Localization of M
            <sub>2</sub>
            and M
            <sub>3</sub>
            Muscarinic Receptors in Human Bladder Disorders and Their Clinical Correlations

Mukerji, Gaurav; Yiangou, Y.; Grogono, Joanna; Underwood, Jenny; Agarwal, Sanjiv; Khullar, Vikram; Anand, Praveen

doi:10.1016/s0022-5347(06)00563-5

Cited by 163 publications

(133 citation statements)

References 17 publications

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“…It has been reported that nicotinic and muscarinic cholinergic receptors are widely expressed on non-neuronal cells including intestinal, skin and urinary bladder epithelial cells, immune cells as well as myofibroblasts Hegde, 2006;Beckel et al, 2005;Mukerji et al, 2006). In the present study, 3 H-ACh evoked release was unmasked by atropine suggesting this was mediated by activation of nicotinic receptors.…”

Section: Discussionsupporting

confidence: 56%

Non-neuronal acetylcholine and urinary bladder urothelium

et al. 2007

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Non-neuronal release of acetylcholine (ACh) has been proposed to play a role in urinary bladder function. These studies investigated the expression and function of the non-neuronal cholinergic system in cultured urothelial cells isolated from the rat urinary bladder. Our findings have revealed that urothelial cells express the high-affinity choline transporter (CHT1) and acetylcholine synthesizing enzymes, choline acetyltransferase (ChAT) and carnitine acetyltransferase (CarAT). In contrast to neurons, urothelial cells do not express the vesicular acetylcholine transporter (VAChT) but do express OCT3, a subtype of polyspecific organic cation transporter (OCT) that is thought to be involved in the release of acetylcholine from nonneuronal cells. Following exposure of cultured urothelial cells to 3 H-choline, radioactivity was detected in the cells and increased release of radioactivity into the eternal media was evoked by mechanical stimulation (exposure of the cells to 50% hypotonic Krebs) or chemical stimulation of purinergic receptors by 100 μM ATP. The present experiments did not establish if the evoked release of radioactivity (termed 3 HACh release in this paper) was due to release of acetylcholine or choline. 3 H-ACh release was not evoked by application of acetylcholine alone, however pretreatment with the non-selective muscarinic receptor antagonist atropine prior to application of acetylcholine facilitated 3 H-ACh release, suggesting that the acetylcholine released from urothelial cells may participate in a negative feedback mechanism by acting on muscarinic receptors to inhibit its own release in the urothelium. Brefeldin, an agent which disrupts vesicular exocytosis, did not block hypotonicevoked 3 H-ACh release. These observations indicate that acetylcholine release from urothelial cells is mediated by different mechanisms than those such as vesicular storage and exocytosis that underlie the release of neurotransmitters from nerves.

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Section: Discussionsupporting

confidence: 56%

Non-neuronal acetylcholine and urinary bladder urothelium

et al. 2007

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“…A recent report (31) also demonstrated a high density of M 2 muscarinic receptors in the human bladder mucosa. Furthermore, Mukerji et al (32) reported that M 2 -and M 3 -immunoreactive staining was present in human detrusor, myofibroblast-like cells, nerve fiber bundle, and dorsal root ganglion of small and medium sensory neurons in suburothelium. These muscarinic receptors might be targets of non-neuronal ACh from urothelium.…”

Section: +mentioning

confidence: 99%

Basic and Clinical Aspects of Non-neuronal Acetylcholine: Expression of Non-neuronal Acetylcholine in Urothelium and Its Clinical Significance

et al. 2008

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Abstract.Recently, several reports demonstrate that non-neuronal acetylcholine (ACh) release may contribute to various pathophysiological conditions. In this review, we presented our experiments designed to evaluate the non-neuronal cholinergic system in human bladder. After insertion of the microdialysis probe, human bladder strips were suspended in an organ bath filled with Krebs-Henseleit solution, and Ringer solution was perfused into the probe. ACh release was measured by microdialysis and HPLC. The contribution of urothelium and the effects of age and stretch of bladder strips on non-neuronal ACh release were evaluated. Choline acetyltransferase (ChAT) immunohistochemical staining of bladder was also performed. Immunohistochemistry showed marked ChAT-positive staining in the urothelium. There was tetrodotoxininsensitive non-neuronal ACh release and this was significantly higher in strips with urothelium than in strips without urothelium. The non-neuronal ACh release was increased with age. Stretch of bladder strips caused increases in non-neuronal ACh release. The stretch-induced release of non-neuronal ACh was increased with age. Our data demonstrate that there is a non-neuronal cholinergic system in human bladder and that urothelium contributes to non-neuronal ACh release. There was significant age-related and stretch-induced increase in non-neuronal ACh release. It is suggested that the non-neuronal cholinergic system may contribute to the physiology and pathophysiology of human bladder. We also discussed the clinical significance of the nonneuronal cholinergic system in human bladder.

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“…An increased density of M2 protein and a decrease of M3 protein have been reported in decentralised 14 , obstructed 15 , and neurogenic 17 rat bladders. Also, there is evidence that expression of M2 and M3 mAChR subtypes are altered on the urothelium and suburothelial interstitial cells 29 in different bladder pathologies. These changes may account for the increased sensitivity for mAChR agonists in SCI rats.…”

Section: Discussionmentioning

confidence: 99%

199 Role of M2 and M3 Muscarinic Acetylcholine Receptor Subtypes in Activation of Bladder Afferent Pathways in Spinal Cord Injured Rats

Matsumoto¹,

Kita²,

Miyazato³

et al. 2010

Journal of Urology

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Purpose-In this study, we evaluated the role of M2 and M3 mAChR subtypes in activation of bladder afferent pathways in rats with chronic spinal cord injury (SCI).Materials and Methods-Adult female Sprague-Dawley rats were spinalized at the Th9 level. Continuous cystometry was performed under an awake condition 2 or 4 weeks after SCI. The effects of intravesical administration of an mAChR agonist (oxotremorine-M; Oxo-M), a nonselective antagonist (atropine), an M2-selective antagonist (methoctramine) and an M3-selective antagonist (darifenacin) were examined. After cystometry, the bladder was removed and separated into mucosa and detrusor, and M2 and M3 mAChR mRNA expression in the mucosa was determined with real time quantitative PCR.Results-At 2 and 4 weeks after SCI, intravesical administration of a non-selective mAChR agonist (25μM Oxo-M) increased the area under the curve of non-voiding contractions (NVCs) although intercontraction interval (ICI) of voiding contractions and maximum voiding pressure (MVP) did not change. This effect was blocked by atropine and methoctramine (10μM), but not by darifenacin (50μM). However, mAChR antagonists alone (50μM) had no effect on cystometric parameters. M2 mAChR mRNA expression was increased in mucosa of SCI rats compared to normal rats.Conclusions-Our results suggest that the M2 mAChR subtype plays an important role in bladder afferent activation that enhances detrusor overactivity in SCI rats. However, because mAChR antagonists alone did not affect any cystometric parameters, the muscarinic mechanism controlling bladder afferent activity may not be involved in the emergence of detrusor overactivity in SCI.

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Localization of M ₂ and M ₃ Muscarinic Receptors in Human Bladder Disorders and Their Clinical Correlations

Cited by 163 publications

References 17 publications

Non-neuronal acetylcholine and urinary bladder urothelium

Non-neuronal acetylcholine and urinary bladder urothelium

Basic and Clinical Aspects of Non-neuronal Acetylcholine: Expression of Non-neuronal Acetylcholine in Urothelium and Its Clinical Significance

199 Role of M2 and M3 Muscarinic Acetylcholine Receptor Subtypes in Activation of Bladder Afferent Pathways in Spinal Cord Injured Rats

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Localization of M 2 and M 3 Muscarinic Receptors in Human Bladder Disorders and Their Clinical Correlations

Cited by 163 publications

References 17 publications

Non-neuronal acetylcholine and urinary bladder urothelium

Non-neuronal acetylcholine and urinary bladder urothelium

Basic and Clinical Aspects of Non-neuronal Acetylcholine: Expression of Non-neuronal Acetylcholine in Urothelium and Its Clinical Significance

199 Role of M2 and M3 Muscarinic Acetylcholine Receptor Subtypes in Activation of Bladder Afferent Pathways in Spinal Cord Injured Rats

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Localization of M ₂ and M ₃ Muscarinic Receptors in Human Bladder Disorders and Their Clinical Correlations