PHARMACOLOGICAL STUDY OF ATYPICAL BETA-ADRENOCEPTORS IN RAT ESOPHAGEAL SMOOTH-MUSCLE

The chemical specificity for the beta-adrenoceptor mediated relaxation of rat esophageal smooth muscle was evaluated using selective and non -selective beta-adrenoceptor agonists and antagonists. Pindolol, ICI 8 9,406, ICI 118551 ethylindan-4-yloxy)-3-(isopropylamine)-butan-2-ol] a nd the beta-adrenoceptor alkylating agent, pindobind, produced only sm all rightward shifts in the concentration-response curves of (-)-isopr enaline and (-)-trimetoquinol in this preparation. Rank order potency (pD(2) values) of agonists was: (+/-)-trimetoquinol zyl)-6,7-dihydroxy -1,2,3,4-tetrahydroisoquinoline] (8.34) = (-)-trimetoquinol (8.26) = B RL 37344 -2-(3-chlorophenyl)ethylamino}propyl]phenoxyacetic acid] (8.1 6) = ICI D7114 ylamino-ethoxy)-N-(2-methoyethyl)phenoxyacetamide] (8.0 3) greater than or equal to (-)-isoprenaline (7.82) > 3',5'-diiodotrim etoquinol zyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (7.28) > 3'-iodotrimetoquinol zyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline ] (7.04) > ractopamine (6.84) = 5,8-difluorotrimetoquinol -trimethoxyb enzyl)-1,2,3,4-tetrahydroisoquinoline] (6.82) > 8-fluorotrimetoquinol -trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline] (6.56) greater than or equal to (-)-noradrenaline (6.46) greater than or equal to (-)-adr enaline (6.36) > (+/-)-noradrenaline (6.24) > (+/-)-adrenaline (6.00) > clenbuterol (5.83) > enzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinol ine (5.75). Isomeric activity ratios of trimetoquinol isomers [(-)-(S) - >> (+)-(R)-] in esophageal smooth muscle in the presence and absence of 1 mu M pindolol were 1995- and 2951-fold, respectively; and were m uch greater than those in rat atria (282-fold) and rat trachea (107-fo ld). The atypical beta/beta(3)-adrenoceptor partial agonist, ICI D7114 , produced concentration-dependent rightward shifts of the concentrati on-response curves of (-)-isoprenaline, (-)-trimetoquinol and the refe rence atypical beta/beta(3)-adrenoceptor agonist, BRL 37344. Schild pl ot analysis of ICI D7114 against trimetoquinol gave slope and pA(2) va lues of 0.91 and of 7.9, respectively. These results clearly demonstra te that the relaxant effects of these agonists in rat esophageal smoot h muscle are primarily mediated through the activation of atypical bet a/beta(3)-adrenoceptors. (-)-Trimetoquinol was as potent as (-)-isopre naline and BRL 37344, and was the most stereoselective agonist evaluat ed in this tissue system.