AGMATINE RECOGNIZES ALPHA(2)-ADRENOCEPTOR BINDING-SITES BUT NEITHER ACTIVATES NOR INHIBITS ALPHA(2)-ADRENOCEPTORS

It has been suggested that agmatine (decarboxylated arginine) is an endogenous clonidine-displacing substance (CDS) which recognizes alpha(2)-adrenoceptor and non-adrenoceptor, imidazoline binding sites. We have examined the effect of agmatine at alpha(2)-adrenoceptor binding sites and pre- and postjunctional alpha(2)-adrenoceptors. Agmatine produced a concentration-dependent inhibition of 1 nmol/l H-3-clonidine binding to both rat (pK(i)-5.10+/-0.05) and bovine (pK(i)-4.77+/-0.38) cerebral cortex membranes. However, agmatine (0.1-100 mu M) failed to activate pre-junctional alpha(2)-adrenoceptors regulating transmitter release in the guinea-pig isolated ileum and rat isolated vas deferens, nor did it activate post-junctional alpha(2)-adrenoceptors of the porcine isolated palmar lateral vein which mediate contraction or inhibition of forskolin-stimulated cyclic AMP formation. High concentrations of agmatine (10-30-fold the pK(i) at alpha(2)-adrenoceptor binding sites) failed to influence alpha(2)-adrenoceptor activation by either clonidine or UK-14304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate) in any of the peripheral preparations examined. Moreover, even in a preparation where an interaction with alpha(2)-adrenoceptor binding sites on cell membranes can be demonstrated, the rat cerebral cortex, agmatine failed to inhibit forskolin-stimulated cyclic AMP in the intact tissue or affect the inhibition produced by the selective alpha(2)-adrenoceptor agonist UK-14304. Agmatine was also devoid of agonist activity in two preparations, the rat isolated thoracic aorta and the rat isolated gastric fundus, in which CDS has been reported to produce non-adrenoceptor effects. Thus, we have confirmed that agmatine recognizes alpha(2)-adrencoceptor binding sites and, therefore, is a CDS. However, since agmatine is devoid of pharmacological activity at either peripheral or central alpha(2)-adrenoceptors it can not account for earlier reports suggesting that brain-derived CDS can activate alpha(2)-adrenoceptors.