CHARACTERIZATION OF SUBTYPE OF ALPHA(1)-ADRENOCEPTOR MEDIATING VASOCONSTRICTION IN PERFUSED RAT HIND-LIMB

The subtype of alpha(1)-adrenoceptor mediating the exogenous noradrena line-induced vasopressor response in perfused rat hind limb was determ ined by functional measurements and radioligand binding assays. The po tencies (pA(2) values) of alpha(1A)-adrenoceptor-selective antagonists , RS-17053 chloro-alpha,alpha-dimethyl-1H-indole-3-ethanamine hydrochl oride), WB 4101 (2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4 benzodio xane), 5-methyl-urapidil, and the alpha(1D)-adrenoceptor-selective ant agonist, BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl to inhibit the noradrenaline induced vasopressor response determined by Schild pl ot were 9.47 +/- 0.21, 9.48 +/- 0.19, 8.10 +/- 0.27 and 6.66 +/- 0.14, respectively, with no slope significantly different from unity. The a ffinities (K-i values) of these antagonists were determined by displac ement of I-125-BE 2254 beta(4-hydroxyphenyl)-ethylaminomethyl)-tetralo ne) binding from the cloned alpha(1a)-, alpha(1b)-, alpha(1d)-adrenoce ptor, stably expressed in human embryonic kidney (HEK) 293 cells. The pA(2) values of the above antagonists correlated well with the binding K-i Values only for alpha(1A)-adrenoceptors (r = 0.93), but not for a lpha(1B)-adrenoceptors (r = 0.51) and alpha(1D)-adrenoceptors (r = 0.1 3). The concentration-vasopressor response curve for noradrenaline was not significantly affected by pretreatment with 50 mu M chloroethylcl onidine for 30 min. The results suggest that only alpha(1A)-adrenocept ors mediate the noradrenaline-induced vasopressor response in perfused rat hind limb. (C) 1997 Elsevier Science B.V.