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 beta-adrenoceptors (ARs); however, the beta-AR subtypes involved are unknown. beta(2)-ARs have been associated with caveolae, plasmalemmal scaffolding domains that are absent in caveolin-1 (cav-1) knockout (KO) mice. Here, we studied detrusor responses in the absence and presence of beta-AR subtype-selective antagonists in wild-type (WT) and cav-1 KO mice. To inquire whether the murine detrusor model is relevant to man, beta-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 beta 2-AR-selective antagonist ICI 118,551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl) oxy]3-[(1-methylethyl) amino]-2-butanol] (pK(B) = 9.28) but not affected by the beta(1)-AR-selective antagonist CGP 20712 [1-[2((3- carbamoyl-4-hydroxy) phenoxy) ethylamino]- 3-[4-(1methyl-4- trifluoromethyl-2-imidazolyl) phenoxy]- 2-propanol] and beta(3)-AR-selective L-748,337[(S)-M-[4-[2-[3-[3-[acetamidomethyl) phenoxy)-2-hydroxypropyl]-amino]-ethyl]-phenylbenzsulfonamide)], suggesting involvement of beta(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 (-log(EC)50M, 7.76; E-max = 44%), but ICI 118,551 caused similar antagonism (pK(B) = 9.15), suggesting that beta(2)-AR function persisted in cav-1 KO. The beta(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 beta(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 (pK(B) = 7.65). We conclude that murine detrusor relaxation occurs via beta(2)-AR, and loss of caveolae does not perturb beta(2)-AR function but unmasks an additional activation of beta(3)-AR. In contrast, detrusor relaxation in man is mediated exclusively via beta(3)-AR.