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Objectives: To investigate the pathophysiological mechanism leading to lower urinary tract symptoms in prostate cancer (PCa) by using an animal model., Methods: An orthotopic PCa model in mice was established by injection of human DU145 cells into the prostate gland lateral lobe of NOD.CB17-Prkdc scid /NcrCrlBltw (NOD-SCID) mice. Cancer growth was quantified by a luciferase-based in vivo imaging system (IVIS) serially every 7 days. Comparisons were made for urodynamic parameters, bladder histology, and biological markers until the sixth week. Bladder wall structural changes were assessed by the bladder wall thickness and degree of fibrosis. Biomarker expressions in bladder tissue including muscarinic acetylcholine receptor 2 (M 2 ), transient receptor potential cation channel subfamily V member 4 (TRPV4), BCL2-associated X protein (Bax), and caspase3 were evaluated by immunohistochemical staining and immunofluorescence confocal laser scanning microscopy., Results: DU145 cell growth in the prostate was successfully monitored by a luciferase-based IVIS. after orthotopic injection. Using our injection technique, no anatomical obstruction of the bladder outlet and urethra was noted up to 6 weeks after injection. The presence of PCa induced changes in urinary bladder histology, biomarkers, and urodynamic parameters. Cystometry showed features of detrusor overactivity with increased voiding frequency and high-amplitude voiding contractions from the fourth week onward. Histological analyses 4 weeks after DU145 injection demonstrated detrusor thickening and bladder wall fibrosis. Immunohistochemistry showed increased expressions of bladder M 2 , TRPV4, Bax, and caspase3 in the PCa mice as early as in the first or second week., Conclusions: PCa can induce bladder microenvironment changes involving neural receptors and biological mediators leading to histological and functional alterations even in the absence of overt anatomical obstruction., (© 2021 John Wiley & Sons Australia, Ltd.)

Objectives: To investigate the effect of high-fat diet (HFD) on bladder M 1,3 muscarinic receptor expression and contractile function in the rat., Methods: Eight-week-old male rats were divided into two groups including one with HFD for 8 weeks (short-term) and the other for 24 weeks (long-term). Each group was compared to age-matched rats fed with normal chow as controls. The body weight, food intake amount and blood biochemistry were monitored. Bladder muscle contractile responses to acetylcholine (0.1-10 μM), bethanechol (10 μM) and KCl (50 mM) were studied in an organ bath set-up. Bladder M 1 and M 3 muscarinic receptor protein expressions were measured by Western blotting analysis., Results: Increase in body weight as well as blood triglyceride, cholesterol and sugar levels compared to controls were noted in both 8- and 24-week HFD rats. Eating appetite change with increased food and water intakes was noted in the HFD rats. Significantly decreased bladder contractile responses to acetylcholine and bethanechol were shown in both HFD groups. On the other hand, decreased bladder contractile response to KCl was demonstrated in the 24-week group but not the 8-week group. The expressions of bladder M 1 and M 3 muscarinic receptor proteins were significantly and progressively decreased by HFD feeding from 8 to 24 weeks., Conclusions: High-fat diet induces obesity and polyphagia in rats. Short-term and long-term HFD feeding decrease rat bladder M 1 and M 3 receptor expressions as well as contractile responses to the agonistic stimulation. In addition, bladder muscle dysfunction develops after long-term HFD feeding., (© 2017 John Wiley & Sons Australia, Ltd.)

Objectives: To investigate the effect of metabolic syndrome on the bladder cannabinoid receptors 1 and 2 (CB1/CB2) expression and function in the fructose-fed rats (FR)., Methods: Adult male Sprague-Dawley rats were divided into two groups: (i) Control rats fed with normal chow; and (ii) Rats fed with high-fructose diet (FR) for 9 weeks. The body weight, blood pressure, plasma sugar, insulin, triglyceride and cholesterol were measured. Bladder muscle strips were prepared in organ bath and pre-contracted with 1 µM/L acetylcholine (ACh) or 50 mM/L KCl. The relaxation responses to CB1/CB2 agonist Bay59-3047 (0.01-1 µM/L) were recorded. The effects of CB1 antagonist AM251, CB2 antagonist AM630, protein kinase A (PKA) inhibitor H-89 and ATP-sensitive potassium channel (K ATP ) inhibitor glibenclamide on the Bay59-3047-induced response were tested. Western blotting and real-time polymerase chain reaction (RT-PCR) analyses were performed for bladder CB1/CB2 receptors., Results: Significant increases of body weight, blood pressure, plasma glucose, insulin, cholesterol and triglyceride levels were found in the FR. Bay59-3047 reduced ACh and KCl pre-contracted bladder strip tension in a dose-dependent fashion. The relaxation responses were significantly decreased in the FR. The Bay59-3047-induced relaxation was attenuated by AM251, glibenclamide and H-89. Western blotting and RT-PCR showed decreased expressions of FR bladder CB1 and CB2 receptor protein and mRNA., Conclusion: CB1/CB2 receptors mediate rat bladder relaxation through the PKA and K ATP pathway. The CB1 receptor may play a more prominent role. The response is decreased in the FR bladder due to reduced expressions of the cannabinoid receptors., (© 2017 John Wiley & Sons Australia, Ltd.)

Objectives: The effect of agmatine on bladder contractility and the diabetes-induced alteration of this action were studied in the rat., Methods: Bladder strips were isolated from 9-week-old streptozotocin (STZ)-diabetic rats and control Wistar rats. Strips were hung in an organ bath for measurement of isometric tension and pre-contracted with either 1 µmol/L acetylcholine (ACh) or 50 mmol/L KCl. Dose-dependent relaxation of the bladder strips was studied by cumulative administration of agmatine 1-100 µmol/L into the organ bath. Effects of specific imidazoline receptor (IR) antagonists on the agmatine-induced relaxation were studied. Western blotting analysis was used to measure bladder IR, sulphonylurea receptor (SUR) and inwardly rectifying K(+) channel subunit 6.2 (Kir 6.2) protein levels., Results: Agmatine reduced ACh and KCl pre-contracted bladder strip tension in a dose-dependent fashion. Relaxation was significantly increased in STZ-diabetic rats. The relaxation was inhibited by BU224, a selective I2 IR antagonist; but not by efaroxan (I1 IR antagonist) or KU14R (I3 IR antagonist). Moreover, the agmatine-induced relaxation was attenuated by glibenclamide (inhibitor of KATP channel) and H-89 (inhibitor of protein kinase A), but enhanced by 3-isobutyl-1-methylxanthine (IBMX, inhibitor of cyclic AMP phosphodiesterase). Western blotting showed increased expression of bladder IR but not SUR or Kir 6.2 in the STZ-diabetic rat., Conclusion: Agmatine causes rat bladder relaxation by activation of the I2 IR, which opens KATP channels through the cyclic AMP/protein kinase A pathway. Agmatine-induced bladder relaxation in STZ-diabetic rats is increased due to a higher expression of IR., (© 2013 Wiley Publishing Asia Pty Ltd.)

Objectives: To study the effects of metabolic syndrome on prostate α-adrenergic contractile function using fructose-fed rats (FR)., Methods: Age-matched male Wistar rats were divided into two groups: group I, normal control rats; and group II, 9-week FR. Animal body weight, blood pressure and serum metabolic parameters were monitored. The prostate was removed 9 weeks after induction of metabolic syndrome in the FR. The contractile responses of prostatic strips to phenylephrine (10(-7) to 10(-6) M) and KCl (50 mM) were tested. Prostate α1 -adrenoceptor (α1 -AR) protein expression was studied by Western blotting analysis with a polyclonal antiserum., Results: At week 9, the FR showed significant increases in body weight, blood pressure, plasma glucose, insulin and triglyceride levels. The FR prostate weight was significantly higher than that of the controls (610.5 ± 13.2 vs 422.3 ± 7.7 mg, P < 0.05 for n = 8). FR prostate contractile responses to phenylephrine and KCl were both significantly increased. Interestingly, prostate α1 -AR protein expression level was lower in the FR. However, after in vitro 10(-6) M phenylephrine stimulation, FR prostate α1 -AR protein expression was significantly increased., Conclusion: Metabolic syndrome in FR significantly increases prostate contractile responses to KCl and α-adrenergic stimulation. Paradoxically, FR prostate α1 -AR protein expression is decreased, but significantly enhanced after in vitro phenylephrine stimulation., (© 2012 Wiley Publishing Asia Pty Ltd.)

Objectives: The effect of agmatine on prostate contractility as well as the roles of imidazoline receptors and potassium channels in this action were studied using isolated Wistar rat prostate tissue., Methods: Rat prostate strips were pre-contracted with 1 µmol/L phenylephrine or 50 mmol/L KCl. The relaxation response to agmatine (1-100 µmol/L) was measured. The effects of imidazoline receptor blockers: efaroxan, BU224, KU14R; ATP-sensitive K(+) channels (KATP ) channel inhibitor: glibenclamide; cyclic AMP (cAMP) phosphodiesterase inhibitor: IBMX; or protein kinase A (PKA) inhibitor: H-89 on the agmatine-induced relaxation were studied., Results: Agmatine produced relaxation in prostate strips pre-contracted with phenylephrine or KCl in a dose-dependent manner. This relaxation was significantly reduced by BU224, a selective I2 imidazoline receptor (IR) blocker, but not by I1 or I3 IR blockers (efaroxan, KU14R respectively). Moreover, the agmatine-induced relaxation was attenuated by glibenclamide and H-89, but enhanced by IBMX., Conclusion: The results suggest that agmatine causes rat prostate relaxation by activation of the I2 IR, which opens KATP channels through cAMP/PKA pathway., (© 2012 Blackwell Publishing Asia Pty Ltd.)