Catecholamines relax detrusor through beta 2-adrenoceptors in mouse and beta 3-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, 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 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-(1-methyl-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 (-logEC(50)M, 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.
Wuest
Melinda
M
Department of Pharmacology and Toxicology, Dresden University of Technology, Fetscher-strasse 74, 01307 Dresden, Germany. melinda.wuest@tu-dresden.de
Eichhorn
Birgit
B
Grimm
Marc O
MO
Wirth
Manfred P
MP
Ravens
Ursula
U
Kaumann
Alberto J
AJ
D000368:Aged; D000818:Animals; D002395:Catecholamines / Q000502:physiology*; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017931:DNA Primers; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009092:Mucous Membrane / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology*; D001743:Urinary Bladder / Q000502:physiology*
D002395:Catecholamines; D051242:Caveolin 1; D017931:DNA Primers; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D007545:Isoproterenol; D004837:Epinephrine