Catecholamines Relax Detrusor through β2-Adrenoceptors in Mouse and β3-Adrenoceptors in Man

(-)-Isoproterenol [4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]-1,2-benzene diol hydrochloride] relaxes murine detrusor through β-adrenoceptors (ARs); however, the β-AR subtypes involved are unknown. β 2 -ARs have been associated with caveolae, plasma-lemmal scaffolding domains that are absent in caveolin-1 (cav-1) knockout (KO) mice. Here, we studied detrusor responses in the absence and presence of β-AR subtype-selective antagonists in wild-type (WT) and cav-1 KO mice. To inquire whether the murine detrusor model is relevant to man, β-AR subtypes that mediate (-)-isoproterenol-evoked human detrusor relaxation were investigated. In WT mice, (-)-isoproterenol concentration-dependently relaxed the KCl (40 mM)-precontracted detrusor (-logEC 50 M = 8.04, E max = 62%). The effects of (-)-isoproterenol were surmountably antagonized by the β 2 -AR-selective antagonist ICI 118,551 [(±)-1-[2,3-(dihydro-7-methyl-1 H -inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol] (p K B = 9.28) but not affected by the β 1 -AR-selective antagonist CGP 20712 [1-[2-((3-carbamoyl-4-hydroxy)phenoxy)ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol] and β 3 -AR-selective L-748,337 [( S )- M -[4-[2-[3-[3-[acetamidomethyl)phenoxy)-2-hydroxypropyl]-amino]-ethyl]-phenylbenzsulfonamide)], suggesting involvement of β 2 -AR only. The cav-1 KO detrusor displayed significant contractile dysfunction. (-)-Isoproterenol was less potent and efficient in relaxing detrusor from cav-1 KO (-logEC 50 M, 7.76; E max = 44%), but ICI 118,551 caused similar antagonism (p K B = 9.15), suggesting that β 2 -AR function persisted in cav-1 KO. The β 3 -AR-selective antagonist L-748,337 in the presence of ICI 118,551 and CGP 20712 caused additional blockade of (-)-isoproterenol effects in cav-1 KO, consistent with a β 3 -AR involvement during relaxation and suppression of this effect in WT. (-)-Isoproterenol relaxed human detrusor muscle precontracted with carbachol (-logEC 50 M = 6.39, E max = 52%). However, the effects of (-)-isoproterenol in human detrusor were not blocked by CGP 20712 or ICI 118,551 but antagonized by L-748,337 (p K B = 7.65). We conclude that murine detrusor relaxation occurs via β 2 -AR, and loss of caveolae does not perturb β 2 -AR function but unmasks an additional activation of β 3 -AR. In contrast, detrusor relaxation in man is mediated exclusively via β 3 -AR.