Local Effects of Antimuscarinics

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Muscarinic receptors in the bladder urothelium

Radioligand-binding studies with [3H] quinuclidinyl benzylate have indicated that in humans, the density of mAChRs in the bladder mucosa was equal to that in the detrusor [17], whereas in the pig, the density of mAChRs in the mucosa was higher than that in the detrusor [11]. Immunohistochemical staining of human bladder tissues with an antibody directed against choline acetyltransferase detected the presence of immunoreactive cells in smooth muscles and urothelium. The immunoreactivity in the

Muscarinic receptor subtypes in the detrusor and urothelium

Five subtypes of G protein–coupled mAChRs (M1–M5) have been cloned and pharmacologically characterized. Detrusor smooth muscle from several species contains M2 and M3 receptor subtypes [5], [9], [18]. The ratio of M2 to M3 in the bladder is 9:1 in the rat but 3:1 in other species [18]. In the human bladder, the occurrence of mRNA for all mAChR subtypes has been demonstrated, with a predominant expression of mRNA encoding M2 and M3 receptors [19], [20]. Recently, competitive-binding assay

Non-neuronal acetylcholine

It is well known that postganglionic parasympathetic neurons are the major source of ACh in the bladder; however, it has been reported that non-neuronal ACh is synthesized in cells other than neurons and may act in an autocrine or paracrine manner [21], [22]. Non-neuronal ACh has also been detected in bronchial and placental epithelial cells, the mucosa of alimentary tract, the corneal epithelium, keratinocytes, glandular tissues, endothelial cells, and blood cells [21], [22], [23], [24].

In the

Acetylcholine and muscarinic acetylcholine receptors related to functional modulation of afferent pathways

Recent data suggest that bladder stretch or small contractions can cause the release of different factors from the urothelium, including ATP, prostaglandins [10], [25], [26], and nitric oxide [27]. It is generally thought that ATP and prostaglandins can stimulate afferent neurons [10], [25], [26], whereas nitric oxide can inhibit afferent activity [27]. Therefore, it is possible that non-neuronal ACh released from the urothelium by distension and small contractions of the detrusor can also

Functional studies related to bladder muscarinic acetylcholine receptors

It has been reported that M3 knockout mice of either sex had longer voiding intervals and increased micturition volumes than wild-type controls, suggesting that muscarinic receptors, especially M3 receptors, may be involved in volume threshold regulation for micturition during the storage phase [33].

Recently, the authors reported that intravesical application of carbachol or ACh can induce detrusor overactivity in rats. Because intravesical application of mAChRs agonists such as oxotremoline-M

Antimuscarinic agents

It has been reported that in anesthetized rats that had acetone-induced cystitis, high-dose oxybutynin but not atropine prolonged micturition intervals and significantly suppressed micturition pressure, suggesting that the effects of oxybutynin on micturition intervals are considered to be mainly linked to its direct smooth muscle–relaxant effect [44], [45]. Oxybutynin was also shown to increase micturition intervals in spinal cord–injured rats, although the systemic effective dose for

Summary

It is likely that local muscarinic receptors have an important role in the modulation of bladder afferent excitability and voiding. Thus, interactions between muscarinic receptors in the urothelium, afferent nerves, or myofibroblasts and locally released ACh that is increased by bladder stretch and aging might be involved in the emergence of detrusor overactivity and OAB (see Fig. 2). Therefore, antimuscarinic agents may be effective in treating OAB not only by suppression of muscarinic

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References (61)

  • B.V. Sastry

    Human placental cholinergic system

    Biochem Pharmacol

    (1997)
  • B.M. Conti-Fine et al.

    Neuronal nicotinic receptors in non-neural cells: new mediators of tobacco toxicity?

    Eur J Pharmacol

    (2000)
  • W.C. de Groat

    The urothelium in overactive bladder: passive bystander or active participant?

    Urology

    (2004)
  • C.A. Maggi

    Prostanoids as local modulators of reflex micturition

    Pharmacol Res

    (1992)
  • N. Yoshimura et al.

    Targeting afferent hyperexcitability for therapy of the painful bladder syndrome

    Urology

    (2002)
  • J. Nishiguchi et al.

    Detrusor overactivity induced by intravesical application of adenosine of adenosine 5′-triphosphate under different delivery conditions in rats

    Urology

    (2005)
  • G.O. Dussor et al.

    Cholinergic modulation of nociceptive responses in vivo and neuropeptide release in vitro at the level of the primary sensory neurons

    Pain

    (2004)
  • Y. Kim et al.

    Antimuscarinic agents exhibit local inhibitory effects on muscarinic receptors in bladder-afferent pathways

    Urology

    (2005)
  • H. Masuda et al.

    Roles of bladder muscarinic receptors in the regulation of storage function in rats

    J Urol

    (2005)
  • O.J. Wiseman et al.

    The ultrastructure of bladder lamina propria nerves in healthy subjects and patients with detrusor hyperreflexia

    J Urol

    (2002)
  • K.M. Sanders

    A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract

    Gastroenterology

    (1996)
  • N.A. Salas et al.

    Intravesical cholinergic receptor activated spinal ATP release in normal and chronic spinal cord injured rats

    J Urol

    (2005)
  • B. Chaiyaprasithi et al.

    Inhibition of human detrusor contraction by a urothelium derived factor

    J Urol

    (2003)
  • I. Shimizu et al.

    Effects of AH-9700, (+)-pentazocine, DTG and oxybutynin on micturition in anesthetized rats with acetone-induced cystitis

    Life Sci

    (2001)
  • G. Buyse et al.

    Intravesical oxybutynin for neurogenic bladder dysfunction: less systemic side effects due to reduced first pass metabolism

    J Urol

    (1998)
  • S. De Wachter et al.

    Intravesical oxybutynin: a local anesthetic effect on bladder C afferents

    J Urol

    (2003)
  • O. Yokoyama et al.

    Effects of tolterodine on an overactive bladder depend on suppression of C-fiber bladder afferent activity in rats

    J Urol

    (2005)
  • E.C. Burgard et al.

    Modulation of calcium currents in bladder sensory neurons by antimuscarinic agents

    J Urol

    (2005)
  • H. Ozturk et al.

    Effects of methoctramine on bladder overactivity in a rat model

    Urology

    (2003)
  • T. Yamanishi et al.

    The role of M2 muscarinic receptor subtypes in mediating contraction of the pig bladder base after cyclic adenosine monophosphate elevation and/or selective M3 inactivation

    J Urol

    (2002)
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    This work was supported by grants from the National Institutes of Health (DK57267, DK68557, DK66138, P01 HD39768) and Indevus, Inc.

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