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