title: Characterization of the alpha 1-adrenoceptor subtype mediating contraction of guinea-pig spleen.
abstract: A series of alpha 1-adrenoceptor agonists evoked concentration-dependent contraction of isolated guinea-pig spleen strips ((-)-adrenaline > (-)-noradrenaline >> L-phenylephrine > (-)-(4aR, 10aR)-3, 4,4a,5,10,10a-hexahydro-6-methoxy-4-methyl-9-methylthio-2H-naphth [2,3-b]-1,4-oxazine (SDZ NVI 085) > cirazoline), whereas indanidine, methoxamine, oxymetazoline and UK-14.304 were ineffective. (-)-Noradrenaline-induced contractions were inhibited by chloroethylclonidine (3 x 10(-6)-6 x 10(-5) M) and partially attenuated by SZL-49 (10(-7)-10(-6) M), but remained resistant to (+/-)-isradipine (10(-9)-10(-7) M). The contractions of the splenic strips were competitively antagonized by low concentrations of the alpha 1B-adrenoceptor-selective antagonist, spiperone (pA2 8.05), but by relatively high concentrations of the alpha 1A-adrenoceptor-selective antagonists, (+)-niguldipine (pA2 6.32) and 5-methyl-urapidil (pA2 6.95). The affinities of subtype-selective antagonists determined at guinea-pig spleen alpha-adrenoceptors significantly correlated with pKi values at rat liver alpha 1B binding sites (r = 0.96) and pA2 values at putative alpha 1B-adrenoceptors in rat aorta (r = 0.95), but differed from pKi values at rat cortical alpha 1A binding sites and pA2 values at alpha 1A-adrenoceptors in rat vas deferens. Also no correlation was obtained between antagonist affinities at guinea-pig spleen alpha-adrenoceptors and alpha 1C binding sites in rabbit liver. Thus, from the (1) potencies of agonists, (2) affinities of subtype-selective antagonists and (3) differential sensitivity of the contractions to alpha 1-adrenoceptor inactivating agents and their resistance to Ca2+ channel blockade, the alpha 1-adrenoceptor mediating smooth muscle contraction of guinea-pig spleen can be best characterized as being of the B subtype.
authors.affiliation: Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Eltze
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D016014:Linear Models; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000145:classification / Q000187:drug effects*; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011942:Receptors, Adrenergic, alpha