Publications by authors named "Russ Chess-Williams"

57 Publications

Psychological stress induced bladder overactivity in female mice is associated with enhanced afferent nerve activity.

Sci Rep 2021 09 1;11(1):17508. Epub 2021 Sep 1.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD, 4229, Australia.

Psychological stress has been linked to the development and exacerbation of overactive bladder symptoms, as well as afferent sensitisation in other organ systems. Therefore, we aimed to investigate the effects of water avoidance stress on bladder afferent nerve activity in response to bladder filling and pharmaceutical stimulation with carbachol and ATP in mice. Adult female C57BL/6J mice were exposed to either water avoidance stress (WAS) for 1 h/day for 10 days or normal housing conditions. Voiding behaviour was measured before starting and 24-h after final stress exposure and then animals were euthanised to measure afferent nerve activity in association with bladder compliance, spontaneous phasic activity, contractile responses, as well as release of urothelial mediators. WAS caused increased urinary frequency without affecting urine production. The afferent nerve activity at low bladder pressures (4-7 mmHg), relevant to normal physiological filling, was significantly increased after stress. Both low and high threshold nerves demonstrated enhanced activity at physiological bladder pressures. Urothelial ATP and acetylcholine release and bladder compliance were unaffected by stress as was the detrusor response to ATP (1 mM) and carbachol (1 µM). WAS caused enhanced activity of individual afferent nerve fibres in response bladder distension. The enhanced activity was seen in both low and high threshold nerves suggesting that stressed animals may experience enhanced bladder filling sensations at lower bladder volumes as well as increased pain sensations, both potentially contributing to the increased urinary frequency seen after stress.
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http://dx.doi.org/10.1038/s41598-021-97053-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410840PMC
September 2021

Chronic psychological stress and lower urinary tract symptoms.

Low Urin Tract Symptoms 2021 Oct 16;13(4):414-424. Epub 2021 Jun 16.

Centre for Urology Research, Faculty of Health Sciences & Medicine, Bond University, Gold Coast, Queensland, Australia.

It is well established that lower urinary tract symptoms (LUTS), particularly urinary urgency and incontinence, cause stress and anxiety for patients. However, there is mounting evidence that the relationship between these two factors is bidirectional and that chronic psychological stress itself can result in the development of symptoms such as urinary frequency, urgency, incontinence, and pelvic pain. This review considers the evidence that such a relationship exists and reviews the literature from clinical and animal studies to identify some of the mechanisms that might be involved. Inflammatory responses induced by chronic stress appear to offer the strongest link to bladder dysfunction. There is overwhelming evidence, both in patients and animal models, for a release of pro-inflammatory cytokines and chemokines during periods of chronic stress. Furthermore, cytokines have been shown to cause bladder dysfunction and pain via actions in the central nervous system and locally in the bladder. In the brain and spinal cord, pro-inflammatory cytokines influence the regulation of micturition pathways by corticotropin-releasing factor (CRF) and its receptors, while peripherally cytokines affect bladder function, directly causing detrusor hypertrophy and afferent nerve hypersensitivity. There is little information on which treatments may have most benefit for stressed/anxious patients with LUTS, but animal studies suggest traditional drugs for overactive bladder (solifenacin, mirabegron) are more effective on LUTS than anxiolytic drugs (fluoxetine, imipramine). The preliminary preclinical data for CRF receptor antagonists is not consistent. A clearer understanding of the mechanisms involved in stress-induced LUTS should provide a basis for improved treatment of this condition.
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http://dx.doi.org/10.1111/luts.12395DOI Listing
October 2021

Current and emerging pharmacological targets for medical expulsive therapy.

Basic Clin Pharmacol Toxicol 2021 May 15. Epub 2021 May 15.

Centre for Urology Research, Faculty of Health Science & Medicine, Bond University, Gold Coast, QLD, Australia.

The primary goals of medical expulsive therapy are to increase the rate of stone expulsion along the ureter to avoid ureteral obstruction and reduce ureteral colic and thus avoid the need for surgical and more invasive interventions. This review focussed on the findings from in vivo and in vitro animal and human studies that have investigated the pharmacological mechanisms controlling ureteral motility and their translation to current and potentially new clinically used drugs for increasing the rate of stone expulsion along the ureter. The complicated contractility profile of the ureter, which alters with age, tissue segment region, orientation and species contributes to the difficulty of interpreting studies on ureteral pharmacology, which translates to the complexity of discovering ideal drug targets for medical expulsive therapy. Nevertheless, the current drug classes clinically used for patients with stone lodgement include α -adrenoceptor antagonists, calcium channel blockers and NSAIDS, whilst there are promising targets for drug development that require further clinical investigations including the phosphodiesterase type 5 enzyme, β-adrenoceptors and 5-HT receptors.
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http://dx.doi.org/10.1111/bcpt.13613DOI Listing
May 2021

The anxiolytic sertraline reduces the impact of psychological stress on bladder function in mice.

Life Sci 2021 Aug 10;278:119598. Epub 2021 May 10.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Robina, QLD 4229, Australia. Electronic address:

Aims: To determine if treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline reduces the bladder dysfunction caused by water avoidance stress in mice.

Main Methods: Adult female mice were randomly allocated to (1) Unstressed, (2) Stressed or (3) Stress + Sertraline experimental groups. Stressed mice were subjected to water avoidance for 1 h/day for 10 days and received sertraline or vehicle in drinking water, starting 10-days prior to the first stress exposure. Age matched control/unstressed mice were house under normal conditions without stress exposure. Voiding behaviour was assessed throughout the experimental protocol. After the final stress exposure, a blood sample was taken to measure plasma corticosterone levels and bladders were removed, catheterised and intravesical pressure responses recorded during distension and in response to pharmacological agents.

Key Findings: Plasma corticosterone levels in sertraline-treated animals were equivalent to unstressed controls and significantly decreased compared to the stressed group. Voiding frequency was significantly increased in the stressed group, and treatment with sertraline significantly decreased voiding frequency, however, this remained elevated compared to unstressed control animals. Bladders from stressed mice displayed enhanced maximal contractile response to the muscarinic agonist carbachol and greater release of ACh in the serosal fluid, which was reduced to control levels by sertraline treatment. Spontaneous phasic contractions were not altered by stress but were significantly reduced in bladders from sertraline treated animals, relative to controls.

Significance: These results indicate that management of voiding dysfunction caused by psychological stress may be aided by the addition of an SSRI such as sertraline.
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http://dx.doi.org/10.1016/j.lfs.2021.119598DOI Listing
August 2021

Renal artery responses to trace amines: Multiple and differential mechanisms of action.

Life Sci 2021 Jul 20;277:119532. Epub 2021 Apr 20.

Faculty of Health Sciences and Medicine, Bond University, 4229, Queensland, Australia. Electronic address:

Purpose: The rise in consumption of dietary supplements containing the trace amines p-tyramine, p-synephrine and p-octopamine has been associated with cardiovascular side effects. Since renal blood flow plays an important role in blood pressure regulation, this study investigated the mechanisms of action of these trace amines on isolated porcine renal arteries.

Main Methods: Contractile responses to amines were investigated in noradrenaline-depleted rings of porcine main renal arteries in the absence and presence of the α-adrenoceptor antagonist, prazosin (1 μM), β-adrenoceptor antagonist, propranolol (1 μM), or the trace amine-associated receptor (TAAR-1) antagonist, EPPTB (RO-5212773; 100 nM or 100 μM).

Key Findings: All three amines induced constrictor responses of similar magnitude and potency. However, their mechanisms of action on the renal artery appeared to differ. Depleting endogenous noradrenaline stores significantly reduced maximum responses to tyramine and synephrine, but less for octopamine. When direct responses were examined after depleting tissues of noradrenaline, responses to synephrine and octopamine, but not tyramine, were reduced in the presence of prazosin(1 μM) and potentiated in the presence of propranolol (1 μM) or L-NNA (100 μM). Generally, vasoconstrictor responses remaining after noradrenaline-depletion and α-adrenoceptor blockade were not affected by the TAAR-1 antagonist EPPTB (0.1-100 μM), although responses to low concentration of synephrine and octopamine were enhanced by this antagonist.

Significance: Tyramine appears to mediate constriction of the renal artery mainly via an indirect sympathomimetic mechanism, whereas synephrine and octopamine exert additional direct effects on α-adrenoceptors and possibly contractile TAAR (not TAAR-1). The two amines also activate simultaneous inhibitory responses via β-adrenoceptors, TAAR-1 and nitric oxide release.
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http://dx.doi.org/10.1016/j.lfs.2021.119532DOI Listing
July 2021

Racemic synephrine found in Citrus aurantium-listing pre-workout supplements suggests a non-plant-based origin.

Drug Test Anal 2021 Aug 16;13(8):1569-1575. Epub 2021 Apr 16.

Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Queensland, Australia.

Multi-ingredient pre-workout supplements (MIPS) contain Citrus aurantium as a source of bioactive amines such as p-synephrine, but concerns regarding the authenticity of ingredients in some supplements as well as adverse effects from consumption have been raised. R-(-)-Synephrine is the predominant enantiomer in Citrus aurantium extracts while synthetic preparations are often racemic. The aims of this study were to develop a screening method to determine the ratio of synephrine enantiomers in pre-workout supplements listing Citrus aurantium and to assess the ingredient authenticity by directly comparing their ratios to that found in Citrus aurantium standardised reference materials (SRMs). Quantification of enantiomers in the supplements and SRMs was achieved using a validated, high-performance liquid chromatography-single quadrupole mass spectrometry (HPLC-UV-QDa) direct enantioseparation method with a cellobiohydrolase (CBH) column (100 × 4.0 mm, 5 μM) and UV detection at 225 nm. Citrus aurantium SRMs were found to have an average enantiomeric ratio of 94:6 (R:S) with total synephrine ranging from 5.7 to 90.2 mg/g. Within the pilot sample of pre-workout supplements tested, only 42% (5/12) had enantiomeric ratios consistent with the SRMs with total synephrine ranging from 0.03 to 91.2 mg/g. For the remaining supplements, four had racemic ratios of synephrine (0.14 to 5.4 mg/g), two lacked any detectable levels of synephrine, and one had solely the S-(+)-enantiomer (0.15 mg/g). These results bring the authenticity of labelling of some pre-workout supplements into question and highlight the need for more stringent labelling regulations and testing for dietary supplements.
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http://dx.doi.org/10.1002/dta.3042DOI Listing
August 2021

17β-estradiol and ureteral contractility: A role for the G protein-coupled estrogen receptor.

Eur J Pharmacol 2021 May 16;899:174024. Epub 2021 Mar 16.

Centre for Urology Research, Faculty of Health Science & Medicine, Bond University, QLD, 4229, Australia. Electronic address:

The aim of this study was to investigate the unknown effects of 17β-estradiol (E2) on ureteral contractility and the receptor and mechanisms involved. By utilising isolated porcine distal ureteral strips, we observed that E2 (30-300 μM) and a G protein-coupled estrogen receptor specific agonist G-1 (30 μM) both increased the frequency of phasic contractions of the ureter (P<0.05). E2 also decreased the maximum amplitude of these contractions (P<0.05). The G protein-coupled estrogen receptor specific antagonist G-36 (10 μM) reversed E2 enhancement effects on frequency, but did not alter its effects on maximum amplitude of contractile responses. Additionally, it was observed that the effects of E2 were unaltered by removing the urothelium, inhibiting nitric oxide and prostaglandin production or preventing neuronal conduction. In the presence of a potassium channel blocker, 4-aminopyridine (10 μM), the effects of E2 on frequency were prevented. This finding suggests that G protein-coupled estrogen receptor mediates the increase in frequency of ureteral phasic contractions induced by E2 via activation of potassium channels, while E2 alters the amplitude of these contractions through an unknown mechanism.
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http://dx.doi.org/10.1016/j.ejphar.2021.174024DOI Listing
May 2021

Quinazoline alpha-adrenoreceptor blockers as an adjunct cancer treatment: From bench to bedside.

Eur J Pharmacol 2021 Feb 23;893:173831. Epub 2020 Dec 23.

School of Pharmacy and Pharmacology, Griffith University, Queensland, Australia. Electronic address:

Drug repurposing has been increasingly used by both researchers and clinicians to identify new cancer treatments. The alpha-1 adrenoreceptor blockers are a class of drugs that have been used for many years in the treatment of hypertension and benign prostatic hyperplasia. Some of the drugs in this class, notably the quinazoline derivatives, have been found to display cytotoxic properties, identifying them as potential options in the treatment of cancer. This review will examine the currently available evidence that investigates the cytotoxic and anti-cancer properties of these agents, the mechanisms behind these properties and how the alpha-1 blockers fit within current cancer therapies. It aims to answer the question of whether these agents can go from the laboratory bench top into cancer clinics.
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http://dx.doi.org/10.1016/j.ejphar.2020.173831DOI Listing
February 2021

HPLC-UV-QDa analysis of Citrus aurantium-labelled pre-workout supplements suggest only a minority contain the plant extract.

J Pharm Biomed Anal 2021 Jan 5;193:113746. Epub 2020 Nov 5.

Faculty of Health Sciences and Medicine, Bond University, 4229 Queensland, Australia. Electronic address:

Bitter orange (Citrus aurantium) is a common ingredient in pre-workout supplements with purported weight-loss and performance-enhancing effects. Supplements listing Citrus aurantium or p-synephrine have been associated with reports of adverse cardiovascular events attributed to the active biogenic amines, p-synephrine, p-octopamine or p-tyramine. Additionally, questions have been raised as to the authenticity of the plant-derived active components listed on the supplement labels. The aim of this study was to determine the quantities of these amines in a sample of pre-workout supplements which specifically listed Citrus aurantium, and assess the authenticity of plant material by comparing the ratios of amines found to that found in Citrus aurantium standardized reference materials (SRM). The quantities of amines in the supplements and SRMs were determined using a validated high-performance liquid chromatography-single quadrupole mass spectrometry (HPLC-UV-QDa) method. In the Citrus aurantium SRMs the quantities of trace amines found ranged from 5.30 to 38.00 mg/g (synephrine) 0.14-0.35 mg/g (octopamine) and 0.15-1.90 mg/g (tyramine) with an average ratio of 100:1:5 (synephrine: octopamine: tyramine). Only 42 % (5/12) of the supplements tested had ratios consistent with that found in the SRMs. The average trace amine ratio in those supplements was 100:1:3 while the quantities of trace amines found ranged from 0.35 to 31.31 mg/g (synephrine); 0.005 - 0.10 mg/g (octopamine) and 0.01-1.51 mg/g (tyramine). For the remaining supplements, some did not contain any detectable levels of trace amines or only synephrine was detected with concentrations ranging from 0.003 - 0.95 mg/g. These results suggest a role for authenticity/quality assurance testing of pre-workout supplements and more stringent regulation of pre-workout supplements.
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http://dx.doi.org/10.1016/j.jpba.2020.113746DOI Listing
January 2021

Bladder overactivity induced by psychological stress in female mice is associated with enhanced bladder contractility.

Life Sci 2021 Jan 7;265:118735. Epub 2020 Nov 7.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Robina, QLD 4229, Australia. Electronic address:

Aims: To investigates the effects of water avoidance stress on voiding behaviour and functional bladder responses in mice.

Main Methods: Mice in the Stress group were exposed to water avoidance stress (WAS) for 1 h/day for 10 days, Controls were age-matched and housed normally. Voiding behaviour was measured periodically throughout the stress protocol and bladders were isolated 24-h after final stress exposure to measure bladder compliance, spontaneous phasic activity, contractile responses, and release of urothelial mediators.

Key Findings: Repeated stress exposure induced a significant increase in plasma corticosterone levels in the WAS group compared to control. An overactive bladder phenotype was observed in WAS mice, causing a significant increase in the number of voiding events observed from as early as day-3, and a 7-fold increase following 10-days' stress. This increase in voiding frequency was associated with a significant decrease in void size, an increase in the number of small voids, but no change in total voided volume. Bladders from stressed mice showed a significant increase in the maximum responses to the muscarinic agonist carbachol (p < 0.01), in addition to enhanced pressure responses to the purinergic agonists ATP (p < 0.05) and αβ-mATP (p < 0.05), and non-receptor mediated contractions to KCl (p < 0.05) compared to controls. Nerve-mediated bladder contractions to electric field stimulation were not significantly affected by stress, nor were spontaneous phasic contractions or release of urothelial ATP and acetylcholine.

Significance: Repeated exposure to water avoidance stress produced an overactive bladder phenotype, confirmed by increased voiding frequency, and associated with enhanced bladder contractile responses.
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http://dx.doi.org/10.1016/j.lfs.2020.118735DOI Listing
January 2021

Comparative effects of angiotensin II on the contractility of muscularis mucosae and detrusor in the pig urinary bladder.

Neurourol Urodyn 2021 01 19;40(1):102-111. Epub 2020 Oct 19.

Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

To explore contractile actions of angiotensin II (ATII) on the muscularis mucosae (MM) of the bladder, ATII-induced contractions were compared between MM and the detrusor smooth muscle (DSM) of the pig bladder by isometric tension recordings. Effects of ATII on spontaneous Ca transients in MM were visualized using Cal-520 fluorescence. ATII receptor type 1 (ATR1) expression in MM and DSM was also examined by immunohistochemistry. ATII (1 nM-1 μM) caused phasic contractions of MM in a concentration-dependent manner, while ATII (10 nM-10 μM) had no or marginal effects on DSM contractility. ATII (100 nM)-induced MM contractions had an amplitude of approximately 70% of carbachol (1 μM)-induced or 90% of U46619 (100 nM)-induced contractions. Candesartan (10 nM), an ATR1 blocker, prevented the contractile effects of ATII (1 nM) in MM, while ATR1 immunofluorescence was greater in MM than DSM. ATII (10-100 pM) increased the frequency but not the amplitude of spontaneous Ca transients in MM. Both urothelium-intact and -denuded MM strips developed comparable spontaneous phasic contractions, but ATII, carbachol and U46619-induced contractions were significantly larger in urothelium-denuded than urothelium-intact MM strips. In conclusion, the MM appears to have a much greater sensitivity to ATII compared with DSM that could well sense circulating ATII, suggesting that MM may be the predominant target of contractile actions induced by ATII in the bladder while the urothelium appears to inhibit MM contractility.
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http://dx.doi.org/10.1002/nau.24548DOI Listing
January 2021

Prostaglandin E2 and F2alpha Modulate Urinary Bladder Urothelium, Lamina Propria and Detrusor Contractility via the FP Receptor.

Front Physiol 2020 23;11:705. Epub 2020 Jun 23.

Centre for Urology Research, Faculty of Health Sciences & Medicine, Bond University, Gold Coast, QLD, Australia.

Current pharmacological treatment options for many bladder contractile dysfunctions are not suitable for all patients, thereby bringing interest to the investigation of therapies that target a combination of receptors. This study aimed to compare responses of PGE on the urinary bladder urothelium with lamina propria (U&LP, also called the bladder mucosa) or detrusor smooth muscle and attempt to identify the receptor subtypes mediating PGE contractile responses in these tissues. In the presence of selective EP1 - 4 receptor antagonists, varying concentrations of PGE were applied to isolated strips of porcine U&LP and detrusor that were mounted in organ baths filled with Krebs-bicarbonate solution and gassed with carbogen. The addition of PGE (1 and 10 μM) and PGF (10 μM) to U&LP preparations caused significant increases in the baseline tension and in the spontaneous phasic contractile frequency. In detrusor preparations, significant increases in the baseline tension were observed in response to PGE (1 and 10 μM) and PGF (10 μM), and spontaneous phasic contractions were initiated in 83% of preparations. None of the selective PGE receptor antagonists inhibited the increases in baseline tension in both U&LP and detrusor. However, the antagonism of PGF receptor showed significantly inhibited contractile responses in both layers of the bladder. This study presents prostaglandin receptor systems as a potential regulator of urinary bladder contractility. The main contractile effects of PGE in both U&LP and detrusor are mediated via the FP receptor with no observed contribution from any of the four EP receptors.
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http://dx.doi.org/10.3389/fphys.2020.00705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344237PMC
June 2020

Hypersensitivity of bladder low threshold, wide dynamic range, afferent fibres following treatment with the chemotherapeutic drugs cyclophosphamide and ifosfamide.

Arch Toxicol 2020 08 22;94(8):2785-2797. Epub 2020 May 22.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD, 4229, Australia.

The cytotoxic drugs cyclophosphamide (CPO) and ifosfamide (IFO) cause toxic urological effects due to the production of urinary metabolites that cause bladder inflammation. This study aimed to identify changes in the bladder afferent system following treatment with these drugs that might explain reported urological adverse effects. Intravesical pressure and afferent nerve activity were recorded during bladder distension and drug administration in isolated bladders from mice, 24 h after intraperitoneal treatment with cyclophosphamide (100 mg/kg), ifosphamide (200 mg/kg) or saline (control). In isolated bladders, total afferent nerve activity at maximum bladder distension was increased from 182 ± 13 imp/s in control animals, to 230 ± 14 imp/s in CPO-treated (p < 0.05) and 226 ± 17 imp/s in IFO-treated (p < 0.001) mice. Single fibre analysis revealed the increase resulted from an enhanced activity in low threshold, wide dynamic range fibres (23.3 ± 1.9 imp/s/fibre in controls to 31.5 ± 2.5 (p < 0.01) in CPO and 29.9 ± 2.0 imp/s/fibre (p < 0.05) in IFO treated). CPO treatment was accompanied by an increase in urinary frequency in vivo, but was not associated with increases in urothelial release of ATP or acetylcholine, bladder compliance or spontaneous muscle activity. Also, CPO-treatment did not affect afferent nerve responses or pressure responses to purinergic, muscarinic or nicotinic agonists. This is the first report of CPO and IFO-induced changes in specific populations of bladder afferents, namely an increase in low threshold, wide dynamic range fibres. These effects appear to be direct and not secondary to increases in smooth muscle activity or the release of urothelial mediators.
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http://dx.doi.org/10.1007/s00204-020-02773-8DOI Listing
August 2020

A Pilot retrospective analysis of alpha-blockers on recurrence in men with localised prostate cancer treated with radiotherapy.

Sci Rep 2020 05 18;10(1):8191. Epub 2020 May 18.

Menzies Health Institute, Griffith University, Queensland, Australia.

While alpha-blockers are commonly used to reduce lower urinary tract symptoms in prostate cancer patients receiving radiotherapy, their impact on response to radiotherapy remains unknown. Therefore, this pilot study aimed to retrospectively determine if alpha-blockers use, influenced response to radiotherapy for localised prostate cancer. In total, 303 prostate cancer patients were included, consisting of 84 control (alpha-blocker naïve), 72 tamsulosin and 147 prazosin patients. The main outcomes measured were relapse rates (%), time to biochemical relapse (months) and PSA velocity (ng/mL/year). Recurrence free survival was calculated using Kaplan-Meier analysis. Prazosin significantly reduced biochemical relapse at both two and five-years (2.72%, 8.84%) compared to control (22.61%, 34.52%). Recurrence free survival was also significantly higher in the prazosin group. This remained after multivariable analysis (HR: 0.09, 95% CI: 0.04-0.26, p < 0.001). Patients receiving prazosin had a 3.9 times lower relative risk of biochemical relapse compared to control. Although not statistically significant, tamsulosin and prazosin extended recurrence free survival by 13.15 and 9.21 months respectively. We show for the first time that prazosin may reduce risk of prostate cancer recurrence and delay time to biochemical relapse and provides justification for prospective studies to examine its potential as an adjunct treatment option for localised prostate cancer.
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http://dx.doi.org/10.1038/s41598-020-65238-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235269PMC
May 2020

The five primary prostaglandins stimulate contractions and phasic activity of the urinary bladder urothelium, lamina propria and detrusor.

BMC Urol 2020 Apr 29;20(1):48. Epub 2020 Apr 29.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Queensland, 4226, Australia.

Background: Inflammation is often associated with several bladder dysfunctions, including overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/PBS). As such, inflammation of the bladder and the actions of inflammatory mediators may contribute to the development of urinary symptoms. This study assessed the actions of PGE, PGF, PGD, TXA, and PGI on urinary bladder urothelium with lamina propria (U&LP), and detrusor smooth muscle.

Methods: Studies were carried out using isolated tissue baths, where strips of porcine bladder U&LP or detrusor were exposed to varying concentrations of prostaglandin agonists (1 μM and 10 μM).

Results: All assessed prostaglandin agonists contracted both the U&LP and detrusor smooth muscle, with the rank order of contractile response effectiveness as: PGE > PGF > TXA > PGD > PGI. In U&LP, treatment with PGE (10 μM) increased tonic contractions by 1.36 ± 0.09 g (n = 42, p < 0.001) and phasic contractions by 40.4 ± 9.6% (n = 42, p < 0.001). In response to PGF (10 μM), U&LP tonic contractions increased by 0.79 ± 0.06 g (n = 14, p < 0.001) and phasic activity by 13.3% ± 5.3% (n = 15, p < 0.05). In detrusor preparations, PGE (10 μM) increased tonic contractions by 1.32 ± 0.13 g (n = 38, p < 0.001) and PGF (10 μM) by 0.97 ± 0.14 g (n = 12, p < 0.001). Only 34% (n = 48) of all detrusor preparations exhibited spontaneous activity prior to the addition of any agonist at a frequency of 2.03 ± 0.12 cpm. In preparations that did not exhibit initial phasic activity, all of the prostaglandin agonists were capable of commencing phasic activity.

Conclusions: The urinary bladder U&LP and detrusor respond to a variety of prostaglandin agonists, with their activation resulting in direct contractions, as well as increases to spontaneous contractile activity. This study presents the prostaglandin receptor system as a potential therapeutic target for lower urinary tract dysfunction.
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http://dx.doi.org/10.1186/s12894-020-00619-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191740PMC
April 2020

Voiding Behavior and Efferent Bladder Function Altered in Mice Following Social Defeat but Not Witness Trauma.

Front Physiol 2020 20;11:247. Epub 2020 Mar 20.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Robina, QLD, Australia.

Psychological stress is associated with bladder dysfunction, however, the local bladder mechanisms affected are not well understood. This study aimed to determine how psychological stress, caused by social defeat or witness trauma, affects voiding behavior and bladder function. Pairs of male C57Bl/6J mice were placed in a custom-made plexiglass chamber with an aggressor ARC(S) mouse for 1 h/day for 10 days. The social defeat mouse was in physical contact with the aggressor, while the witness was physically separated but could observe interactions between its cage-mate and the aggressor. Age matched control pairs were used for comparison. Voiding analysis was conducted periodically over the 10 days. An whole bladder preparation was used to assess functional changes after the period of stress. Plasma corticosterone levels were significantly increased by both social defeat and witness trauma stress when compared to unstressed controls. Voiding analysis revealed a significant decrease in voiding frequency in the social defeat group compared to control animals, indicating an altered voiding phenotype. Witness trauma did not alter voiding behavior. Bladder contractile responses to cholinergic stimulation were not significantly altered in either stress group, nor was relaxation to the beta-adrenoceptor agonist isoprenaline. However, nerve evoked contractile responses were significantly increased at all frequencies in bladders from social defeat but not witness trauma mice. Purinergic contractile responses were also significantly enhanced in this group. Social defeat also resulted in increased urothelial acetylcholine release during bladder distension, with no change in ATP release. In conclusion, functional bladder changes are dependent upon stressor type. Enhanced urothelial acetylcholine may desensitize bladder sensory nerves, which, coupled with more efficient voiding contractions due to enhanced nerve-mediated and purinergic detrusor responses, may account for the altered voiding phenotype observed. This study reports a male model of social defeat stress with reduced urinary frequency, with no voiding changes observed in the witness.
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http://dx.doi.org/10.3389/fphys.2020.00247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098992PMC
March 2020

Alterations in histamine responses between juvenile and adult urinary bladder urothelium, lamina propria and detrusor tissues.

Sci Rep 2020 03 5;10(1):4116. Epub 2020 Mar 5.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Queensland, 4229, Australia.

Inflammatory mediators may have a role in various lower urinary tract disorders. Histamine is known to induce significant increases in both the tension and frequency of spontaneous phasic contractions in both urothelium with lamina propria (U&LP) and detrusor muscle via the activation of H1 receptor in juvenile animal models. However, it is unclear whether age affects these contractile responses to histamine. This study assessed the histamine receptor subtypes mediating contraction in juvenile and adult porcine bladders and compared the urothelium with lamina propria and detrusor responses to histamine. Isolated tissue bath studies were conducted using strips of porcine U&LP and detrusor obtained from juvenile (6 months) and adult (3 years) animals exposed to histamine receptor agonists and antagonists. Treatment with histamine (100 µM) in U&LP of juvenile animals caused increases in baseline tension by 47.84 ± 6.52 mN/g (p < 0.001, n = 51) and by 50.76 ± 4.10 mN/g (p < 0.001, n = 55) in adult animals. Furthermore, the frequency of spontaneous phasic contractions was significantly enhanced in response to histamine in U&LP of both juvenile and adult tissues (p < 0.001 for both age groups). Treatment with an H2 agonist in U&LP of juvenile animals decreased baseline tension by 13.97 ± 3.45 mN/g (n = 12, p < 0.05), but had no effect in adult animals. Inhibition of H1 receptors resulted in significantly reduced contractile responses of U&LP and detrusor to histamine in both juvenile and adult animals (p < 0.05). Treatment with an H2 receptor antagonist significantly enhanced contractions in juvenile preparations (n = 10, p < 0.05) but had no effect in adult preparations (n = 8). In detrusor, treatment with histamine (100 µM) in juvenile tissues showed a significantly higher increase in baseline tension of 19.10 ± 4.92 mN/g (n = 51) when compared to adult tissues exhibiting increases of 8.21 ± 0.89 mN/g (n = 56, p < 0.05). The increases in the baseline tension were significantly inhibited by the presence of H1 receptor antagonists in both juvenile and adult detrusor preparations. Treatment with either the H2 receptor antagonist or agonist in detrusor had no effect on both juvenile and adult tissues. Therefore, the histamine receptor system may play an essential role in the maintenance of bladder function or in bladder dysfunction observed in some lower urinary tract disorders.
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http://dx.doi.org/10.1038/s41598-020-60967-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057986PMC
March 2020

A porcine model of ureteral contractile activity: Influences of age, tissue orientation, region, urothelium, COX and NO.

J Pharmacol Toxicol Methods 2020 Mar - Apr;102:106661. Epub 2019 Dec 24.

Centre for Urology Research, Faculty of Health Science & Medicine, Bond University, QLD 4229, Australia. Electronic address:

Introduction: We aimed to investigate factors contributing to ureteral responses and establish a reliable porcine model for studying ureteral contractility.

Methods: Isolated ureteral strips from young (6-month old) and older (3-year old) pigs were mounted in organ baths and subjected to phenylephrine, 5-HT, carbachol and histamine. Ureteral strips developed bursts of contractile activity which was measured as area under the curve (AUC) and frequency. Phenylephrine and 5-HT-induced responses of proximal and distal ureters were obtained, in the presence and absence of indomethacin (10 μM) and L-NNA (100 μM), and the influence of an intact mucosa was examined.

Results: Phenylephrine and 5-HT-induced contractile responses were greater than those to carbachol in the porcine ureter. In fact, responses to carbachol were only present in ureters from older animals. Ureters suspended longitudinally had increased phenylephrine-induced contractions compared to those suspended circularly (p < .05). A greater amount of tissue strips developed spontaneous contractions from the proximal region compared to distal (83% vs 25%). There was an increase in maximum phenylephrine-induced responses in the distal ureter when compared to the proximal ureter (p < .05). In the presence of indomethacin, only 5-HT-induced contractions in the young animals were depressed (p < .05) while L-NNA did not affect any ureteral responses. The intact mucosa significantly decreased contractile responses to phenylephrine and 5-HT in the porcine ureter.

Discussion: The complexity of ureteral contractions depicting bursts of phasic activity requires AUC assessment. Porcine ureteral contractile properties, such as regional differences, influence of mucosa and lack of response to carbachol, are similar to those reported in the literature for human ureter.
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http://dx.doi.org/10.1016/j.vascn.2019.106661DOI Listing
November 2020

Novel insights into the mechanism of cyclophosphamide-induced bladder toxicity: chloroacetaldehyde's contribution to urothelial dysfunction in vitro.

Arch Toxicol 2019 11 9;93(11):3291-3303. Epub 2019 Oct 9.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Robina, QLD, 4229, Australia.

The clinical use of cyclophosphamide and ifosfamide is limited by a resultant bladder toxicity which has been attributed to the metabolite acrolein. Another metabolite chloroacetaldehyde (CAA) associated with nephrotoxicity, has not been investigated for toxicity in the bladder and this study investigates the effects of acrolein and CAA on human urothelial cells in vitro. Human urothelial cells (RT4 and T24) were treated with acrolein or CAA and changes in cell viability, reactive oxygen species, caspase-3 activity and release of urothelial mediators ATP, acetylcholine, PGE were measured. The protective effects of N-acetyl cysteine (NAC) were also assessed. Both metabolites were toxic to human urothelial cells, however, CAA significantly decreased cell viability at a ten-fold lower concentration (10 µM) than acrolein (100 µM). This was associated with increased ROS production and caspase-3 activity. NAC protected cells from these changes. In RT4 cells 100 µM acrolein caused a significant increase in basal and stretch-induced ATP, Ach and PGE release. In T24 cells chloroacetaldehyde (10 µM) increased basal and stimulated ATP and PGE levels. Again, NAC protected against changes in urothelial mediator release following acrolein or CAA. This study is the first to report that CAA in addition to acrolein contributes to the urotoxicity of cyclophosphamide and ifosfamide. Both metabolites altered urothelial mediator levels which could contribute to the sensory and functional bladder changes experienced by patients after treatment with cyclophosphamide or ifosfamide. Alterations in urothelial cell viability and mediator release may be causally linked to oxidative stress, with NAC providing protection against these changes.
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http://dx.doi.org/10.1007/s00204-019-02589-1DOI Listing
November 2019

Elevated release of inflammatory but not sensory mediators from the urothelium is maintained following epirubicin treatment.

Eur J Pharmacol 2019 Nov 1;863:172703. Epub 2019 Oct 1.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Queensland, 4229, Australia. Electronic address:

Intravesical treatment of superficial bladder cancer with epirubicin is associated with local urological adverse effects, the causes of which are unknown. Our aim was to investigate the effects of epirubicin on the release of urothelial mediators and inflammatory cytokines. UROtsa cells were treated with epirubicin for 1 h at 37 °C. Release of urothelial transmitters and inflammatory cytokines was examined immediately, 24 h and 7 days following treatment. Release of ATP and nitric oxide were increased transiently after treatment with epirubicin (0.01 mg/ml), but this was not evident one-week after treatment. Basal prostaglandin E release was decreased at 24 h but not at 7 days. An increase in basal acetylcholine release and decrease in stretch-induced acetylcholine release were observed 24-h after treatment (0.01 mg/ml). One week following epirubicin treatment (0.001 mg/ml), stretch-induced, but not basal acetylcholine release, was observed. Secretion of interleukin-6 and interleukin-8 was increased 70-fold and 5-fold respectively, at 24 h (0.01 mg/ml). This was sustained and one week after epirubicin treatment (0.001 mg/ml), the increase in the secretion of both inflammatory cytokines was still evident. Epirubicin treatment induces several transient changes in urothelial function. However, the increased secretion of inflammatory cytokines (IL-6 and IL-8) is sustained and these mediators may be involved in the pathophysiology of bladder toxicity following intravesical epirubicin treatment.
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http://dx.doi.org/10.1016/j.ejphar.2019.172703DOI Listing
November 2019

Differential mechanisms of action of the trace amines octopamine, synephrine and tyramine on the porcine coronary and mesenteric artery.

Sci Rep 2019 07 29;9(1):10925. Epub 2019 Jul 29.

Faculty of Health Sciences and Medicine, Bond University, 4229, Queensland, Australia.

Trace amines such as p-tyramine, p-octopamine and p-synephrine are found in low concentrations in animals and plants. Consumption of pre-workout supplements containing these plant-derived amines has been associated with cardiovascular side effects. The aim of this study was to determine the mechanisms of action of these trace amines on porcine isolated coronary and mesenteric arteries. Noradrenaline caused contraction of mesenteric arteries and relaxation of coronary arteries. In both tissues, all three trace amines induced contractions with similar potencies and responses were unaffected by the β-adrenoceptor antagonist propranolol (1 µM), the nitric oxide synthase inhibitor L-NNA (100 µM), or the TAAR-1 antagonist, EPPTB (100 nM). However, the contractile responses of mesenteric arteries, but not coronary arteries, were significantly reduced by depletion of endogenous noradrenaline. Mesenteric responses to all three amines were abolished in the presence of prazosin (1 µM) whereas residual contractile responses remained in the coronary artery which were inhibited by a high concentration (100 µM) of EPPTB. The results suggest complex responses of the coronary artery to the trace amines, with activity at α-adrenoceptors and potentially TAARs other than TAAR-1. In contrast the actions of the amines on the mesenteric artery appeared to involve indirect sympathomimetic actions and direct actions on α-adrenoceptors.
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http://dx.doi.org/10.1038/s41598-019-46627-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662849PMC
July 2019

Histamine modulation of urinary bladder urothelium, lamina propria and detrusor contractile activity via H1 and H2 receptors.

Sci Rep 2019 03 7;9(1):3899. Epub 2019 Mar 7.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Queensland, 4229, Australia.

The mechanisms underlying bladder contractile disorders such as overactive bladder are not fully understood, and there is limited understanding of the receptor systems modulating spontaneous bladder contractions. We investigated the potential for histamine to have a role in mediating contractility of the urothelium with lamina propria (U&LP) or detrusor via the H1-H4 histamine receptor subtypes. Isolated strips of porcine U&LP or detrusor smooth muscle were mounted in gassed Krebs-bicarbonate solution and responses to histamine obtained in the absence and presence of selective receptor antagonists. The presence of histamine increases the frequency of U&LP spontaneous phasic contractions and baseline tensions. In response to histamine, H1-antagonists pyrilamine, fexofenadine and cyproheptadine were effective at inhibiting contractile responses. Cimetidine (H2-antagonist) enhanced increases in baseline tension in response histamine, whereas amthamine (H2-agonist) induced relaxation. Although thioperamide (H3/H4-antagonist) increased baseline tension responses to histamine, selective H1/H2-receptor antagonism revealed no influence of these receptors. In detrusor preparations, pyrilamine, fexofenadine and cyproheptadine were effective at inhibiting baseline tension increases in response to histamine. Our findings provide evidence that histamine produces contractile responses both in the U&LP and detrusor via the H1-receptor, and this response is significantly inhibited by activation of the H2-receptor in the U&LP but not the detrusor.
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http://dx.doi.org/10.1038/s41598-019-40384-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405771PMC
March 2019

α-adrenoceptors mediate contraction of human erectile tissue.

J Pharmacol Sci 2018 Aug 9;137(4):366-371. Epub 2018 Aug 9.

Centre for Urology Research, Bond University, Robina, Queensland, Australia.

α-adrenoceptor antagonists can impact upon sexual function and have potential in the treatment of erectile dysfunction. Human erectile tissue contains predominantly α-adrenoceptors, and here we examined whether contractions of this tissue are mediated by the functional phenotype, the α-adrenoceptor. Functional experiments using subtype selective agonists and antagonists, along with radioligand ([H]tamsulosin) binding assays, were used to determine the α-adrenoceptor population. A61603, a α-adrenoceptor agonist, was a full agonist with a potency 21-fold greater than that of noradrenaline. The α- and α-adrenoceptor antagonist tamsulosin antagonized noradrenaline responses with high affinity (pK = 9.7 ± 0.3), whilst BMY7378 (100 nM) (α-adrenoceptor antagonist) failed to antagonize responses. In contrast, relatively low affinity estimates were obtained for both prazosin (pK = 8.2 ± 0.1) and RS17053 (pK = 6.9 ± 0.2), antagonists which discriminate between the α- and α-adrenoceptors. [H]Tamsulosin bound with high affinity to the receptors of human erectile tissue (pK = 10.3 ± 0.1) with a receptor density of 28.1 ± 1.4 fmol mg protein. Prazosin displacement of [H]tamsulosin binding revealed a single homogenous population of binding sites with a relatively low affinity for prazosin (pK = 8.9). Taken together these data confirm that the receptor mediating contraction in human erectile tissue has the pharmacological properties of the α-adrenoceptor.
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http://dx.doi.org/10.1016/j.jphs.2018.08.003DOI Listing
August 2018

A central role for Toll-like 4 receptors in interstitial cystitis?

Am J Physiol Renal Physiol 2018 10 27;315(4):F910-F912. Epub 2018 Jun 27.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia.

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http://dx.doi.org/10.1152/ajprenal.00290.2018DOI Listing
October 2018

Diabetes-induced alterations in urothelium function: Enhanced ATP release and nerve-evoked contractions in the streptozotocin rat bladder.

Clin Exp Pharmacol Physiol 2018 11 17;45(11):1161-1169. Epub 2018 Jul 17.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD, Australia.

Up to 80% of patients with diabetes mellitus develop lower urinary tract complications, most commonly diabetic bladder dysfunction (DBD). The aim of this study was to investigate the impact of diabetes on the function of the inner bladder lining (urothelium). Bladder compliance and intraluminal release of urothelial mediators, adenosine triphosphate (ATP) and acetylcholine (ACh) in response to distension were investigated in whole bladders isolated from 2- and 12-week streptozotocin (STZ)-diabetic rats. Intact and urothelium-denuded bladder strips were used to assess the influence of the urothelium on bladder contractility. Intraluminal ATP release was significantly enhanced at 2 weeks of diabetes, although not at 12 weeks. In contrast, intraluminal ACh release was unaltered by diabetes. Bladder compliance was also significantly enhanced at both 2 and 12 weeks of diabetes, with greatly reduced intravesical pressures in response to distension. Nerve-evoked contractions of bladder strips were significantly greater at 2 weeks of diabetes. When the urothelium was absent, nerve-evoked contractions were reduced, but contractions remained significantly elevated at lower frequencies of stimulation (<5 Hz) in diabetics. Interestingly, although relaxations of bladder strips to isoprenaline were unaltered by diabetes, removal of the urothelium unmasked significantly enhanced relaxations in strips from 2- and 12-week diabetic animals. In conclusion, diabetes alters urothelial function. Enhanced urothelial ATP release may be involved in the hypercontractility observed at early time points of diabetes. These alterations are time-dependent and may contribute to the mechanisms at play during the development of diabetic bladder dysfunction.
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http://dx.doi.org/10.1111/1440-1681.13003DOI Listing
November 2018

NKA enhances bladder-afferent mechanosensitivity via urothelial and detrusor activation.

Am J Physiol Renal Physiol 2018 10 13;315(4):F1174-F1185. Epub 2018 Jun 13.

Department of Biomedical Science, University of Sheffield , Sheffield , United Kingdom.

Tachykinins are expressed within bladder-innervating sensory afferents and have been shown to generate detrusor contraction and trigger micturition. The release of tachykinins from these sensory afferents may also activate tachykinin receptors on the urothelium or sensory afferents directly. Here, we investigated the direct and indirect influence of tachykinins on mechanosensation by recording sensory signaling from the bladder during distension, urothelial transmitter release ex vivo, and direct responses to neurokinin A (NKA) on isolated mouse urothelial cells and bladder-innervating DRG neurons. Bath application of NKA induced concentration-dependent increases in bladder-afferent firing and intravesical pressure that were attenuated by nifedipine and by the NK2 receptor antagonist GR159897 (100 nM). Intravesical NKA significantly decreased bladder compliance but had no direct effect on mechanosensitivity to bladder distension (30 µl/min). GR159897 alone enhanced bladder compliance but had no effect on mechanosensation. Intravesical NKA enhanced both the amplitude and frequency of bladder micromotions during distension, which induced significant transient increases in afferent firing, and were abolished by GR159897. NKA increased intracellular calcium levels in primary urothelial cells but not bladder-innervating DRG neurons. Urothelial ATP release during bladder distention was unchanged in the presence of NKA, whereas acetylcholine levels were reduced. NKA-mediated activation of urothelial cells and enhancement of bladder micromotions are novel mechanisms for NK2 receptor-mediated modulation of bladder mechanosensation. These results suggest that NKA influences bladder afferent activity indirectly via changes in detrusor contraction and urothelial mediator release. Direct actions on sensory nerves are unlikely to contribute to the effects of NKA.
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http://dx.doi.org/10.1152/ajprenal.00106.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230738PMC
October 2018

Modulation of lower urinary tract smooth muscle contraction and relaxation by the urothelium.

Naunyn Schmiedebergs Arch Pharmacol 2018 07 28;391(7):675-694. Epub 2018 May 28.

Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Str. 67, 55131, Mainz, Germany.

The epithelial inner layer of the lower urinary tract, i.e., the urothelium, and other parts of the mucosa are not just a passive barrier but play an active role in the sensing of stretching, neurotransmitters, paracrine mediators, hormones, and growth factors and of changes in the extracellular environment. We review the molecular and cellular mechanisms enabling the urothelium to sense such inputs and how this leads to modulation of smooth muscle contraction and relaxation. The urothelium releases various mediators including ATP, acetylcholine, prostaglandins, nitric oxide, and nerve growth factor. These may affect function and growth of smooth muscle cells and afferent nerves. However, the molecular identity of the urothelium-derived mediator directly modulating contractile and relaxant responses of isolated bladder strips has remained elusive. The morphology and function of the urothelium undergo changes with aging and in many pathophysiological conditions. Therefore, the urothelium may contribute to the therapeutic effects of established drugs to treat lower urinary tract dysfunction and may also serve as a target for novel therapeutics. However, therapeutics may also change urothelial function, and it is not always easy to determine whether such changes are part of the therapeutic response or reflect secondary alterations.
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http://dx.doi.org/10.1007/s00210-018-1510-8DOI Listing
July 2018

Ibuprofen Decreases Spontaneous Activity and Enhances Nerve-Evoked Contractions to Minimize Mitomycin C-Induced Bladder Dysfunction.

J Pharmacol Exp Ther 2018 08 21;366(2):282-290. Epub 2018 May 21.

Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia

Inflammation may play a causal role in urological side effects reported following intravesical mitomycin C (MMC). Our aim was to investigate the effects of the nonsteroidal anti-inflammatory drug ibuprofen (IBU) on the cytotoxic potency of MMC and the potential for IBU to protect against bladder dysfunction. Malignant (RT4, T24) and normal (UROtsa) urothelial lines were treated with MMC followed by ibuprofen, with cell viability and caspase-3 activity assessed. Female C57BL/6JArc mice (Saline/Control, MMC, Saline + IBU, and MMC + IBU) received intravesical treatment (1 hour) with saline or MMC (2 mg/ml), with IBU (1 mg/ml) delivered in drinking water (for 7 days). Voiding pattern analysis was conducted prior to and following (1, 3, 7 days) treatment. A whole-bladder preparation was used to assess compliance, contractile responses, and urothelial-mediator release. Ibuprofen selectively increased the cytotoxic potency of MMC and caspase-3 activity in both malignant cells lines but not in UROtsa. MMC significantly increased voiding frequency at 24 hours and 3 days, whereas administration of ibuprofen significantly reduced this effect. MMC significantly increased the frequency of spontaneous contractions from 2.3 ± 0.5 contractions/min in saline controls to 4.8 ± 0.16 contractions/min, with ibuprofen protecting against this change. Interestingly, although nerve-evoked responses were not altered by MMC, they were increased in both IBU groups. Ibuprofen improved voiding dysfunction following MMC treatment by reducing spontaneous phasic activity and enhancing nerve-mediated contractions. Ibuprofen use in bladder cancer patients may help to minimize the urological adverse effects associated with intravesical MMC.
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http://dx.doi.org/10.1124/jpet.118.248989DOI Listing
August 2018

Prazosin but Not Tamsulosin Sensitises PC-3 and LNCaP Prostate Cancer Cells to Docetaxel.

Pharmacology 2018 Apr 17;102(1-2):10-18. Epub 2018 Apr 17.

School of Pharmacy and Pharmacology, Griffith University, Gold Coast Campus, Gold Coast, Queensland, Australia.

Background/aims: Docetaxel is currently the first-line chemotherapeutic agent available for the treatment of patients with advanced prostate cancer (PCa). While docetaxel has been shown to modestly improve survival times for patients; they also experience significant docetaxel-induced toxicities. If treatment failure occurs, there are currently limited alternatives that show survival benefits for patients and therefore there is an urgent need for adjunct therapies. Some quinazoline-based alpha1-adrenoceptor (ADR) antagonists have previously been shown to have cytotoxic actions in PCa cells, but there is no research into their effects on docetaxel-induced toxicity. Therefore, the aim of this study was to determine if the quinazoline ADR, prazosin influenced the sensitivity of PCa cells to docetaxel in vitro. We hypothesised that prazosin, but not tamsulosin, in combination with docetaxel would possess synergistic cytotoxic actions on PC-3 and LNCaP PCa cells.

Methods: PC-3 and -LNCaP cells were pre-treated (1 h) with prazosin (30 µmol/L) or tamsulosin (30 µmol/L), followed by docetaxel (12.5-100 μmol/L) for 24 h. Docetaxel-induced toxicity was measured in terms of changes in cell proliferation, autophagy, apoptosis and the production of reactive oxygen species (ROS).

Results: Prazosin sensitised both cell lines (PC-3 and LNCaP) to docetaxel-induced toxicity. This effect appears to be mediated by autophagy and may also involve apoptosis. These sensitising effects of prazosin appear to be largely independent of ROS production. In contrast, tamsulosin did not affect docetaxel-induced toxicity.

Conclusion: We have shown for the first time that prazosin increases docetaxel-induced toxicity in PC-3 and LNCaP cells. Prazosin may therefore offer a viable treatment option in combination with docetaxel in metastatic PCa.
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http://dx.doi.org/10.1159/000488713DOI Listing
April 2018
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