Distinct α-noradrenergic receptors differentiated by binding and physiological relationships

In brain and peripheral tissues the α-noradrenergic agonists ³H-clonidine, ³H-epinephrine and ³H-norepinephrine label sites which are distinct from and do not interconvert with those labeled by the α-noradrenergic antagonist ³H-WB-4101 (2-([2', 6'-dimethoxy]-phenoxyethylamino) methylbenzodioxane). In general agonists have higher affinity for sites labeled by the ³H-agonists while antagonists prefer sites labeled by ³H-WB-4101, though ergots and the α-antagonist phentolamine have similar affinities for the two sites. Peripheral tissues vary in relative numbers of ³H-agonist and ³H-WB-4101 sites with heart and vas deferens having almost exclusively ³H-WB-4101 sites, the rabbit duodenum only ³H-agonist sites, while salivary gland, spleen and cerebral cortex display similar numbers of both sites. The two sites appear to be postsynaptic since 6-hydroxydopamine treatment does not reduce their numbers. In vas deferens, heart and spleen pharmacological potencies of α-agonists and antagonists correlate closely with affinities for ³H-WB-4101 but not ³H-clonidine sites, while potencies in rabbit duodenum correlate with affinities for ³H-clonidine but not ³H-WB-4101 sites. The correspondence of separate binding sites with distinctive patterns of physiological responses indicates the existence of two discrete types of postsynaptic α-receptors. We propose to designate sites labeled by WB-4101 as α-1 receptors and those labeled by ³H-clonidine, ³H-norepinephrine and ³H-epinephrine as α-2 receptors. Drug potencies at α-2 binding sites resemble their affinities for presynaptic α-noradrenergic autoreceptors.