The adrenoceptor agonist, SDZ NVI 085, discriminates between α1A- and α1B-adrenoceptor subtypes in vas deferens, kidney and aorta of the rat

Abstract

The potency of the α 1-adrenoceptor agonist (−)-(4aR, 10aR)-3,4,4a,5,10,10a-hexahydro-6-methoxy-4-methyl-9-methylthio-2H-naphth [2,3-b]-1,4-oxazine (SDZ NVI 085) was investigated both in isolated vas deferens and perfused kidney of the rat, two tissues with α 1 A -adrenoceptor subtype characteristics, and in the rat thoracic aorta, in which the contribution of different α 1-adrenoceptor subtypes mediating contraction is controversial. In vas deferens and kidney, SDZ NVI 085 evoked smooth muscle contraction and vascular constriction and was of similar potency to L-phenylephrine. Contractions of vas deferens in response to (−)-noradrenaline and SDZ NVI 085 were resistant to chloroethylclonidine treatment (3 × 10 −5 M), sensitive to (±)-isradipine (10 −8 M) and competitively antagonized by 5-methyl-urapidil (pA 2 = 9.04 and 8.82, respectively). The potencies of a number of α 1A-/ α 1B-adrenoceptor-discriminating antagonists to reverse renal vasoconstriction due to either (−)-nora or SDZ NVI 085, and their affinities in vas deferens correlated significantly with their pK i values at α 1A binding sites in rat cortex. In rat aorta, SDZ NVI 085 up to 5 × 10 −4 M failed to evoke contraction. The affinities of subtype-selective antagonists determined in aorta correlated significantly with the pK i values at α 1B binding sites but differed from pK i values at α 1A sites in rat cortex. Thus, the contractile α 1-adrenoceptor in rat aorta can be best characterized as B subtype. SDZ NVI 085 might be a selective α 1A-adrenoceptor agonist and thus be used as a new tool either to detect (rat vas deferens and kidney) or exclude (rat aorta) a contribution of α 1A-adrenoceptors functionally involved in smooth muscle contraction.