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Pharmacological study of atypical β-adrenoceptors in rat esophageal smooth muscle

1996; Elsevier BV; Volume: 308; Issue: 1 Linguagem: Inglês

10.1016/0014-2999(96)00236-1

1879-0712

E Lezama, Anish Konkar, M. Margarita Salazar-Bookaman, Duane D. Miller, Dennis R. Feller,

Antibiotics Pharmacokinetics and Efficacy

The chemical specificity for the β-adrenoceptor mediated relaxation of rat esophageal smooth muscle was evaluated using selective and non-selective β-adrenoceptor agonists and antagonists. Pindolol, ICI 89,406, ICI 118551 [erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamine)-butan-2-ol] and the β-adrenoceptor alkylating agent, pindobind, produced only small rightward shifts in the concentration-response curves of (−)-trimetoquinol in this preparation. Rank order potency (pD2 values) of agonists was: (±)-trimetoquinol [1-(3′,4′,5′-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (8.34) = (−)-trimetoquinol (8.26) = BRL 37344 [(R∗R∗)-(±)-4-[2′-{{2-hydroxy-2-(3-chlorophenyl)ethylaminoc̊ub;}propyl]phenoxyacetic acid] (8.16) = ICI D7114 [(S)-4-(2-hydroxy-3-phenoxy-propylamino-ethoxy)-N-(2-methoxyethyl)phenoxyacetamide] (8.03) ≥ (−)-isoprenaline (7.82) > 3′,5′-diiodotrimetoquinol [1-(3′,5′-diiodo-4′-methoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (7.28) > 3′-iodotrimetoquinol [1–3′-iodo-4′,5′-dimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (7.04) > ractopamine (6.84) = 5,8-difluorotrimetoquinol [5,8-difluoro-6,7-dihydroxy-1-(3′,4′,5′-trimethoxybenzy)-1,2,3,4-tetrahydroisquinoline] (6.82) > 8-fluorotrimetoquinol [6,7-dihydroxy-8-fluoro-1-(3′,4′,5′-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline] (6.56) ≥ (−)-noradrenaline (6.46) ≥ (−)-adrenaline (6.36) > (±)-noradrenaline (6.24) > (±)-adrenaline (6.00) > clenbuterol (5.83) > (−)-1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (5.75). Isomeric activity ratios of trimetoquinol isomers [(−)-(S)- ⪢ (+)-)R)-] in esophageal smooth muscle in the presence and absence of 1 μM pindolol were 1995- and 2951-fold, respectively; and were much greater than those in rat atria (282-fold) and rat trachea (107-fold). The atypical β/β3-adrenoceptor partial agonist, ICI D7114, produced concentration-dependent rightward shifts of the concentration-response curves of (−)-isoprenaline, (−)-trimetoquinol and the reference atypical β/β3-adrenoceptor agonist, BRL 37344. Schild plot analysis of ICI D7114 against trimetoquinol gave slope and pA2 values of 0.91 and of 7.9, respectively. These results clearly demonstrate that the relaxant effects of these agonists in rat esophageal smooth muscle are primarily mediated through the activation of atypical β/β3-adrenoceptors. (−)-Trimetoquinol was as potent as (−)-isoprenaline and BRL 37344, and was the most stereoselective agonist evaluated in this tissue system.