Pharmacological differentiation of pre- and post-junctional alpha 2-adrenoceptors.

It is now recognized that two post-junctional alpha-adrenoceptors mediate vascular constriction. The vascular alpha 2-adrenoceptors seem to be particularly sensitive to circulating catecholamine levels, in contrast to the alpha 1-adrenoceptors, which are activated primarily by neuronally released norepinephrine. Most alpha 2-adrenoceptor antagonists do not discriminate between the pre-junctional neuroinhibitory alpha 2-adrenoceptor and the post-junctional vascular alpha 2-adrenoceptor. However, we have synthesized and characterized a compound (SK&F 104078: 6-chloro-9-[(3-methyl-2-butenyl)oxy]-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine) which is a potent antagonist at post-junctional vascular alpha 2-adrenoceptors in vitro but has no effect at pre-junctional neuroinhibitory alpha 2-adrenoceptors. The post-junctional selectivity of SK&F 104078 has been confirmed by in vivo studies determining pre- and post-junctional alpha 2-adrenoceptor antagonist activity in the pithed rat. The ability to selectively block post-junctional alpha 2-adrenoceptors offers a novel approach to antihypertensive therapy, since the vasoconstrictor effects of circulating catecholamines can be attenuated without influencing the feedback control of transmitter release operating via pre-junctional alpha 2-adrenoceptors, and excess sympathoadrenal tone can be reduced without affecting normal neurovascular transmission.