title: Evidence that alpha(1B)-adrenoceptors are involved in noradrenaline-induced contractions of rat tail artery.
abstract: The present study characterizes the alpha(1)-adrenoceptor subtypes mediating contractions to noradrenaline in isolated ring preparations of rat tail artery. Concentration-response (E/[A]) curves to noradrenaline were apparently monophasic (pEC(50) 6.47) but became biphasic in the presence of the selective alpha(1A)-adrenoceptor antagonist (+/-)-1,3,5-trimethyl-6-[[3-[4-((2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl]amino]-2,4(1H,3H)-pyrimidinedione (B8805-033). Whereas the first phase of contraction to noradrenaline remained nearly unaffected in the presence of B8805-033 (0.03-3 microM), the second phase was concentration-dependently shifted to the right (pK(B) 8.06). In the presence of B8805-033 (3 microM), noradrenaline-induced contractions (pEC(50) 6.55) were antagonized in a competitive manner by prazosin (pK(B) 9.24), tamsulosin (pK(B) 8.55), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101; pK(B) 7.81), spiperone (pK(B) 7.69), 4-amino-2-[4-[1-(benzyloxycarbonyl)-2(S)-[[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6,7-dimethoxyquinazoline (L-765,314; pK(B) 7.31), 5-methylurapidil (pK(B) 6.55), 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY 7378; pK(B) 6.43), and 8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspiro[4.5]decane-7,9-dione (MDL 73005EF; pK(B) 5.71), and were also antagonized by 100 microM chloroethylclonidine. N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha,alpha-dimethyl-1H-indole-3-ethanamine (RS-17053) behaved as a noncompetitive antagonist (apparent pA(2) 6.55). Antagonist affinities obtained under these experimental conditions correlated highly with affinities at native and cloned alpha(1B)-adrenoceptors. Pretreatment of arterial rings with B8805-033 (3 microM) followed by receptor inactivation with chloroethylclonidine (100 microM) yielded monophasic E/[A] curves to noradrenaline (pEC(50) 6.14). Noradrenaline-induced contractions were competitively antagonized by tamsulosin (pK(B) 10.32), 5-methylurapidil (pK(B) 8.66), RS-17053 (pK(B) 8.44), B8805-033 (pK(B) 7.87), BMY 7378 (pK(B) 6.54), and L-765,314 (pK(B) 6.41). Antagonist affinities obtained under these experimental conditions correlated highly with affinities at native and cloned alpha(1A)-adrenoceptors. It is concluded that the contraction to noradrenaline in rat tail artery is mediated by both alpha(1B)- and alpha(1A)-adrenoceptors, each component of contraction being separable by use of selective alpha(1A)-adrenoceptor blockade and alpha(1B)-adrenoceptor alkylation, respectively.
authors.affiliation: Institute of Pharmacy, Free University of Berlin, Königin-Luise-Str. 2+4, Berlin 14195, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Jähnichen
authors.forename: Manfrid
authors.initials: M
authors.lastname: Eltze
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Pertz
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D001158:Arteries / Q000187:drug effects*; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004147:Dioxins / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D013623:Tail / Q000098:blood supply
chemical_list: C438684:1,3,5-trimethyl-6-((3-(4-((2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl)propyl)amino)-2,4(1H,3H)-pirymidinedione; C547718:Adra1b protein, rat; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004147:Dioxins; C111640:L 765314; D010879:Piperazines; D011744:Pyrimidinones; D018340:Receptors, Adrenergic, alpha-1; C057446:5-methylurapidil; C051731:chlorethylclonidine; C053428:BMY 7378; D003000:Clonidine; D009638:Norepinephrine; D011224:Prazosin