Characterization of the α1-adrenoceptor subtype mediating contraction of guinea-pig spleen

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Abstract

A series of α1-adrenoceptor agonists evoked concentration-dependent contraction of isolated guinea-pig spleen strips ((—)-adrenaline > (—)-noradrenalineL-phenylephrine > (—)-(4aR,10a)-3,4,4a,5,10a-hexahydro-6-methoxy-4-methyl-9-methylhio-2H-naphth[2,3-b]-1,4-oxazine methoxy-4-methyl-9-methylthio2H-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 × 10−6 −6 × 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 α1B-adrenoceptor-selective antagonist, spiperone (pA2 8.05), but by relatively high concentrations of the α1A-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 α-adrenoceptors significantly correlated with pKi values at rat liver α1B binding sites (r=0.96) and pA2 values at putative α1B-adrenoceptors in rat aorta (r=0.95), but differed from pKi values at rat cortical α1A binding sites and pA2 values at α1A-adrenoceptors in rat vas defens. Also no correlation was obtained between antagonist affinities at guinea-pig spleen α-adrenoceptors and α1C 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 α1-adrenoceptor inactivating agents and their resistance to Ca2+ channel blockade, the α1-adrenoceptor mediating smooth muscle contraction of guinea-pig spleen can be best characterized as being of the B subtype.

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