Contribution of beta-adrenoceptor subtypes to relaxation of colon and oesophagus and pacemaker activity of ureter in wild-type and beta(3)-adrenoceptor knockout mice

1 The smooth muscle relaxant responses to the mixed beta(3)-, putative beta (4)-adrenoceptor agonist, (-)-CGP 12177 in rat colon are partially resistan t to blockade by the beta(3)-adrenoceptor antagonist SR59230A suggesting in volvement of beta(3)- and putative beta(4)-adrenoceptors. We now investigat ed the function of the putative beta(4)-adrenoceptor and other beta-adrenoc eptor subtypes in the colon, oesophagus and ureter of wild-type (WT) and be ta(3)-adrenoceptor knockout (beta(3)KO) mice. 2 (-)-Noradrenaline and (-)-adrenaline relaxed KCl (30 mM)-precontracted co lon mostly through beta(1)-and beta(3)-adrenoceptors to a similar extent an d 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 me diated entirely through beta(1)-adrenoceptors. (-)-CGP 12177 relaxed colon from beta(3)KO mice with 2 fold greater potency than in WT mice. The mainte nance of potency for (-)-noradrenaline and increase for (-)-CGP 12177 indic ate compensatory increases in beta(1)- and putative beta(4)-adrenoceptor fu nction in beta(3)KO mice. 3 In oesophagi precontracted with 1 mu M carbachol, (-)-noradrenaline cause d relaxation mainly through beta(1)-and beta(3)-adrenoceptors. (-)-CGP 1217 7 (2 mu M) 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. 4 In ureter, (-)-CGP 12177 (2 mu M) reduced pacemaker activity by 31.1+/-2. 3% in WT and 31.3+/-7.5% in beta(3)KO, consistent with mediation through pu tative beta(4)-adrenoceptors. 5 Relaxation of mouse colon and oesophagus by catecholamines are mediated t hrough beta(1)- and beta(3)- adrenoceptors in WT. The putative beta(4)-adre noceptor, which presumably is an atypical state of the beta(1)-adrenoceptor , mediates the effects of(-)-CGP 12177 in colon, oesophagus and ureter.