Characterization of β-Adrenoceptor Subtype in Bladder Smooth Muscle in Cynomolgus Monkey

Abstract

ABSTRACT-We first investigated the relaxations of the urinary bladder induced by b-adrenoceptor agonists in anesthetized cynomolgus monkeys and then employed a variety of b-adrenoceptor agonists and antagonists in vitro to identify the b -adrenoceptor subtype responsible for the relaxation (using isolated monkey detrusors). Isoprenaline reduced bladder pressure in a dose-dependent manner. Isoprenaline, noradrenaline and adrenaline each produced a concentration-dependent relaxation of isolated detrusor strips, the rank order of relaxing potencies being isoprenaline > noradrenaline > adrenaline. Subtype-selective b-adrenoceptor agonists also relaxed isolated detrusor strips, the rank order of potencies being CGP-12177 > BRL 37344 > dobutamine, salbutamol, procaterol > xamoterol. In the antagonist experiment, bupranolol (b-antagonist, 10 -6 to 10 -5 M) and SR 58894A (b3-antagonist, 10 -7 to 10 -5 M) caused a rightward shift of the concentration-relaxation curve for isoprenaline, but CGP-20712A (b1-antagonist, 10 -9 to 10 -7 M) and ICI-118551 (b 2-antagonist, 10 -9 to 10 -7 M) did not. The present functional study provides the first evidence that relaxation of the monkey detrusor by b -adrenoceptor activation is mediated via the b3-subtype.

Effects of Ritobegron (KUC-7483), a Novel Selective β3-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey

“…Moreover, CL316,243 displayed evidence of partial agonistic activity, with the maximum relaxing effect even at the highest concentration being only 73.9%. These results are consistent with previous reports that classic selective ␤ 3 -AR agonists, such as CL316,243 and BRL37344, exhibit partial agonistic activities in both the monkey and human bladder at the same concentration as the maximal concentration used in this study (1 ϫ 10 Ϫ4 M) (Igawa et al, 1999(Igawa et al, , 2001Takeda et al, 2002a). The above results suggest that in humans ritobegron might produce sufficient bladder relaxation and be more potent than classic ␤ 3 -AR agonists.…”

“…It has been reported that in primates, such as cynomolgus monkey (Takeda et al, 2002a) and humans (Igawa et al, , 1999Yamazaki et al, 1998;Takeda et al, 1999), bladder relaxation is mediated via the ␤ 3 -AR, and that in humans 97% of total ␤-AR mRNA is represented by the ␤ 3 -AR subtype (Yamaguchi, 2002;Nomiya and Yamaguchi, 2003). For the above reason, in this study we used the cynomolgus monkey to evaluate the potential usefulness of ritobegron as a drug with beneficial effects on bladder function.…”

Tools to study β3-adrenoceptors

“…Bupranolol is a clinically used β-adrenoceptor antagonist, which also has been used to demonstrate the involvement of β 3 -adrenoceptor in functional responses (Horinouchi and Koike 2001;Igawa et al 1998;Kaumann 1996;Takeda et al 2002a). However, in competition binding studies with human β-adrenoceptor subtypes, bupranolol has lower affinity for β 3 -adrenoceptors than for β 1 -and β 2 -adrenoceptors (Baker 2005;Candelore et al 1999).…”

GW427353 (Solabegron), a Novel, Selective β3-Adrenergic Receptor Agonist, Evokes Bladder Relaxation and Increases Micturition Reflex Threshold in the Dog

“…Evidence suggests that species differences exist in the distributions and roles of ␤-ARs in the bladder (for comprehensive review, see Michel and Vrydag, 2006). Bladder relaxation evoked by ␤-AR agonists is mediated mainly via ␤ 1 -ARs in cats (Nergardh et al, 1977) and guinea pigs (Li et al, 1992), by ␤ 2 -ARs in rabbits, by both ␤ 2 -and ␤ 3 -ARs in rats (Yamazaki et al, 1998) and pigs (Yamanishi et al, 2002), and by ␤ 3 -ARs in the ferrets (Takeda et al, 2000), dogs (Yamazaki et al, 1998), and primates (Takeda et al, 2002a). Based on mRNA expression, at least 95% of the adrenoceptor message in human bladder comprises the ␤ 3 -AR subtype (Nomiya and Yamaguchi, 2003).…”