Effects of nitric oxide inhibitors in mice with bladder outlet obstruction

ABSTRACT Purpose To investigate the lower urinary tract changes in mice treated with L-NAME, a non-selective competitive inhibitor of nitric oxide synthase (NOS), or aminoguanidine, a competitive inhibitor of inducible nitric oxide synthase (iNOS), after 5 weeks of partial bladder outlet obstruction (BOO), in order to evaluate the role of constitutive and non-constitutive NOS in the pathogenesis of this experimental condition. Materials and Methods C57BL6 male mice were partially obstructed and randomly allocated into 6 groups: Sham, Sham + L-NAME, Sham + aminoguanidine, BOO, BOO + L-NAME and BOO + aminoguanidine. After 5 weeks, bladder weight was obtained and cystometry and tissue bath contractile studies were performed. Results BOO animals showed increase of non-voiding contractions (NVC) and bladder capacity, and also less contractile response to Carbachol and Electric Field Stimulation. Inhibition of NOS isoforms improved bladder capacity and compliance in BOO animals. L-NAME caused more NVC, prevented bladder weight gain and leaded to augmented contractile responses at muscarinic and electric stimulation. Aminoguanidine diminished NVC, but did not avoid bladder weight gain in BOO animals and did not improve contractile responses. Conclusion It can be hypothesized that chronic inhibition of three NOS isoforms in BOO animals leaded to worsening of bladder function, while selective inhibition of iNOS did not improve responses, what suggests that, in BOO animals, alterations are related to constitutive NOS.

Effects of chronic administration of tamsulosin and tadalafil, alone or in combination, in rats with bladder outlet obstruction induced by chronic nitric oxide deficiency

Purpose The aim of this study was to define if tadalafil causes detrusor muscle impairment and to observe the effect of combination of tadalafil with tamsulosin on the lower urinary tract of rats with bladder outlet obstruction (BOO) induced by chronic nitric oxide deficiency. Materials and Methods Thirty-one male rats were randomized to following groups: 1 - control; 2 - L-Nitroarginine methyl ester (L-NAME); 3 - Tamsulosin + L-NAME, 4 Tadalafil+L-NAME; and 5 - Tamsulosin + Tadalafil + L-NAME. At the end of the treatment period (30 days), all animals were submitted to urodynamic study. Results The administration of L-NAME increased the number of non-voiding contractions (NVC) (1.04 ± 0.22), volume threshold (VT) (1.86 ± 0.35), and micturition cycle (MC) (1.34 ± 0.11) compared with control (0.52 ± 0.06, 0.62 ± 0.06, and 0.67 ± 0.30), respectively. The administration of tamsulosin reduced the number of NVC (0.57 ± 0.42) and VT (0.76 ± 0.24 ) compared with L-NAME group. Co-treatment with tadalafil decreased the number of VT (0.85 ± 0.53) and MC (0.76 ± 0.22) compared with L-NAME group. The combination of tamsulosin with tadalafil improved the number of NVC (0.56 ± 0.18), VT (0.97 ± 0.52) and MC (0.68 ± 0.30) compared with L-NAME group. Conclusion In rats with BOO induced by chronic nitric oxide deficiency, tadalafil did not cause impairment in detrusor muscle and seems to have an addictive effect to tamsulosin because the combination decreased non voiding contractions as well the number of micturition cycles. .

Stereological Comparison of the Effects of Pentoxifylline, Captopril, Simvastatin, and Tamoxifen on Kidney and Bladder Structure After Partial Urethral Obstruction in Rats

PURPOSE: Limited studies have shown antifibrotic effects of pentoxifylline, captopril, simvastatin, and tamoxifen. No comparisons are available of the effects of these drugs on prevention of renal and bladder changes in partial urethral obstruction (PUO). MATERIALS AND METHODS: The rats were divided into six groups (n=7). The sham-operated rats (group I) only underwent laparotomy and did not receive any treatments. The PUO groups (group II-VI) received normal saline (PUO+NS), pentoxifylline (100 mg/kg/d; PUO+PEN), captopril (35 mg/kg/d; PUO+CAP), simvastatin (15 mg/kg/d; PUO+SIM), or tamoxifen (10 mg/kg/d; PUO+TAM) by gavage for 28 days. Then, the volume and/or length of the kidney components (tubules, vessels, and fibrous tissue) and the bladder components (epithelial and muscular layers, fibrous tissue, fibroblast and fibrocyte number) were quantitatively evaluated on the microscopic sections by use of stereological techniques. RESULTS: The volume of renal and bladder fibrosis was significantly ameliorated in the PUO+PEN group, followed by the PUO+CAP, PUO+SIM, and PUO+TAM groups. Also, the volume and length of the renal tubules and vessels and bladder layers were more significantly protected in the PUO+PEN group, followed by the PUO+CAP, PUO+SIM, and PUO+TAM groups. CONCLUSIONS: Treatment of PUO with PEN was more effective in the prevention of renal and bladder fibrosis and in the preservation of renal and bladder structures.

Effects of Serenoa Repens, Selenium and Lycopene (Profluss®) on chronic inflammation associated with Benign Prostatic Hyperplasia: results of “FLOG” (Flogosis and Profluss in Prostatic and Genital Disease), a multicentre Italian study

Objective To evaluate the efficacy of Profluss® on prostatic chronic inflammation (PCI). Materials and Methods We prospectively enrolled 168 subjects affected by LUTS due to bladder outlet obstruction submitted to 12 cores prostatic biopsy for suspected prostate cancer + 2 cores collected for PCI valuation. First group consisted of 108 subjects, with histological diagnosis of PCI associated with BPH and high grade PIN and/or ASAP, randomly assigned to 1:1 ratio to daily Profluss® (group I) for 6 months or to control group (group Ic). Second group consisted of 60 subjects, with histological diagnosis of BPH, randomly assigned to 1:1 ratio to daily Profluss® + α-blockers treatment (group II) for 3 months or to control group (group IIc). After 6 months first group underwent 24 cores prostatic re-biopsy + 2 cores for PCI while after 3 months second group underwent two-cores prostatic for PCI. Specimens were evaluated for changes in inflammation parameters and for density of T-cells (CD3, CD8), B-cells (CD20) and macrophages (CD68). Results At follow-up there were statistical significant reductions of extension and grading of flogosis, mean values of CD20, CD3, CD68 and mean PSA value in group I compared to Ic, while extension and grading of flogosis in group II were inferior to IIc but not statistical significant. A statistically significant reduction in the density of CD20, CD3, CD68, CD8 was demonstrated in group II in respect to control IIc. Conclusions Serenoa repens+Selenium+Lycopene may have an anti-inflammatory activity that could be of interest in the treatment of PCI in BPH and/or PIN/ASAP patients. .

The effect of alpha-blocker treatment on bladder hypoxia inducible factor-1 alpha regulation during lower urinary tract obstruction

AIMS: To determine whether á1-blocker treatment, in chronic bladder outlet obstruction (BOO), influences bladder tissue ischemia. Materials and methods: This prospective study included 60 patients with BOO, of which 40 were under á1-blocker medication and 20 without treatment. Patients underwent transurethral resection of the prostate (TURP) or suprapubic prostatectomy (SPP). Ten patients with non-muscle invasive bladder cancer underwent transurethral resection of the bladder tumor and served as the control group. Tissue specimens were immunohistochemically stained for hypoxia inducible factor-1á (HIF-1á). Results: Bladder tissue from obstructed subjects showed high immunoreactivity to HIF-1á. The specimens from the control group, showed no or weak, mainly cytoplasmic immunoreactivity to HIF-1á. Patients under á -blocker treatment did not differ in the number of HIF-1á positive cells compared to subjects with no treatment (median number 86.8 [20-150] and 88.6 [0-175], respectively) (p > 0.05). The lowest bladder pressure at which HIF-1á was up regulated, was detected at detrusor pressure Qmax (PdetQmax) = 60 cm H2O. Conclusions: Treatment with á-blockers in obstructed patients considered as non-responders, does not result in HIF-1á down regulation, thus bladder continues to be under chronic stress.

The resolution of detrusor over activity after medical and surgical treatment in patients with bladder outlet obstruction.

OBJECTIVE: This study was design to evaluate the efficacy of transurethral resection of prostate (TURP) compared to alpha-adrenoceptor antagonists (Alfuzosin SR) for the treatment of patients with benign prostatic hyperplasia BPH concomitant with detrusor overactivity (DO). MATERIAL AND METHOD: The patients presenting with lower urinary tract symptoms (LUTS), due to benign prostatic enlargement were invited into the present study. These patients completed the International Prostatic Symptom Score (IPSS), the Quality of Life score (QoL), and underwent urodynamic investigation. Twenty-five patients with urodynamics proving bladder outlet obstruction and concomitant detrusor overactivity were allocated into two groups. Group I was treated by TURP (surgical treatment group) and group 2 was treated with Alfuzosin SR (medical treatment group). Twelve patients were allocated to group 1 and the remainder 13 to group 2. Reassessment was performed after three months when the patients completed the International Prostatic Symptom Score (IPSS), Quality of Life score (QoL), and urodynamics study. RESULTS: Mean patient age was compared for both groups (70 +/- 2.5 years in group I and 70.7 +/- 1.8 in group 2, p = 0.84). There were no statistically significant differences between baseline clinical and urodynamic characteristics of patients in the different treatment groups. IPSS and QoL scores improved significantly after treatment in each group. A statistically significant difference after treatment was noted in group I for the obstruction urodynamic parameters (Qmax, PdetQmax, Bladder outlet obstruction index). In group 2, a significant improvement was found in PdetQmax and Bladder outlet obstruction index, but not in Qmax. Detrusor overactivity persisted in three patients of group 1 (75% resolution), while two patients in group 2 were free from detrusor overactivity (15% resolution) (Chi-square = 0.001). CONCLUSION: Surgical treatment of benign prostatic hyperplasia, particularly TURP, significantly reduces the incidence of detrusor overactivity concurrent with bladder outlet obstruction, when compared with the use of alpha-adrenoceptor antagonists alone.

Double-blind randomized placebo-controlled study of bixa orellana in patients with lower urinary tract symptoms associated to benign prostatic hyperplasia

OBJECTIVE: To determine the efficacy of Bixa Orellana (BO) in patients with benign prostatic hyperplasia (BPH) presenting moderate lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: It is a prospective double-blind randomized placebo-controlled study. One thousand four hundred and seventy eight patients presenting moderate LUTS associated to BPH were interviewed, from whom we selected 136 to fulfill the criteria of inclusion and exclusion. Assignation was performed at random in blocks of four to receive B0 at a dose of 250 mg 3 times a day or placebo (Pbo) for 12 months, 68 patients were assigned to each group. From the patients in the study we obtained data of demographic, epidemiologic, symptom score, uroflowmetry and post void residual urine variables. RESULTS: Basically both groups were compared clinically, demographically and biochemically. Throughout the study variations of symptom score, mean delta symptom score during each visit and the final average delta were similar for both groups (BO - 0.79 ± 1.87 and Pbo - 1.07 ± 1.49) (p = 0.33). Similarly variations of Qmax mean, Qmax average delta and final average delta were similar (BO 0.44 ± 1.07 and Pbo 0.47 ± 1.32) (p = 0.88). Variations of post void residual urine mean, post void residual urine average delta in each visit and the final average delta were similar for both groups (BO 4.24 ± 11.69 and Pbo 9.01 ± 18.66) (p = 0.07). No differences were found in the answers of clinically significant improvement assessed with relative risk and risk differences, even though the proportion of adverse effects was similar for both groups. CONCLUSION: Patients with BPH that present moderate LUTS did not show any benefit receiving BO when compared to placebo.

Effects of thyrotropin-releasing hormone on urethral closure pressure in females with voiding dysfunction

To evaluate the effect of intravenous thyrotropin releasing hormone [TRH] on the urethral closure pressure [UCP]. Twenty-two female patients with either bladder outlet obstruction [BOO] or detrusor under activity were included in this study. They divided into two study and control groups randomly. Twelve patients in study group received 200 gr of TRH intravenously and patients in control group received intravenous normal saline as placebo. Standard urethral pressure profilometry was performed before injection and after injection at 5, 10, 20 and 30 minutes. Functional profile length [FPL], maximum urethral closure pressure [MUCP], and urethral closure pressure at the proximal quarter of the FPL [1/4 FLP] and at the distal quarter of FPL [3/4 FLP] were measured in both groups. The mean age of the study and control groups were 41.61 +/- 21.7 years and 43.59 +/- 19 years respectively .The study and control groups included 5 BOO and 6 detrusor under activity and 4 BOO and 5 detrusor under activity respectively. The mean peak flow rate was 5.69 +/- 8.4 ml/s in the study group and 6.31 +/- 81 ml/s in control group. There wasn't significant difference between two groups. Mean maximum urethral closure pressure demonstrated no significant difference in two groups before and after TRH injection, but a marked reduction in 3/4 UCP and 3/4 FPL in patients after TRH injection was seen. TRH injection significantly reduces the distal urethral pressure