Ej. Lezama et al., PHARMACOLOGICAL STUDY OF ATYPICAL BETA-ADRENOCEPTORS IN RAT ESOPHAGEAL SMOOTH-MUSCLE, European journal of pharmacology, 308(1), 1996, pp. 69-80
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.