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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Departments of Pharmacology and Toxicology (M.W., B.E., U.R.) and Urology (M.O.G., M.P.W.), Dresden University of Technology, Dresden, Germany; and Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom (A.J.K.)

(-)-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. β₂-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 (-logEC₅₀M = 8.04, E_max = 62%). The effects of (-)-isoproterenol were surmountably antagonized by the β₂-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 β₁-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 β₃-AR-selective L-748,337 [(S)-M-[4-[2-[3-[3-[acetamidomethyl)phenoxy)-2-hydroxypropyl]-amino]-ethyl]-phenylbenzsulfonamide)], suggesting involvement of β₂-AR only. The cav-1 KO detrusor displayed significant contractile dysfunction. (-)-Isoproterenol was less potent and efficient in relaxing detrusor from cav-1 KO (-logEC₅₀M, 7.76; E_max = 44%), but ICI 118,551 caused similar antagonism (pK_B = 9.15), suggesting that β₂-AR function persisted in cav-1 KO. The β₃-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 β₃-AR involvement during relaxation and suppression of this effect in WT. (-)-Isoproterenol relaxed human detrusor muscle precontracted with carbachol (-logEC₅₀M = 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 β₂-AR, and loss of caveolae does not perturb β₂-AR function but unmasks an additional activation of β₃-AR. In contrast, detrusor relaxation in man is mediated exclusively via β₃-AR.

Address correspondence to: Melinda Wuest, Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology, Fetscher-strasse 74, 01307 Dresden, Germany. E-mail: melinda.wuest{at}tu-dresden.de