Cyclophosphamide-induced alterations of the micturition reflex in a novel in situ urinary bladder model in the anesthetized rat

Aronsson, Patrik; Carlsson, Thomas; Winder, Michael; Tobin, Gunnar

doi:10.1002/nau.22562

Cited by 14 publications

(9 citation statements)

References 24 publications

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“…To note, in contrast to in vitro methacholine administration, methacholine was given at a submaximal dose in vivo, which could be one reason for more or less identical cholinergic contractions in irradiated bladders and controls. In another model for bladder pathology (cyclophosphamide-induced cystitis), we showed that bladder contractions in response to methacholine in vivo was reduced at 10 mg/kg, but not at 5 mg/kg, compared with controls (Aronsson et al, 2015).…”

Section: Discussionmentioning

confidence: 80%

“…On the day of the experiment, the rat was sedated with isoflurane and a small sagittal incision was made on the lower abdomen of the rat over the urinary bladder. The experiment was conducted as previously described with an in situ half bladder preparation (Aronsson et al, 2014(Aronsson et al, , 2015. In brief, the urinary bladder was cut into two sagittal parts (A and B).…”

Section: Methodsmentioning

confidence: 99%

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Changes in the Neuronal Control of the Urinary Bladder in a Model of Radiation Cystitis

Giglio

Podmolíková

Tobin

2018

J Pharmacol Exp Ther

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Currently, we have assessed the neuronal control of the urinary bladder in radiation cystitis and whether interstitial cells contribute to the condition. Fourteen days after bladder irradiation (20 Gy), rats were sedated and the urinary bladder was cut into two sagittal halves where electrical field stimulation (EFS; 5-20 Hz) was applied on the pelvic nerve afferents or stretch (80 mN) on one-half of the bladder, while contractions were registered on the contralateral half of the bladder in the absence and presence of increasing doses of imatinib (1-10 mg/kg; inhibitor of c-kit-positive interstitial cells), atropine (1 mg/kg; to block muscarinic M receptors), or pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (2 mg/kg; P2 purinoceptor antagonist). Urinary bladders were also excised for organ bath experiments, Western blot, quantitative polymerase chain reaction, and immunohistochemistry. In vivo, EFS contractions were enhanced after irradiation, and imatinib (1-10 mg/mg) inhibited contractions by EFS and stretched dose-dependently in controls but not in irradiated bladders. In the irradiated bladder in vitro, atropine resistance was increased and imatinib (100 M) inhibited contractions by EFS and agonists (ATP, methacholine) in irradiated bladders and controls. The urinary bladder expressions of P2 purinoceptors, muscarinic M receptor, choline acetyltransferase, c-kit, and the agonist of c-kit, stem cell factor, were not changed by irradiation. In conclusion, bladder irradiation affects several levels of neuronal control of the urinary bladder. Interstitial cells may contribute to some of the symptoms associated with radiation cystitis.

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Section: Discussionmentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Changes in the Neuronal Control of the Urinary Bladder in a Model of Radiation Cystitis

Giglio

Podmolíková

Tobin

2018

J Pharmacol Exp Ther

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“…It has also been shown that contractile responses elicited by electrical field stimulation increases in rat detrusor strips after intravesical LPS administration [3]. An increase in micturition reflex in cyclophosphamide-induced cystitis in male Sprague-Dawley rats has also been demonstrated [30]. Furthermore, the activation of voltage-gated calcium 3.2 T-type channels is related to bladder pain and referred hyperalgesia in mice with cyclophosphamide-induced cystitis [31].…”

Section: Discussionmentioning

confidence: 97%

Rho Kinase and Protein Kinase C Pathways are Responsible for Enhanced Carbachol Contraction in Permeabilized Detrusor in a Rat Model of Cystitis

Denizalti

Durlu-Kandilci

Şimşek

et al. 2018

Basic Clin Pharma Tox

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Interstitial cystitis is a syndrome characterized by detrusor overactivity and chronic inflammation of the bladder. The mechanisms responsible for the altered smooth muscle contractility remain poorly understood. The aim of the study was to investigate the role of intracellular signalling pathways in carbachol-induced detrusor contraction in a rat model of interstitial cystitis. Cyclophosphamide (150 mg/kg, dissolved in saline) was injected to rats (Sprague-Dawley, female, 200-250 g) intraperitoneally once a day on days 1, 4 and 7 to induce interstitial cystitis. Control groups were injected with saline (0.9% NaCl). Detrusor smooth muscle strips were mounted in 1-ml organ baths containing HEPES-buffered modified Krebs' solution and permeabilized with 40 μM β-escin for 30 min. Carbachol-induced contractions were significantly increased from 21.2 ± 1.6% (saline-treated) to 44 ± 4.4% in cyclophosphamide-treated group. The Rho kinase inhibitor Y-27632 (8.8 ± 2%) and the protein kinase C inhibitor GF-109203X (11.7 ± 2.8%) inhibited the increased contractile response (44 ± 4.4%) in rats with cystitis. The increased carbachol-induced contraction (44 ± 4.4%) was also significantly inhibited by the sarcoplasmic reticulum ryanodine channel blocker ryanodine (25.8 ± 3.2%) and the sarcoplasmic reticulum IP receptor blocker heparin (17.2 ± 2.2%) in cystitis. RhoA protein levels in the bladder of cyclophosphamide-treated rats were significantly increased while pan-protein kinase C (α, β and γ isoforms) protein expression was unaltered between experimental groups. Carbachol-induced calcium sensitization at constant and clamped calcium (pCa 6) was also increased in cystitis (from 15.8 ± 2.2% to 24.7 ± 2.8%). This increased response (24.7 ± 2.8%) was significantly inhibited by both Y-27632 (7.9 ± 0.7%) and GF-109203X (4.4 ± 1.5%). We conclude that interstitial cystitis is characterized by an enhanced carbachol contractile response as well as by calcium sensitization of the detrusor smooth muscle. Activation of Rho kinase and protein kinase C pathways may be the molecular culprits responsible for the augmented muscarinic response observed in cystitis.

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“…The responses to ATP in the Parkinsonian animals were significantly altered, in particular following muscarinic receptor blockage by atropine, which may also suggest that this system could be affected by the central dopamine denervation by 6-OHDA. It has previously been shown that ATP can act in concert with acetylcholine to facilitate detrusor muscle contraction [ 24, 34 ]. It has also been reported that purinergic P2X1 receptors can be desensitized by low concentrations of ATP and mask the true potency of an agonist [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Local Change in Urinary Bladder Contractility Following CNS Dopamine Denervation in the 6-OHDA Rat Model of Parkinson’s Disease

Mitra

Aronsson

Winder

et al. 2015

JPD

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Background: Urinary problems, including urinary frequency, urgency, and nocturia are some of the non-motor symptoms that correlate most with poor quality of life in Parkinson’s disease. However, the mechanism behind these symptoms is poorly understood, in particular regarding peripheral bladder pathophysiology following dopamine degeneration.Objective: In this study, we compared the contractile responsiveness of urinary bladder from the 6-OHDA unilateral rat model of Parkinson’s disease with that of normal untreated animals.Methods: The contractility of the urinary detrusor muscle was evaluated in bladder strip preparations using electrical field stimulation, and muscarinic and purinoceptor stimulations in an vitro organ bath setup.Results: Our data show that the overall contractile response following electrical field stimulation was significantly higher (43% at maximum contraction by 20–40 Hz stimulation) in the 6-OHDA-lesioned rats as compared to control animals. This increase was associated with a significant increase in the cholinergic contractile response, where the muscarinic agonist methacholine produced a 44% (at 10 −4 M concentration) higher response in the 6-OHDA-treated rats as compared to controls with a significant left-shift of the dose response. This indicates an altered sensitivity of the muscarinic receptor system following the specific central 6-OHDA-induced dopamine depletion. In addition a 36% larger contraction of strips from the 6-OHDA animals was also observed with purinoceptor activation using the agonist ATP (5×10 −3 M) during atropine treatment.Conclusions: Our data shows that it is not only the central dopamine control of the micturition reflex that is altered in Parkinson’s disease, but also the local contractile function of the urinary bladder. The current study draws attention to a mechanism of urinary dysfunction in Parkinson’s disease that has previously not been described.

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Cyclophosphamide-induced alterations of the micturition reflex in a novel in situ urinary bladder model in the anesthetized rat

Abstract: The micturition reflex response is increased following cyclophosphamide-induced cystitis, as compared to control. The likely cause is sensitization at mechanosensor level in the micturition arc, which overrides the decrement of the efferent cholinergic effects.

Cited by 14 publications

References 24 publications

Changes in the Neuronal Control of the Urinary Bladder in a Model of Radiation Cystitis

Changes in the Neuronal Control of the Urinary Bladder in a Model of Radiation Cystitis

Rho Kinase and Protein Kinase C Pathways are Responsible for Enhanced Carbachol Contraction in Permeabilized Detrusor in a Rat Model of Cystitis

Local Change in Urinary Bladder Contractility Following CNS Dopamine Denervation in the 6-OHDA Rat Model of Parkinson’s Disease

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