladder and prostate, and reduced PI-induced bladder overactivity evident as longer intercontraction intervals in association with reductions of TRPV1 and TRPA1 mRNA expression levels in DRG. mRNA expression of Kv1.4 in DRG was reduced after PI, but improved in the PI-OND group. CONCLUSIONS: These results indicate that NGF locally expressed in the bladder is an important mediator inducing bladder overactivity with upregulation of C-fiber afferent markers and downregulation of an A-type K+ channel subunit in DRG following PI, and that liposome-based, local NGF-targeting therapy could be effective for not only bladder overactivity and afferent sensitization, but also PI. Thus, local blockade of NGF in the bladder could be a therapeutic modality for male LUTS due to BPH with PI.

Functional changes in low- and high-threshold afferents in obstruction-induced bladder overactivity.

Neural mechanisms of lower urinary tract symptoms in obstruction-induced bladder overactivity remain unclear. We made the first single unit recordings from different types of spinal afferents to determine the effects of bladder outlet obstruction in guinea pigs. A model of gradual bladder outlet obstruction in male guinea pigs was used to produce overactive bladder. Conscious voiding was assessed in metabolic cages, and micturition was recorded in anesthetized guinea pigs in vivo. Single unit extracellular recordings were made ex vivo from spinal afferent nerves in flat sheet preparations of the bladder. Guinea pigs with partially obstructed bladders showed a significant increase in conscious voiding frequency compared with sham-operated guinea pigs. Also, nonvoiding contractions increased significantly in both frequency and amplitude. Although spontaneous firing of low-threshold bladder afferents was increased, their stretch-induced firing was reduced. The proportion of capsaicin-sensitive low-threshold afferents increased in obstructed bladders. Interestingly, spontaneous and stretch-induced firing were both significantly increased in high-threshold afferents after obstruction. In summary, sensory signaling increased in the obstructed bladder during the filling phase. This is largely mediated by low-threshold stretch-sensitive afferents that are activated by increased local nonvoiding contractions. Increased spontaneous firing by high-threshold afferents also contributes. Our findings revealed a complex effect of bladder outlet obstruction on different types of bladder afferents that needs consideration for potential therapeutic targeting of lower urinary tract symptoms in obstruction-induced bladder overactivity.

TRPV4 blockade reduces voiding frequency, ATP release, and pelvic sensitivity in mice with chronic urothelial overexpression of NGF.

Transient receptor potential vanilloid family member 4 (TRPV4) transcript and protein expression increased in the urinary bladder and lumbosacral dorsal root ganglia of transgenic mice with chronic urothelial overexpression of nerve growth factor (NGF-OE). We evaluated the functional role of TRPV4 in bladder function with open-outlet cystometry, void spot assays, and natural voiding (Urovoid) assays with the TRPV4 antagonist HC-067047 (1 µM) or vehicle in NGF-OE and littermate wild-type (WT) mice. Blockade of TRPV4 at the level of the urinary bladder significantly (P ≤ 0.01) increased the intercontraction interval (2.2-fold) and void volume (2.6-fold) and decreased nonvoiding contractions (3.0-fold) in NGF-OE mice, with lesser effects (1.3-fold increase in the intercontraction interval and 1.3-fold increase in the void volume) in WT mice. Similar effects of TRPV4 blockade on bladder function in NGF-OE mice were demonstrated with natural voiding assays. Intravesical administration of HC-067047 (1 µM) significantly (P ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in littermate WT mice. Blockade of urinary bladder TRPV4 or intravesical infusion of brefeldin A significantly (P ≤ 0.01) reduced (2-fold) luminal ATP release from the urinary bladder in NGF-OE and littermate WT mice. The results of the present study suggest that TRPV4 contributes to luminal ATP release from the urinary bladder and increased voiding frequency and pelvic sensitivity in NGF-OE mice.

Long-lasting bladder overactivity and bladder afferent hyperexcitability in rats with chemically-induced prostatic inflammation.

BACKGROUND: Benign prostatic hyperplasia (BPH) is one of the major causes of lower urinary tract symptoms (LUTS), including storage LUTS such as urinary frequency and urgency. Recently, a growing number of clinical studies indicate that prostatic inflammation could be an important pathophysiological mechanism inducing storage LUTS in patients with BPH. Here we aimed to investigate whether nonbacterial prostatic inflammation in a rat model induced by intraprostatic formalin injection can lead to long-lasting bladder overactivity and changes in bladder afferent neuron excitability. METHODS: Male Sprague-Dawley rats were divided into four groups (n = 12 each): normal control group, 1-week prostatic inflammation group, 4-week inflammation group, and 8-week inflammation group. Prostatic inflammation was induced by formalin (10%; 50 µL per lobe) injection into bilateral ventral lobes of the prostate. Voiding behavior was evaluated in metabolic cages for each group. Ventral lobes of the prostate and the bladder were then removed for hematoxylin and eosin (HE) staining to evaluate inflammation levels. Continuous cystometrograms (CMG) were recorded to measure intercontraction intervals (ICI) and voided volume per micturition. Whole-cell patch clamp recordings were performed on dissociated bladder afferent neurons labeled by fluorogold injected into the bladder wall, to examine the electrophysiological properties. RESULTS: Results of metabolic cage measurements showed that formalin-treated rats exhibited significantly (P < 0.05) increases in micturition episodes/12 hours and decrease in voided volume per micturition at every time point post injection. Continuous CMG illustrated the significant ( P < 0.05) higher number of nonvoiding contractions per void and shorter ICI in formalin-treated rats compared with control rats. HE staining showed significant prostatic inflammation, which declined gradually, in prostate tissues of formalin-induced rats. In patch clamp recordings, capsaicin-sensitive bladder afferent neurons from rats with prostatic inflammation had significantly ( P < 0.05) lower thresholds for spike activation and a "multiple" firing pattern compared with control rats at every time point post injection. CONCLUSIONS: Formalin-induced prostatic inflammation can lead to long-lasting bladder overactivity in association with bladder afferent neuron hyperexcitability. This long-lasting model could be a useful tool for the study of inflammation-related aspects of male LUTS pathophysiology.

Association of genetic polymorphisms in the pore domains of mechano-gated TREK-1 channel with overactive lower urinary tract symptoms in humans.

AIMS: Mechanosensitivity of the urinary bladder is regulated by many factors including mechano-gated two-pore domain (K2 P, KCNK) potassium channels. TWIK-related K+ channel, TREK-1, is a predominantly expressed member of K2 P channel family in the human detrusor, and its expression and function are diminished in patients with overactive lower urinary tract symptoms (LUTS). The changes in channel activity may result from spontaneously occurring gene mutations. The aim of this study was to compare single nucleotide polymorphisms (SNPs) in TREK-1 channel between patients with LUTS and healthy donors. METHODS: Six SNPs (rs370266806, rs373919966, rs758937019, rs769301539, rs772497750, and rs775158737) in two pore domains of human TREK-1 gene were analyzed using TaqMan SNP genotyping assay with manufacturer-designed primers and allele-specific probes. The screening was done in control bladders and detrusor specimens from patients with overactive LUTS. Statistical analyses were performed using R, Fisher's exact test and Hardy-Weinberg Equilibrium. RESULTS: Six SNPs in two pore domains of the human TREK-1 gene were analyzed in human bladder specimens. The frequencies of rs758937019-CT genotype (P = 0.0016) and rs758937019-T allele (P = 0.0022) were significantly higher in the group with overactive LUTS. There was no significant association of rs775158737-GA genotype and rs775158737-A allele with the overactive LUTS, though they were present only in the overactive LUTS group. CONCLUSIONS: Our results provide evidence that altered expression and function of TREK-1 channel in patients with overactive LUTS could be due to genetic polymorphisms in the pore domains of TREK-1 channel (rs758937019).

BDNF overexpression in the bladder induces neuronal changes to mediate bladder overactivity.

Elevated levels of brain-derived neurotrophic factor (BDNF) in urine of overactive bladder (OAB) patients support the association of BDNF with OAB symptoms, but the causality is not known. Here, we investigated the functionality of BDNF overexpression in rat bladder following bladder wall transfection of either BDNF or luciferase (luciferase) transgenes (10 µg). One week after transfection, BDNF overexpression in bladder tissue and elevation of urine BDNF levels were observed together with increased transcript of BDNF, its cognate receptors (TrkB and p75NTR), and downstream PLCγ isoforms in bladder. BDNF overexpression can induce the bladder overactivity (BO) phenotype which is demonstrated by the increased voiding pressure and reduced intercontractile interval during transurethral open cystometry under urethane anesthesia. A role for BDNF-mediated enhancement of prejunctional cholinergic transmission in BO is supported by the significant increase in the atropine- and neostigmine-sensitive component of nerve-evoked contractions and upregulation of choline acetyltransferase, vesicular acetylcholine transporter, and transporter Oct2 and -α1 receptors. In addition, higher expression of transient receptor channels (TRPV1 and TRPA1) and pannexin-1 channels in conjunction with elevation of ATP and neurotrophins in bladder and also in L6/S1 dorsal root ganglia together support a role for sensitized afferent nerve terminals in BO. Overall, genomic changes in efferent and afferent neurons of bladder induced by the overexpression of BDNF per se establish a mechanistic link between elevated BDNF levels in urine and dysfunctional voiding observed in animal models and in OAB patients.

[Consequences of prostatic obstruction on bladder function, impact of removal, and management of recurrence after surgery]. / Conséquences de l'obstruction prostatique sur le fonctionnement vésical, impact de la désobstruction, et prise en charge des récidives après chirurgie.

OBJECTIVE: Our objective was to evaluate bladder outlet obstruction (BOO) consequences on the detrusor activity, to analyze the impact of medical and surgical treatments, and to study the reasons for recurrence of urinary symptoms after surgical treatment. METHOD: A non-systematic review of the scientific literature was conducted from the PubMed database to retrieve the most relevant scientific publications between 2000 and July 2018 with the keywords: BPH, bladder obstruction, bladder instability, surgery, and reoperation. A first research was crossed with the results of the reviews of literature already published and was enriched by the contributions of the various authors. A synthesis has been proposed. RESULTS: The consequences of bladder outlet obstruction (BOO) on the detrusor may be detrusor overactivity (DOA) or detrusor hypocontractility. DOA is found in about 50% of patients at the time of their surgery and its evolution is most often favorable after surgical treatment (resolved or reduced in 2/3 of cases). Bladder hypocontractility is responsible for acute or chronic urinary retention. It can be the cause for poor postoperative micturition recovery requiring self-catheterization which the patient must have been informed before surgical treatment. Surgery reduces urinary symptoms with a low but significant surgical revision rate (10 to 30% depending on the surgical technique). The less efficient technique with regard to surgical revision rates are prostatic radiofrequency or cervico-prostatic incision, followed by laser vaporization techniques, TURP and adenomectomy (surgical or endoscopic). Adenomectomy is the surgical technique that has the lowest recurrence rate. The identified risk factors for surgical revision are the surgeon's experience, the power of the laser (in case of photovaporization), the surgical technique employed, the length of operative time, the low or excessive volume of the prostate, the significant pre-operative post-void residual volume, and the slight decrease of postoperative PSA level. Prior to any surgical revision for recurrence of urinary symptoms, the assessment should include the review of previous surgical report, the evaluation of the resected prostatic volume and the residual prostatic volume, the IPSS score, the calendar of micturition, the urethrocystoscopy and the urodynamic assessment. CONCLUSION: BOO can lead to bladder dysfunction such as DOA or detrusor hypocontractility. Resolution of BOO by a suitable surgical treatment allows, in the majority of the cases, to resolve bladder dysfunctioning. In case of failure, the assessment must be complete to define the causes and to find the most suitable solution.

Roles of adenosine A1 and A2A receptors in the control of micturition in rats.

AIMS: Adenosine is a neurotransmitter that exerts numerous physiological effects in many organs. However, few studies have focused on the role of adenosine receptors in the control of micturition. Therefore, we examined the role of adenosine A1 and A2A receptors in the control of bladder activity in rats with normal or acetic acid (AA) irritated bladders. METHODS: Cystometrograms during saline or 0.2% AA infusion were recorded under urethane anesthesia in female Sprague-Dawley rats. After a stabilization period, CCPA (A1 receptor agonist) and/or ZM24138 (A2A receptor antagonist) were administered intravenously (i.v.), intrathecally (i.t.), intracerebroventricularly (i.c.v.), or intravesically. Micturition parameters were recorded and compared before and after drug administration. RESULTS: I.v., i.t., or i.c.v. administration of CCPA or ZM24138 significantly increased intercontraction intervals (ICIs) in both saline and AA infusion groups. During AA infusion, the inhibitory effects induced by i.c.v. CCPA or i.t. ZM24138 were significantly greater than those by i.t. or i.c.v. administration, respectively. Intravesical administration of CCPA, but not ZM24138, significantly increased ICI. CONCLUSIONS: These results indicated that: (1) when nociceptive signals from the bladder increase, adenosine A1 receptor-mediated inhibition of micturition is enhanced in the brain, compared to the normal condition, (2) A1 receptor activation also exerts a peripheral inhibitory effect on micturition, and (3) adenosine A2A receptor-mediated excitatory mechanisms are enhanced in the spinal cord following C-fiber bladder afferent stimulation. Thus adenosine A1 receptor agonists and A2A receptor antagonists might be effective for the treatment of overactive bladder and/or bladder hypersensitive disorders, in which C-fiber afferent function is enhanced.

Central nervous targets for the treatment of bladder dysfunction.

BACKGROUND: The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the urinary bladder, urethra, and external urethral sphincter. This activity is in turn controlled by neural circuits in the brain, spinal cord, and peripheral ganglia. AIMS: This paper will review recent advances in our understanding of the pathophysiology of voiding disorders, especially focusing on the central nervous system. METHODS: Various neurotransmitters, including acetylcholine, norepinephrine, dopamine, serotonin, excitatory and inhibitory amino acids, adenosine triphosphate, nitric oxide, and neuropeptides, have been implicated in the neural regulation of the lower urinary tract. RESULTS: Injuries or diseases of the nervous system, as well as drugs and disorders of the peripheral organs, can produce voiding dysfunctions such as urinary frequency, urgency, or incontinence. CONCLUSION: We discuss the potential targets in the central nervous system and new modalities for the treatment of voiding dysfunction.

The serotonin(5-HT)2A receptor is involved in the hypersensitivity of bladder afferent neurons in cyclophosphamide-induced cystitis.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic bladder inflammation characterized by the main symptoms of urinary frequency, urgency, and pelvic pain. The hypersensitivity of bladder afferent neurons is considered a significant pathophysiologic mechanism in IC/PBS. Serotonin (5-HT, 5-hydroxytryptamine) receptors are known to be involved in the regulation of the micturition reflex and hyperalgesia, but the effect of 5-HT receptors on cystitis remains unknown. In this study, a rat model of interstitial cystitis induced by intraperitoneal injection of cyclophosphamide (CYP) was used to investigate the role of 5-HT receptors on cystitis. The histology and urodynamics exhibited chronic cystitis and overactive bladder in CYP-treated rats. Notably, among 5-HT1A, 5-HT2A and 5-HT7 receptors, the expression of 5-HT2A receptor was significantly increased in bladder afferent neurons in CYP-treated rats. Intrathecal administration of the 5-HT2A receptor antagonist M100907 could alleviate bladder overactivity and hyperalgesia in CYP-induced cystitis rats. Neuronal calcium imaging of bladder afferent neurons revealed increased calcium influx induced by the 5-HT2A receptor agonist or capsaicin in cystitis rats, which could be inhibited by M100907. Moreover, RNA sequencing indicated that differentially expressed genes were enriched in inflammation-related pathways and cellular calcium homeostasis. These findings suggest that the 5-HT2A receptor is involved in the hypersensitivity of bladder afferent neurons in CYP-induced cystitis, and M100907 could alleviate bladder overactivity and hyperalgesia in CYP-induced cystitis by inhibiting neuronal hypersensitivity in the afferent pathways. The 5-HT2A receptor may be a potential therapeutic target for the treatment of IC/BPS.

Effect of Electroacupuncture Combined with Pelvic Floor Muscle Exercise on Urinary Symptoms, Sexual Dysfunction and Pelvic Floor Muscle Strength in Female Patients with Overactive Bladder: A Retrospective Study.

OBJECTIVE: This study aimed to investigate the effect of electroacupuncture combined with pelvic floor muscle exercise in the treatment of female overactive bladder (OAB). METHODS: The clinical data of 134 female patients with OAB admitted to our hospital from April 2022 to June 2023 were retrospectively analysed. The patients were divided into the combination group (n = 74) and the single group (n = 60). The general demographic data, total effective rate, pad weight, female sexual function index (FSFI) score, oxford muscle grading scale and incontinence impact questionnaire short form (IIQ-7) were collected. Propensity score matching (PSM) was used to match the baseline data of the two groups at 1:1 ratio, and t test, chi-square test and analysis of variance were used for calculation. RESULTS: A total of 90 patients were selected after PSM. No significant difference in baseline data was found between the two groups (p > 0.05). Before treatment, no significant difference in FSFI score, oxford muscle grading scale and IIQ-7 score was found between the two groups (p > 0.05). The total effective rate of the combination group was higher than that of the single group (p < 0.05). After 3 weeks and 1 month of treatment, in addition to orgasm and sexual desire, the scores of sexual excitement and sexual satisfaction in the combination group were higher than those in the single group (p < 0.05). The combination group displayed higher oxford muscle grading scale and lower IIQ-7 and pad weight than the single group, and the differences were statistically significant (p < 0.05). CONCLUSIONS: The effect of electroacupuncture stimulation combined with pelvic floor muscle exercise is more significant, which can alleviate urinary symptoms, reduce urine leakage, enhance pelvic floor muscle strength and alleviate sexual dysfunction.