THE ADRENOCEPTOR AGONIST, SDZ NVI 085, DISCRIMINATES BETWEEN ALPHA-1A-ADRENOCEPTOR AND ALPHA-1B-ADRENOCEPTOR SUBTYPES IN VAS-DEFERENS, KIDNEY AND AORTA OF THE RAT

The potency of the alpha1-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 alpha1A-adrenoceptor subtype characteristics, and in the rat thoracic aorta, in which the contribution of different alpha1-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 x 10(-5) M), sensitive to (+/-)-isradipine (10(-8) M) and competitively antagonized by 5-methyl-urapidil (pA2 = 9.04 and 8.82, respectively). The potencies of a number of alpha1A-/alpha1B-adrenoceptor-discriminating antagonists to reverse renal vasoconstriction due to either (-)-noradrenaline or SDZ NVI 085, and their affinities in vas deferens correlated significantly with their pK(i) values at alpha1A binding sites in rat cortex. In rat aorta, SDZ NVI 085 up to 5 x 10(-4) M failed to evoke contraction. The affinities of subtype-selective antagonists determined in aorta correlated significantly with the pK(i) values at alpha1B binding sites but differed from pK(i) values at alpha1A, sites in rat cortex. Thus, the contractile alpha1-adrenoceptor in rat aorta can be best characterized as B subtype. SDZ NVI 085 might be a selective alpha1A-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 alpha1A-adrenoceptors functionally involved in smooth muscle contraction.