Effects of Tolterodine on an Overactive Bladder Depend on Suppression of C-Fiber Bladder Afferent Activity in Rats

Yokoyama, Osamu; Yusup, Anwar; Miwa, Yoshiji; Oyama, Nobuyuki; Aoki, Yoshitaka; Akino, Hironobu

doi:10.1097/01.ju.0000176793.50410.9e

Cited by 81 publications

(67 citation statements)

References 16 publications

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“…Furthermore, intravesical instillation of oxybutynin (De Wachter and Wyndaele, 2003), tolterodine (Yokoyama et al, 2005), and darifenacin (Iijima et al, 2007) reduces distension-evoked activity of C-fiber afferents in rat bladder, an effect also seen after systemic administration of oxybutynin (De Laet et al, 2006). In patients with overactive bladder, intravesical administration of muscarinic antagonists, such as oxybutynin and trospium, is associated with reduced adverse affects (Madersbacher and Jilg, 1991;Fröhlich et al, 1998;Walter et al, 1999), whereas clinical efficacy remains (Enzelsberger et al, 1995;Fröhlich et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Comparison of Receptor Binding Characteristics of Commonly Used Muscarinic Antagonists in Human Bladder Detrusor and Mucosa

Mansfield¹,

Chandran²,

Vaux³

et al. 2008

J Pharmacol Exp Ther

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Recent studies have described muscarinic receptors on the mucosa and the detrusor of the human urinary bladder. Muscarinic receptor antagonists are effective in the treatment of overactive bladder (OAB), but their site(s) of action and actual therapeutic target are unclear. Our aim was to compare, in human bladder mucosa and detrusor, the radioligand binding characteristics of newer, clinically effective agents: darifenacin, its hydroxylated metabolite UK-148,993, fesoterodine, solifenacin, tolterodine, and trospium. Specimens were collected from asymptomatic patients (50 -72 years old) undergoing open bladder surgery. Radioligand binding studies with the muscarinic antagonist [ 3 H]quinuclidinyl benzilate (QNB) were performed separately on detrusor and mucosal membranes. All antagonists displayed high affinity when competing for [ 3 H]QNB binding in both detrusor and mucosa. Inhibition constants were also obtained for all antagonists against individual muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Here, fesoterodine showed anomalous binding results, suggesting that some conversion to its metabolite had occurred. Global nonlinear regression analysis of bladder binding data with five antagonists demonstrated 82% low-affinity sites in mucosa and 78% low-affinity sites in detrusor, probably representing M 2 /M 4 receptors. There was an excellent correlation (r 2 ϭ 0.99) of low-affinity global estimates between detrusor and mucosa, whereas the corresponding high-affinity estimates (ϳ20% of sites) were dissimilar. In conclusion, commonly used and clinically effective muscarinic receptor antagonists bind to receptors located on the bladder mucosa and the detrusor, providing support for the hypothesis that muscarinic receptors in the mucosa may represent an important site of action for these agents in OAB.Overactive bladder (OAB) is a debilitating disorder where patients experience frequency and urgency of micturition, with or without urgency incontinence. Of these, the symptom of "urgency" (urgency because of fear of leakage) is acknowledged to be the most bothersome (Brubaker, 2004). This condition is experienced by approximately 17% of both men and women over the age of 40 years and is more common with increasing age (Milsom et al., 2001;Stewart et al., 2003). Muscarinic receptor antagonists are widely used to treat OAB (Andersson and Yoshida, 2003;Hegde, 2006;Abrams and Andersson, 2007), but their lack of organ selectivity has resulted in side effects, including dry mouth, constipation, and blurred vision, which often result in patients discontinuing therapy (Colli et al., 2007).Traditionally, muscarinic receptor antagonists were thought to mediate their clinical effects by blocking muscarinic receptors on the detrusor muscle, thus inhibiting bladder contraction because of acetylcholine released from parasympathetic nerves. However, at therapeutic doses, muscarinic antagonists do not seem to inhibit bladder contractility (Andersson and Yoshida, 2003;Finney et al., 2006), and it is n...

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Section: Discussionmentioning

confidence: 99%

Comparison of Receptor Binding Characteristics of Commonly Used Muscarinic Antagonists in Human Bladder Detrusor and Mucosa

Mansfield¹,

Chandran²,

Vaux³

et al. 2008

J Pharmacol Exp Ther

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“…It has been shown that suppression of afferent nerve activity with neurotoxins, such as botulinum toxin and resiniferatoxin, effectively relieves OAB symptoms in both human patients (Schurch et al 2000;Silva et al 2002) and animal models (Atiemo et al 2005;Khera et al 2005;Yokoyama et al 2005Yokoyama et al , 2010, emphasizing the importance of afferent nerve dynamics in the pathogenesis of OAB.…”

Section: Modulation Of Afferent Fibres By Pgementioning

confidence: 99%

Modulation of afferent nerve activity by prostaglandin E₂ upon urinary bladder distension in rats

Kuga¹,

Tanioka²,

Hagihara³

et al. 2016

Experimental Physiology

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New Findings r What is the central question of this study?It has been widely assumed that C fibres innervating the bladder are mainly excited in overactive bladder syndrome. However, it remains unclear whether Aδ fibres are also activated in pathological conditions. r What is the main finding and its importance?We found that a certain population of Aδ fibres, which become active specifically at a bladder pressure of more than 15 cmH 2 O in normal conditions, showed increased excitability in conditions of prostaglandin E 2 -induced overactive bladder. This result suggests that a certain population of Aδ fibres, together with C fibres, triggers pathophysiological activity.In overactive bladder syndrome, afferent C fibres innervating the bladder show an increased activity level. However, it remains unclear whether all C fibres are highly activated and whether Aδ fibres, the other type of bladder afferent fibre, are also involved in pathological conditions. To address these questions, we analysed the relationship between bladder pressure and single-unit firing patterns of afferent nerves in the left L6 dorsal roots in living rats. The recorded fibres were classified as Aδ fibres or C fibres based on the response to 0.3 μm tetrodotoxin. Certain populations of both Aδ fibres and C fibres were activated at bladder pressures below 15 cmH 2 O (classified as low-threshold fibres), indicating their potential contribution to detection of normal bladder filling. Intravesical administration of prostaglandin E 2 (PGE 2 ) induced hyperexcitation in approximately half of such C fibres, whereas the activity patterns of low-threshold Aδ fibres were unchanged. All fibres, regardless of type, which were almost silent in control conditions (classified as high-threshold fibres), were activated by application of PGE 2 . Notably, the firing patterns of Aδ fibres, rather than C fibres, were highly time locked to PGE 2 -induced micro-oscillation of bladder pressure. These modulatory effects of PGE 2 on Aδ fibres and C fibres might trigger pathophysiological activity together in overactive bladder syndrome.

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“…Recent studies showed that several anticholinergics might modulate bladder function through afferent nerve fibers [19,20] , and it cannot be excluded that P4NO in a chronic animal model might influence bladder function. However, an acute inhibitory effect of P4NO on efferent detrusor activation could not be demonstrated in this study.…”

Section: Discussionmentioning

confidence: 99%

Effects of Propiverine and Its Metabolite Propiverine-N-Oxide on Bladder Contraction and Salivation in Mini Pigs

Scheepe¹,

Braun²,

Jünemann³

et al. 2008

Urol Int

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Purpose: The objective of this study was to evaluate the influence of propiverine-HCl (P4) and propiverine-N-oxide (P4NO), one of the major metabolites of P4, on bladder contraction in a standardized in vivo model. Additionally, salivary flow measurements enabled the evaluation of hyposalivation, one of the most predominant anticholinergic side effects. Materials and Methods: Ten male mini pigs were anesthetized. P4 (0.4 mg/kg b.w.) and P4NO (0.422 mg/kg b.w.) were administered intravenously. Bladder contractions were induced through sacral anterior root stimulation and cystometrogram evaluation was performed. For stimulation-induced salivary flow measurements, the lingual nerve was exposed for neurostimulation. The effects of P4 and P4NO on stimulation-induced bladder contraction and salivation were evaluated in 5 mini pigs, respectively. Results: In all experiments, for each animal reproducible intravesical pressure values (Pves) were elicited during sacral anterior root stimulation before administration of the study drug. After administration of P4, Pves decreased by 64% whereas P4NO decreased Pves by 28%. Inhibition of salivary flow with P4 and P4NO was 71 and 32%, respectively. Directly following intravenous administration of P4, a short-term and reversible period of mild fluctuations in heart rate was observed. Administration of P4NO revealed no changes in either heart rate, or blood pressure. Conclusion: All of the investigated parameters revealed less anticholinergic effects for P4NO compared to P4. Under the experimental conditions described above, it may be assumed that P4NO behaves as a substance with poor anticholinergic effects with respect to side effects. As expected, P4 showed anticholinergic effects on bladder contraction and salivation.

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Effects of Tolterodine on an Overactive Bladder Depend on Suppression of C-Fiber Bladder Afferent Activity in Rats

Abstract: These results suggest that at low doses tolterodine exerts an inhibitory effect on C-fiber bladder afferent nerves, thereby, improving BC during the storage phase.

Cited by 81 publications

References 16 publications

Comparison of Receptor Binding Characteristics of Commonly Used Muscarinic Antagonists in Human Bladder Detrusor and Mucosa

Comparison of Receptor Binding Characteristics of Commonly Used Muscarinic Antagonists in Human Bladder Detrusor and Mucosa

Modulation of afferent nerve activity by prostaglandin E₂ upon urinary bladder distension in rats

Effects of Propiverine and Its Metabolite Propiverine-N-Oxide on Bladder Contraction and Salivation in Mini Pigs

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Effects of Tolterodine on an Overactive Bladder Depend on Suppression of C-Fiber Bladder Afferent Activity in Rats

Abstract: These results suggest that at low doses tolterodine exerts an inhibitory effect on C-fiber bladder afferent nerves, thereby, improving BC during the storage phase.

Cited by 81 publications

References 16 publications

Comparison of Receptor Binding Characteristics of Commonly Used Muscarinic Antagonists in Human Bladder Detrusor and Mucosa

Comparison of Receptor Binding Characteristics of Commonly Used Muscarinic Antagonists in Human Bladder Detrusor and Mucosa

Modulation of afferent nerve activity by prostaglandin E2 upon urinary bladder distension in rats

Effects of Propiverine and Its Metabolite Propiverine-N-Oxide on Bladder Contraction and Salivation in Mini Pigs

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Modulation of afferent nerve activity by prostaglandin E₂ upon urinary bladder distension in rats