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The Use of Cystometry in Small Rodents: A Study of Bladder Chemosensation
Published on: August 21, 2012
Demonstration of bladder selective muscarinic receptor binding by intravesical oxybutynin to treat overactive bladder
Tomomi Oki1, Ryohei Kimura, Motoaki Saito
1Department of Biopharmaceutical Sciences and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Purpose:
The current study was done to elucidate the in vivo mechanism of action of intravesical instillation of oxybutynin to treat overactive bladder.
Materials And Methods:
In rats receiving oral and intravesical oxybutynin we measured muscarinic receptors in the bladder and other tissues by radioligand binding assay using [3H]NMS ([N-methyl-3H] scopolamine methyl chloride) with the simultaneous measurement of plasma concentrations of oxybutynin and its active metabolite N-desethyl-oxybutynin. Pilocarpine induced salivary secretion was also measured.
Results:
Following oral administration of oxybutynin there was a significant increase in the apparent dissociation constant (Kd) for specific [3H]NMS binding in the bladder, submaxillary gland, heart and colon of rats at 1 and 3 hours with a consistent decrease in the maximal number of binding sites (Bmax) in the submaxillary gland. Furthermore, a marked and prolonged decrease in pilocarpine induced salivary secretion in rats was observed by oral oxybutynin. In contrast, intravesical instillation of oxybutynin produced a significant increase in Kd for specific [3H]NMS binding in the bladder of rats at 0.5 to 4 hours later and also in the submaxillary gland only at 0.5 hours later. The enhancement in Kd was much larger and longer lasting in the bladder than in the submaxillary gland. Moreover, intravesical oxybutynin had little muscarinic receptor binding activity in the heart and colon, and little significant suppression of pilocarpine induced salivation in rats. The plasma concentrations of oxybutynin and N-desethyl-oxybutynin were much higher in rats receiving oxybutynin orally than intravesically.
Conclusions:
Intravesical oxybutynin in rats may cause selective binding of bladder muscarinic receptors via a direct local effect, while oral oxybutynin may exert predominant binding of salivary gland receptors.
Insights
Intravesical oxybutynin selectively targets bladder muscarinic receptors for overactive bladder treatment. Oral oxybutynin, however, primarily affects salivary gland receptors, leading to reduced salivation.
Area of Science:
- Pharmacology
- Urology
Background:
- Overactive bladder (OAB) is a condition characterized by urinary urgency, frequency, and incontinence.
- Oxybutynin is a commonly prescribed anticholinergic medication for OAB, but its systemic side effects can limit its use.
Purpose of the Study:
- To elucidate the in vivo mechanism of action of intravesical oxybutynin for OAB treatment.
- To compare the receptor binding profiles and systemic effects of oral versus intravesical oxybutynin administration.
Main Methods:
- Rats were administered oxybutynin orally and intravesically.
- Muscarinic receptors in various tissues were measured using radioligand binding assays ([3H]NMS).
- Plasma concentrations of oxybutynin and its metabolite were measured, alongside pilocarpine-induced salivary secretion.
Main Results:
- Oral oxybutynin increased the dissociation constant (Kd) for muscarinic receptors in the bladder, submaxillary gland, heart, and colon, and decreased receptor binding sites in the submaxillary gland.
- Intravesical oxybutynin significantly increased Kd for bladder muscarinic receptors for a prolonged period, with a shorter effect on salivary gland receptors.
- Intravesical oxybutynin showed minimal binding in the heart and colon and did not significantly suppress salivation, unlike oral administration.
Conclusions:
- Intravesical oxybutynin may offer a more targeted approach by selectively binding to bladder muscarinic receptors.
- Oral oxybutynin appears to exert its effects through broader receptor binding, including salivary glands, leading to systemic side effects.
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