RESUMO
1 Several imidazolines were examined for the antagonism of muscarinic (M3) and other receptors on the isolated ileum of guinea-pig. The effect of the muscarinic agonist, carbachol was competitively antagonized by oxymetazoline at 10(-5) m. A dissociation constant (KB) of 3.6 microm for the antagonist was calculated. At higher concentrations, 3 x 10(-5) and 10(-4) m, of the antagonist, the agonist dose-response curve was shifted to the right with a decrease in the maximum effect. Thus, a non-competitive block occurred at higher concentrations of oxymetazoline. Blockade of histamine H, and serotonin receptor-mediated responses by oxymetazoline were also of a non-competitive type. 2 Naphazoline at 10(-4) m shifted the dose-response curves of carbachol and serotonin to the right by two- and 15-fold, respectively. The maximum contraction of the agonist was not affected. Tolazoline also had a weak antihistaminic activity. At similar concentration; tetrahydrozoline clonidine and phentolamine at 10(-5) m produced two-, three- and four-fold shift of the carbachol dose-response curve without significant changes in the maxima. Neither methoxamine, p-amino-clonidine nor cimetidine blocked the responses of carbachol. 3 The isosteric nature of the alpha-adrenoceptor agonist, oxymetazoline and some imidazolines with carbachol, in part, explains its molecular competition at the muscarinic M3 receptor of the guinea-pig ileum. Surprisingly, contractile effects of carbachol (M3), histamine (H1) or serotonin (5HT3/5HT4) were not influenced by methoxamine, tetrahydrozoline, p-amino clonidine and cimetidine.
Assuntos
Íleo/efeitos dos fármacos , Imidazolinas/farmacologia , Antagonistas Muscarínicos/farmacologia , Animais , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Relação Dose-Resposta a Droga , Cobaias , Histamina/farmacologia , Íleo/metabolismo , Imidazolinas/química , Técnicas In Vitro , Masculino , Metoxamina/farmacologia , Antagonistas Muscarínicos/química , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Oximetazolina/farmacologia , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Serotonina/farmacologiaRESUMO
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 89,406, ICI 118551 [erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamine)-but an-2-ol] and the beta-adrenoceptor alkylating agent, pindobind, produced only small rightward shifts in the concentration-response curves of (-)-isoprenaline and (-)-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)ethylamino]propyl] phenoxyacetic acid] (8.16) = ICID7114 [(S)-4-(2-hydroxy- 3-phenoxy-propylamino-ethoxy)-N-(2-methoxyethyl) phenoxyacetamide] (8.03) > or = (-)-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'-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline] (6.82) > 8-fluorotrimetoquinol [6,7-dihydroxy-8-fluoro-1-(3',4',5'- trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline] (6.56) > or = (-)-noradrenaline (6.46) > or = (-)-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 microM 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 beta/beta 3-adrenoceptor partial agonist, ICI D7114, produced concentration-dependent rightward shifts of the concentration-response curves of (-)-isoprenaline, (-)-trimetoquinol and the reference atypical beta/beta 3-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 beta/beta 3-adrenoceptors. (-)-Trimetoquinol was as potent as (-)- isoprenaline and BRL 37344, and was the most stereoselective agonist evaluated in this tissue system.
Assuntos
Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Receptores Adrenérgicos beta/fisiologia , Antagonistas de Receptores Adrenérgicos beta 1 , Antagonistas de Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/farmacologia , Animais , Carbacol/farmacologia , Clembuterol/farmacologia , Monoterpenos Cicloexânicos , Esôfago/efeitos dos fármacos , Etanolaminas/farmacologia , Feminino , Átrios do Coração/efeitos dos fármacos , Técnicas In Vitro , Isoproterenol/farmacologia , Masculino , Músculo Liso/efeitos dos fármacos , Fenetilaminas/farmacologia , Fenoxiacetatos/farmacologia , Fenoxipropanolaminas , Pindolol/análogos & derivados , Pindolol/farmacologia , Propanolaminas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Traqueia/efeitos dos fármacos , Tretoquinol/análogos & derivados , Tretoquinol/farmacologiaRESUMO
Two experiments were performed to examine the effects of various carbohydrates (fructose, lactose, corn starch, wheat starch and potato starch) on the utilization of iron, on Fe-depleted rats. These received a single meal that contained the test carbohydrate at a 60% level, labelled with 59Fe. The rest of the experiment the rats were fed a diet which contained glucose at a 60% level as the carbohydrate source. In both experiments rats were fasted overnight, and the dose was offered in the form of a morning meal. To assay for 59Fe, the animals were counted in a "Whole body counter" between two and four hours after dosing, and every day for the following 10 days. Percentage retention and absorption, as well as hemoglobin values were determined. In the first experiment, the replacement of glucose by fructose at a 60% level enhanced significantly iron absorption and retention. An increase in absorption and retention also occurred when glucose was replaced by lactose at a 60% level, but the difference was not statistically significant. Administration of 59Fe as an 59Fe-fructose chelate did not seem to have a significant effect on retention and absorption when compared to the effect of dosing with 59Fe adsorbed onto a fructose diet. This not rule out the possibility that chelation is the mechanism responsible for the enhancing effect of fructose on iron utilization. The complex could have been formed in the stomach, resulting in a significant absorption for both the 59Fe-labelled meal and the 59Fe-carbohydrate complex-labelled meal. In the second experiment, administration of a meal that contained either of the starches resulted in a reduction on retention and absorption of 59Fe. The decrease, however, was statistically significant only for cooked corn starch, wheat starch and cooked wheat starch. The effect of cooking was to reduce even more the retention and absorption of 59Fe, but this reduction was statistically significant only for corn starch. The depressing effects of starches on iron retention and absorption are quite relevant to human nutrition. In the developing countries, diets are generally high in cereal products - often whole grain cereals - and low in animal products. The inhibitory effects of cereals on iron absorption have been traditionally attributed to the presence of phytates and fiber, but the data herein presented suggest that high intakes of starches may be inhibitory as well.