Mechanism of potentiation by amines of non‐equilibrium blockade of the α‐adrenoceptor

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Abstract
1 The mechanism by which sympathomimetic and certain other amines enhance blockade of the α-adrenoceptors by the non-equilibrium antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) in strips of rabbit aorta was examined. 2 Non-equilibrium blockade of the 5-hydroxytryptamine receptors by EEDQ was not increased by sympathomimetic amines and was decreased by 5-hydroxytryptamine. 3 Low concentrations of reversible competitive antagonists appeared to protect selectively against the additional blockade by EEDQ which develops in the presence of an amine. 4 Phenoxybenzamine potentiated EEDQ blockade of the α-receptors but not of the 5-hydroxytryptamine receptors. 5 Augmentation of EEDQ blockade was also detected in a variety of other tissues, but not in segments of rabbit intestine where α-adrenoceptors mediate an inhibitory response. 6 It was concluded that EEDQ acts at two sites in antagonizing α-receptor mediated responses, and that one of these sites (site II) is separate from the site of action of agonists and phenoxybenzamine (site I). Amines which enhance blockade appear to exert their action by combining with a third site (site III), which may induce a conformational alteration at site II. 7 It appears that the α-adrenoceptor may have multiple sites for drug interaction.