Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists

Gillberg, Per‐Göran; Sundquist, Staffan; Nilvebrant, Lisbeth

doi:10.1016/s0014-2999(98)00214-3

Cited by 81 publications

(45 citation statements)

References 23 publications

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“…The amplitude of volume-induced bladder contractions in the urethane-anesthetized rat is inhibited by subtype-selective muscarinic antagonists with potencies that correlate most favorably with pK i estimates of these compounds at human recombinant M 2 receptors (16). In addition, the M 2 -and M 4 -selective antagonist AQ-RA 741, similar to the nonselective antagonist tolterodine, has a greater selectivity for inhibition of bladder contraction than for inhibition of salivation in the ␣-chloralose-anesthetized cat, suggesting M 2 receptor involvement in bladder contraction (15). Intravenous injection of AF-DX116 (M 2 -selective antagonist) reduces contraction pressure but not frequency or the duration of bladder contraction (21).…”

Section: Discussionmentioning

confidence: 80%

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂

Braverman¹,

Ruggieri²

2003

American Journal of Physiology-Regulatory, Integrative and Comp

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Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2. Am J Physiol Regul Integr Comp Physiol 285: R701-R708, 2003. First published May 22, 2003 10.1152/ajpregu.00009.2003.-Major pelvic ganglion electrocautery (MPGE) and spinal cord injury in the rat induce bladder hypertrophy and a change in muscarinic receptor subtypes mediating bladder contraction from predominantly M 3 to a combination of M2 and M3. To determine whether this is a result of bladder hypertrophy or denervation, we studied the following groups: sham-operated controls, urinary diversion (DIV), MPGE together with urinary diversion (DIV-DEN), bilateral MPGE (DEN), bladder outlet obstruction (BOO), and MPG decentralization (MPG-DEC). The degree of bladder denervation was determined by the maximal carbachol response normalized to the response to electric field stimulation. Receptor subtype density was determined by immunoprecipitation. The affinity of subtypeselective muscarinic antagonists for inhibition of carbacholinduced contractions was used to determine the subtypemediating contraction. DEN, MPG-DEC, and BOO bladders were hypertrophic whereas DIV bladders were atrophic compared with sham operated. Bladder contraction in shamoperated, DIV, and DIV-DEN was mediated by the M3 receptor subtype, whereas the M 2 subtype participated in contraction in the DEN, MPG-DEC, and BOO groups. The hypertrophied bladders had an increase in total and M 2 receptor density while all experimental groups showed a reduction in M3 receptor density. Thus bladder hypertrophy, independent from bladder denervation, causes a shift in the muscarinic receptor subtype mediating bladder contraction from M3 toward M2. denervation; outlet obstruction; urinary diversion PHARMACOLOGICAL DATA, based on the actions of subtypeselective antimuscarinic agents, can distinguish four subtypes of muscarinic acetylcholine receptors (M 1 -M 4 ). Molecular techniques have identified five muscarinic receptor subtypes (M 1 -M 5 ) arising from five separate genes (7,8). Both M 2 and M 3 muscarinic receptor subtypes are found in most smooth muscles. The M 2 receptor preferentially couples to the inhibition of adenylyl cyclase through the G i family of proteins, while the M 3 receptor preferentially couples to IP 3 generation and calcium mobilization through the G q family of proteins (7,8). Pertussis toxin (PTX), which ADP ribosylates and therefore inactivates the G i family of proteins, has no apparent effect on contraction (23). Even though the M 2 muscarinic receptor density is greater than the M 3 receptor density in bladder and other smooth muscles, the affinity of subtype-selective muscarinic receptor antagonist drugs indicates that contraction is mediated by the M 3 receptor in most smooth muscles under normal conditions (7,9).A number of studies have shown that under certain conditions the M 2 receptor subtype can contribute to the contractile response. This includes selective alkylation of M 3 receptors in an environment of increased intrac...

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Section: Discussionmentioning

confidence: 80%

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂

Braverman¹,

Ruggieri²

2003

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Compounds with high affinity for the M 3 receptor have therefore been used in the management of overactive bladder (OAB) (Wallis and Napier, 1999). Indeed, the major current therapies for OAB, oxybutynin and tolterodine, both display high-affinity antagonism at the M 3 receptor and potently inhibit mACh receptor agonist-induced urinary bladder contractions in vitro and in vivo (Nilvebrant et al, 1997;Gillberg et al, 1998). However, the clinical utility of mACh receptor antagonists has been limited by lack of selectivity, which leads to classical antimuscarinic side-effects, such as dry mouth, tachycardia, and blurred vision.…”

mentioning

confidence: 99%

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Nelson¹,

Gupta²,

Napier³

et al. 2004

J Pharmacol Exp Ther

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Binding and functional affinities of the muscarinic acetylcholine (mACh) receptor antagonists darifenacin, tolterodine, oxybutynin, and atropine were assessed in Chinese hamster ovary (CHO) cells expressing the human recombinant M 2 (CHO-m2) or M 3 (CHO-m3) receptors, and in guinea pig bladder and submandibular gland. In [N-methyl-3 H]scopolamine methyl chloride binding studies in CHO cells, darifenacin displayed selectivity (14.8-fold) for the M 3 versus M 2 mACh receptor subtype. Oxybutynin was nonselective, whereas atropine and tolterodine were weakly M 2 -selective (5.1-and 6.6-fold, respectively). Antagonist functional affinity estimates were determined by the inhibition of agonist-induced [ 3 H]inositol phosphate accumulation in CHO-m3 cells and antagonism of the agonist-induced inhibition of forskolin-stimulated cyclic AMP accumulation in CHO-m2 cells. Darifenacin was the most M 3 -selective antagonist (32.4-fold), whereas oxybutynin, atropine, and tolterodine exhibited lesser selectivity. Functional affinity estimates in guinea pig urinary bladder and submandibular salivary gland using indices of phosphoinositide turnover revealed that oxybutynin, darifenacin, and tolterodine each displayed selectivity for the response in the bladder, relative to that seen in the submandibular gland (9.3-, 7.9-, and 7.4-fold, respectively). In contrast, atropine displayed a similar affinity in both tissues. These data demonstrate that in bladder, compared with submandibular gland from a single species, the mACh receptor antagonists darifenacin, tolterodine, and oxybutynin display selectivity to inhibit agonist-mediated phosphoinositide responses. It is proposed that both responses are mediated via M 3 mACh receptor activation and that differential functional affinities displayed by some, but not all, antagonists are indicative of the influence of cell background upon the pharmacology of the M 3 mACh receptor.The cholinergic nervous system is the major pathway by which bladder contraction is initiated in humans (Andersson, 1993). Molecular techniques have identified five muscarinic acetylcholine (mACh) receptor subtypes (m1-m5), whereas pharmacological data can distinguish only four subtypes, denoted as M 1 to M 4 (Caulfield and Birdsall, 1998). Both M 2 and M 3 mACh receptors have been identified in bladder (detrusor) smooth muscle at the level of mRNA (Yamaguchi et al., 1996) and protein, with quantitative immunoprecipitation demonstrating a 75 to 90% predominance of the M 2 subtype in all species studied (Wang et al., 1995). Roles for the majority M 2 receptor population in the contraction of various smooth muscle types (including bladder detrusor) have been proposed, based upon observations in tissues treated with N-2-chloroethyl-4-piperidinyl diphenylacetate selectively to inactivate the M 3 receptor population. Under these conditions M 2 receptor activation may potentiate M 3 -stimulated contraction (via activation of nonselective cation currents or inhibition of Ca 2ϩ -dependent K ϩ efflux), in addition to ...

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“…In addition, the M3 specific antagonists may be at a disadvantage due to the M2 up regulation in the diseased bladder state. The feline model has demonstrated greater potency of M2/M3 antagonists on the bladder when compared with an M3 selective antagonist in the diseased bladder (2). The potential for disadvantage of the M3 selective agents in the denervated bladder over the M2 receptors has been noted by others as well (3).…”

Section: Editorial Commentmentioning

confidence: 89%

“…That the authors noted that the urethral pressure profiles were not particularly useful is not overly surprising in view that past authors have found no significant difference in resting urethral pressure profile and functioning urethral profile before and after anti-incontinence surgery (1). In addition, the potential puzzling nature of urethral pressure profiles pre and post operatively has been discussed by others (2).…”

mentioning

confidence: 94%

Female urology

Petrou

2005

Int. braz j urol.

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Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists

Cited by 81 publications

References 23 publications

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Female urology

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Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists

Cited by 81 publications

References 23 publications

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M3-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland

Female urology

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Product

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Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂

Functional Selectivity of Muscarinic Receptor Antagonists for Inhibition of M₃-Mediated Phosphoinositide Responses in Guinea Pig Urinary Bladder and Submandibular Salivary Gland