title: Noradrenaline-induced inositol phosphate formation in rat striatum is mediated by alpha 1A-adrenoceptors.
abstract: The aim of this study was to assess the contribution of alpha 1-adrenoceptor subtypes to noradrenaline (NA)-induced inositol phosphate formation in rat striatum. In cross-chopped slices and in the presence of 10 mM LiCl, NA stimulated the accumulation of [3H]inositol phosphates. After 60-min incubation with 100 microM NA, [3H]IP1 was the major product detected (82 +/- 3% of total [3H]inositol phosphates). Best-fit values for the concentration-response curve for NA-induced [3H]IP1 accumulation yielded an EC50 of 9.4 +/- 1.1 microM, maximum effect of 210 +/- 3% of basal, and Hill coefficient (nH) of 1.1 +/- 0.1. Pre-treatment of the slices for 30 min with the alkylating agent chloroethylclonidine (100 microM) failed to decrease significantly the response to 100 microM NA. Inhibition curves for four alpha 1-antagonists, (+)-niguldipine, prazosin, WB-4101 and 5-methylurapidil (5-MU), best-fit to a single-site model with pKi values of 9.4 ((+)-niguldipine), 9.2 (prazosin and WB-4101) and 8.8 (5-MU). The putative alpha 1 D-selective antagonist BMY 7378 reduced the response to NA only partially (30 +/- 3% inhibition at 1 microM: pKi 7.24). NA-induced [3H]IP1 accumulation was significantly reduced (to 20 +/- 9% of controls) by Ca2+ removal and increased as the extracellular Ca2+ concentration was raised from nominally zero (no added Ca2+) to 1 mM Ca2+. NA-induced [3H]IP1 accumulation was reduced by both the non-selective Ca2+ channel blocker Ni2+ (58 +/- 3% inhibition at 2 mM) and nimodipine, an antagonist of L-type voltage-operated Ca2+ channels (77 +/- 4% inhibition at 3 microM). Taken together these results indicate that NA-induced inositol phosphate formation in striatal slices is mediated by activation of alpha 1A-adrenoceptors coupled to Ca2+ entry and Ca2+ activation of phospholipase C.
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, México, D.F., México.
authors.forename: J A
authors.initials: JA
authors.lastname: Arias-Montaño
authors.forename: J
authors.initials: J
authors.lastname: Aceves
authors.forename: A
authors.initials: A
authors.lastname: Nuñez
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis*; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000477:Alkylating Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D004146:Dioxanes; D007295:Inositol Phosphates; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; C051731:chlorethylclonidine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; C053428:BMY 7378; D003000:Clonidine; D002118:Calcium; D009638:Norepinephrine; C054074:niguldipine