Evidence that α 1B-adrenoceptors are involved in noradrenaline-induced contractions of rat tail artery

Abstract

The present study characterizes the α 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 α 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(1 H,3 H)-pyrimidinedione (B8805-033). Whereas the first phase of contraction to noradrenaline remained nearly unaffected in the presence of B8805-033 (0.03–3 μM), the second phase was concentration-dependently shifted to the right (p K B 8.06). In the presence of B8805-033 (3 μM), noradrenaline-induced contractions (pEC 50 6.55) were antagonized in a competitive manner by prazosin (p K B 9.24), tamsulosin (p K B 8.55), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101; p K B 7.81), spiperone (p K B 7.69), 4-amino-2-[4-[1-(benzyloxycarbonyl)-2( S)-[[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6,7-dimethoxyquinazoline (L-765,314; p K B 7.31), 5-methylurapidil (p K B 6.55), 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY 7378; p K B 6.43), and 8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspiro[4.5]decane-7,9-dione (MDL 73005EF; p K B 5.71), and were also antagonized by 100 μM chloroethylclonidine. N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1 H-indole-3-ethanamine (RS-17053) behaved as a noncompetitive antagonist (apparent p A 2 6.55). Antagonist affinities obtained under these experimental conditions correlated highly with affinities at native and cloned α 1B-adrenoceptors. Pretreatment of arterial rings with B8805-033 (3 μM) followed by receptor inactivation with chloroethylclonidine (100 μM) yielded monophasic E/[ A] curves to noradrenaline (pEC 50 6.14). Noradrenaline-induced contractions were competitively antagonized by tamsulosin (p K B 10.32), 5-methylurapidil (p K B 8.66), RS-17053 (p K B 8.44), B8805-033 (p K B 7.87), BMY 7378 (p K B 6.54), and L-765,314 (p K B 6.41). Antagonist affinities obtained under these experimental conditions correlated highly with affinities at native and cloned α 1A-adrenoceptors. It is concluded that the contraction to noradrenaline in rat tail artery is mediated by both α 1B- and α 1A-adrenoceptors, each component of contraction being separable by use of selective α 1A-adrenoceptor blockade and α 1B-adrenoceptor alkylation, respectively.