The present study investigated the effects of SK&F 104078 (6-chloro-9-[(3-methyl-2-butenyl)oxy]-3-methyl-1H,2,3,4,-tetrahydro-3-benzazapine) at pre- and post-junctional alpha-2-adrenoceptors in the human isolated saphenous vein. Noradrenaline (0.001-100-mu-mol/l) produced concentration-dependent contractions of the human saphenous vein which were competitively antagonised by the alpha-1-adrenoceptor antagonist prazosin (0.01 - 1.0-mu-mol/l) and the alpha-2-adrenoceptor antagonist, rauwolscine (0.01 - 1.0-mu-mol/l), indicating the presence of both post-junctional alpha-1- and alpha-2-adrenoceptors in this preparation. The selective alpha-2-adrenoceptor agonist, UK-14,304 (0.01 - 100-mu-mol/l) also produced concentration-dependent contractions of the human saphenous vein which were antagonised by both rauwolscine (0.1-mu-mol/l) and prazosin (0.1-mu-mol/l). In the presence of angiotensin II (0.05-mu-mol/l), which itself produced a transient contraction, rauwolscine (0.1-mu-mol/l) produced a rightward shift of the UK-14,304 concentration-response curve while prazosin (0.1-mu-mol/l) had no effect. SK&F 104078 (10.0-mu-mol/l) under these conditions also produced a rightward shift of the concentration-response curve to UK-14,304, but was at least 100-fold less potent than rauwolscine. At pre-junctional alpha-2-adrenoceptors, exogenous noradrenaline (0.01 and 0.1-mu-mol/l) induced a concentration-dependent inhibition of stimulation-evoked [7-H-3]-noradrenaline release from the human saphenous vein in vitro, which was antagonised by rauwolscine (0.1-mu-mol/l) and tolazoline (10.0-mu-mol/l) but not by SK&F 104078 (10.0-mu-mol/l). Rauwolscine (0.1-mu-mol/l) produced a small increase in stimulation-evoked [7-H-3]-noradrenaline release while both tolazoline and SK&F 104078 failed to produce any enhancement in release in the absence of exogenous agonist at concentrations up to 10-mu-mol/l. In summary, noradrenaline and UK-14,304 contracted the human isolated saphenous vein by an action at both post-junctional alpha-1- and alpha-2-adrenoceptors. These data demonstrate that SK&F 104078 discriminates between post- and pre-junctional alpha-2-adrenoceptors in the human isolated saphenous vein.
