Contribution of beta-adrenoceptor subtypes to relaxation of colon and oesophagus and pacemaker activity of ureter in wildtype and beta(3)-adrenoceptor knockout mice.
The smooth muscle relaxant responses to the mixed beta(3)-, putative beta(4)-adrenoceptor agonist, (-)-CGP 12177 in rat colon are partially resistant to blockade by the beta(3)-adrenoceptor antagonist SR59230A suggesting involvement of beta(3)- and putative beta(4)-adrenoceptors. We now investigated the function of the putative beta(4)-adrenoceptor and other beta-adrenoceptor subtypes in the colon, oesophagus and ureter of wildtype (WT) and beta(3)-adrenoceptor knockout (beta(3)KO) mice. (-)-Noradrenaline and (-)-adrenaline relaxed KCl (30 mM)-precontracted colon mostly through beta(1)-and beta(3)-adrenoceptors to a similar extent and to a minor extent through beta(2)-adrenoceptors. In colon from beta(3)KO mice, (-)-noradrenaline was as potent as in WT mice but the effects were mediated entirely through beta(1)-adrenoceptors. (-)-CGP 12177 relaxed colon from beta(3)KO mice with 2 fold greater potency than in WT mice. The maintenance of potency for (-)-noradrenaline and increase for (-)-CGP 12177 indicate compensatory increases in beta(1)- and putative beta(4)-adrenoceptor function in beta(3)KO mice. In oesophagi precontracted with 1 microM carbachol, (-)-noradrenaline caused relaxation mainly through beta(1)-and beta(3)-adrenoceptors. (-)-CGP 12177 (2 microM) relaxed oesophagi from WT by 61.4+/-5.1% and beta(3)KO by 67.3+/-10.1% of the (-)-isoprenaline-evoked relaxation, consistent with mediation through putative beta(4)-adrenoceptors. In ureter, (-)-CGP 12177 (2 microM) reduced pacemaker activity by 31.1+/-2.3% in WT and 31.3+/-7. 5% in beta(3)KO, consistent with mediation through putative beta(4)-adrenoceptors. Relaxation of mouse colon and oesophagus by catecholamines are mediated through beta(1)- and beta(3)-adrenoceptors in WT. The putative beta(4)-adrenoceptor, which presumably is an atypical state of the beta(1)-adrenoceptor, mediates the effects of (-)-CGP 12177 in colon, oesophagus and ureter.
Oostendorp
J
J
The Babraham Institute, Cambridge CB2 4AT. Département de Biochimie Médicale, Centre Médical Universitaire, CH-1211 Genève 4, Switzerland.
Preitner
F
F
Moffatt
J
J
Jimenez
M
M
Giacobino
J P
JP
Molenaar
P
P
Kaumann
A J
AJ
D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000502:physiology*; D004149:Dioxoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D004947:Esophagus / Q000502:physiology*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009126:Muscle Relaxation / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3; D014513:Ureter / Q000502:physiology*
C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004149:Dioxoles; D007093:Imidazoles; D011412:Propanolamines; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; C026777:ICI 118551; C049763:CGP 20712A; C033394:CGP 12177; D009638:Norepinephrine; D004837:Epinephrine