CHARACTERIZATION OF THE ALPHA(1)-ADRENOCEPTOR SUBTYPE MEDIATING CONTRACTION OF GUINEA-PIG SPLEEN

A series of alpha(1)-adrenoceptor agonists evoked concentration-dependent contraction of isolated guinea-pig spleen strips ((-)-adrenaline > (-)-noradrenaline much greater than L-phenylephrine > (-)-(4aR,10aR)-3,4,4a,5,10,10a-hexahydro-6-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 ant agonized by low concentrations of the alpha(1B)-adrenoceptor-selective antagonist, spiperone (pA(2) 8.05), but by relatively high concentrations of the alpha(1A)-adrenoceptor-selective antagonists, (+)-niguldipine (pA(2) 6.32) and 5-methyl-urapidil (pA(2) 6.95). The affinities of subtype-selective antagonists determined at guinea-pig spleen alpha-adrenoceptors significantly correlated with pK(i) values at rat liver alpha(1B) binding sites (r = 0.96) and pA(2) values at putative alpha(1B)-adrenoceptors in rat aorta (r = 0.95), but differed from pK(i) values at rat cortical alpha(1A) binding sites and pA(2) 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.