The present study was designed to reexamine the muscarinic acetylcholine receptor subtype mediating carbacholinduced contraction of human urinary bladder and to investigate the underlying signal transduction. Based upon the nonselective tolterodine, the highly M 2 -selective (R)-4-{2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl}-piperidine-1-carboxylic acid amide , and the highly M 3 -selective darifenacin and 3- In contrast, trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide (Y 27,632) (1-10 M), an inhibitor of rho-associated kinases, concentration dependently and effectively attenuated the carbachol responses. We conclude that carbachol-induced contraction of human urinary bladder via M 3 receptors largely depends on Ca 2ϩ entry through nifedipine-sensitive channels and activation of a rho kinase, whereas phospholipase D and store-operated Ca 2ϩ channels contribute only in a minor way. Surprisingly, phospholipase C or protein kinase C do not seem to be involved to a relevant extent.Muscarinic acetylcholine receptors are the physiologically most important mechanism to elicit contraction of the urinary bladder (Andersson, 1993). M 2 and M 3 muscarinic receptors coexist in the bladder of various mammalian species, including humans, but the expression of M 2 receptors is much greater than that of the M 3 receptors (Wang et al., 1995;Goepel et al., 1998;Yamanishi et al., 2000;Kories et al., 2003). Nevertheless, the contractile response to the exogenous agonist carbachol and to endogenous agonist released by field stimulation have been attributed predominantly if not exclusively to M 3 receptors in rats (Longhurst et al

We have reexamined the muscarinic receptor subtype mediating carbachol-induced contraction of rat urinary bladder and investigated the role of phospholipase (PL)C, D, and A 2 and of intra-and extracellular Ca 2ϩ sources in this effect. Based on the nonsubtype-selective tolterodine, the highly M 2 receptorselective (R)-4-{2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl}-piperidine-1-carboxylic acid amide , and the highly M 3 receptor-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M 3 receptors. Carbachol stimulated inositol phosphate formation in rat bladder slices, and this was abolished by the phospholipase C inhibitor 1- Carbachol had only little effect on PLD activity in bladder slices, but the PLD inhibitor butan-1-ol, relative to its negative control butan-2-ol (0.3% each), caused detectable inhibition of carbachol-induced bladder contraction. The cytosolic PLA 2 inhibitor arachidonyltrifluoromethyl ketone weakly inhibited carbacholinduced contraction at a concentration of 300 M, but the cyclooxygenase inhibitor indomethacin (1-10 M) remained without effect. The Ca 2ϩ entry blocker nifedipine (10 -100 nM) almost completely inhibited carbachol-induced bladder contraction. In contrast, 1-[␤-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SKF 96,365; 10 M), an inhibitor of storeoperated Ca 2ϩ channels, caused little inhibition. We conclude that carbachol-induced contraction of rat bladder largely depends on Ca 2ϩ entry through nifedipine-sensitive channels and, perhaps, PLD, PLA 2 , and store-operated Ca 2ϩ channels, whereas cyclooxygenase and, surprisingly, also PLC are not involved to a relevant extent.Muscarinic acetylcholine receptors are the physiologically most important mechanisms to elicit contraction of the urinary bladder (Andersson, 1993). In the bladder of various mammalian species, including humans, M 2 and M 3 muscarinic receptors coexist, but the expression of M 2 receptors is much greater than that of the M 3 receptors (Wang et al., 1995;Goepel et al., 1998;Yamanishi et al., 2000;Kories et al., 2003). Nevertheless, the contractile response to the exogenous agonist carbachol and to endogenous agonists released by field stimulation have been attributed predominantly, if not exclusively, to M 3 receptors in rats (Longhurst et al., 1995;Hegde et al., 1997;Tong et al., 1997;Braverman et al., 1998;Choppin et al., 1998;Longhurst and Levendusky, 2000;Kories et al., 2003), mice (Choppin and Eglen, 2001b), pigs (Yamanishi et al., 2000), dogs (Choppin and Eglen, 2001a), and humans (Chess-Williams et al., 2001;Fetscher et al., 2002). Moreover, at least male M 3 (but not M 2 ) receptorknockout mice exhibit bladder distension and develop urinary retention (Matsui et al., 2000). On the other hand, it should be considered that hitherto available antagonists have only modest subtype selectivity and/or do not act in a purely competitive manner; hence, they were not well suited for detecting a pot...

The extent of the therapeutic response to tolterodine is largely determined by the extent of baseline symptoms. While gender does not affect the efficacy or tolerability of tolterodine in a clinically relevant manner, advanced age is associated with a slight decrease in efficacy but not in tolerability.

placebo on UUI episodes (primary endpoint), micturitions, urgency and most other diary endpoints, and on the PPBC, UPS and all OAB Questionnaire scales and domains (all P < 0.05).• Superiority of fesoterodine 8 mg over tolterodine ER 4 mg was seen as early as week 4 (3 weeks after escalation to fesoterodine 8 mg). At week 1, fesoterodine 4 mg was superior to placebo on most diary variables, the PPBC and the UPS (all P < 0.05). Dry mouth and constipation rates were 28% and 4% with fesoterodine, 13% and 3% with tolterodine ER, and 5% and 2% with placebo.• Discontinuation rates as a result of adverse events were 5%, 3% and 2% for fesoterodine, tolterodine ER and placebo, respectively. CONCLUSIONS• In this randomized study, which is the largest to compare antimuscarinic efficacy performed to date, fesoterodine 8 mg was superior to tolterodine ER 4 mg for UUI episodes, micturitions and urgency episodes, as well as for self-reported patient assessments of bladder-related problems, urgency, symptom bother and health-related quality of life.• The superiority of fesoterodine 8 mg over tolterodine ER 4 mg was observed as early as 3 weeks after escalation from fesoterodine 4 mg for most outcomes. These data may have important implications for the clinical management of OAB patients previously treated with tolterodine ER. KEYWORDSantimuscarinic, fesoterodine, tolterodine, head-to-head, efficacy, quality of life What's known on the subject? and What does the study add? A previous trial found greater efficacy with the maximum available dose of fesoterodine 8 mg compared with the maximum available dose of tolterodine ER 4 mg and placebo for improving overactive bladder symptoms, and patient-reported outcomes were demonstrated by a recent placebo-controlled, head-to-head trial.The results of this trial, the largest to date to compare antimuscarinic efficacy, confirms the superior efficacy of fesoterodine 8 mg over tolterodine ER 4 mg for the treatment of OAB symptoms, and further emphasize the clinical advantage of the availability of an additional 8-mg dose over single-dose tolterodine ER 4 mg. Study Type -Therapy (RCT) Level of Evidence 1b OBJECTIVE• To show the superior efficacy of fesoterodine over tolterodine extended release (ER) in a placebo-controlled overactive bladder (OAB) trial with predefined treatment comparisons for both diary measures and patient-reported outcomes. MATERIALS AND METHODS• In this 12-week, double-blind, doubledummy trial, subjects reporting > 1 urgency urinary incontinence (UUI) episode and ≥ 8 micturitions per 24 h at baseline were randomized to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks), tolterodine ER 4 mg, or placebo.• Subjects completed 3-day bladder diaries, the Patient Perception of Bladder Condition (PPBC) and the Urgency Perception Scale (UPS) at baseline and weeks 1, 4 and 12 and the OAB Questionnaire at baseline and week 12. RESULTS• A total of 2417 subjects were randomized. At week 12, fesoterodine 8 mg showed superiority over tolterodine ER 4 mg and