Comparative analysis of the effects of antimuscarinic agents on bladder functions in both nonhuman primates and rodents

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 338; no. 1; pp. 220 - 227
• Main Authors: Nagabukuro, Hiroshi, Villa, Katherine L, Wickham, L Alexandra, Kulick, Alison A, Gichuru, Loise, Donnelly, Marcie J, Voronin, Gregory O, Pereira, Tony, Tong, Xinchun, Nichols, Andrew, Alves, Stephen E, O'Neill, Gary P, Johnson, Christopher V, Hickey, Emily J
• Format: Journal Article
• Language: English
• Published: United States 01.07.2011
• Subjects: Animals; Benzhydryl Compounds - pharmacology; Cresols - pharmacology; Female; Macaca mulatta; Mandelic Acids - pharmacology; Muscarinic Antagonists - pharmacology; Phenylpropanolamine - pharmacology; Rats; Rats, Sprague-Dawley; Species Specificity; Tolterodine Tartrate; Urinary Bladder - drug effects; Urinary Bladder - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.111.179747

Both the physiological role of muscarinic receptors for bladder function and the therapeutic efficacy of antimuscarinic agents for overactive bladder syndrome are well documented. We investigated the effect of antimuscarinic agents with different subtype selectivity on urodynamic parameters in nonhuman primates and rodents and compared plasma levels of these agents between species. Anesthetized rhesus monkeys were transurethrally catheterized, and the bladder was infused with saline. Urodynamic parameters were measured before and after intravenous drug administration. Tolterodine (nonselective) and oxybutynin (moderately M(3)-selective) increased bladder capacity at lower doses than those required to decrease micturition pressure. However, higher doses of darifenacin (M(3)-selective) were needed to increase the bladder capacity than those needed to decrease the micturition pressure. In rats, tolterodine had no effect on the bladder capacity but decreased the micturition pressure at all of the doses administered. Oxybutynin also decreased micturition pressure and increased bladder capacity at the highest dose. Plasma levels of these drugs overlap in both species. These results suggest that, in addition to the M(3) receptor, other muscarinic receptor subtypes contribute to regulate bladder storage function in nonhuman primates, since less subtype-selective tolterodine and oxybutynin showed higher specificity to the bladder capacity effect than the effect on micturition pressure compared with M(3)-selective darifenacin. In addition, the role of muscarinic receptors in bladder storage function varies between primates and rodents. Compared with rodents, muscarinic receptors may play a more active role during the storage phase to regulate the functional bladder capacity in primates.