INHIBITORY PRESYNAPTIC IMIDAZOLINE RECEPTORS ON SYMPATHETIC-NERVES INTHE RABBIT AORTA DIFFER FROM I-1 AND I-2 IMIDAZOLINE BINDING-SITES

The involvement of imidazoline receptors in modulation of noradrenalin e release was investigated in the rabbit aorta preincubated with [H-3] noradrenaline and superfused with physiological salt solution containi ng cocaine, corticosterone and propranolol. After blockade of alpha(2) -autoreceptors by rauwolscine, the electrically evoked tritium overflo w was inhibited by various imidazolines and guanidines. The rank order of potency was BDF 7579 (4-chloro-2-isoindolinyl) guanidine) greater than or equal to BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindo line) > BDF 6100 [2-(2-imidazolin-2-ylamino)-isoindoline] > clonidine > ST587 (2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine nitra te) greater than or equal to cirazoline > tolazoline > idazoxan > phen tolamine. Comparison of the potencies of these drugs with those previo usly found for the presynaptic imidazoline receptors in the rabbit pul monary artery revealed a very good correlation. In contrast, no positi ve correlation was found with their affinities for the I-1- and I-2-im idazoline binding sites in bovine adrenal medullary membranes and with their lipophilicity (log P values). The electrically evoked tritium o verflow was also inhibited by the recently identified endogenous imida zoline receptor ligand agmatine, but was not affected by amiloride. In further series of experiments, the ability of putative antagonist at presynaptic imidazoline receptors to counteract the inhibitory effect of imidazoline derivatives was determined. Amiloride, imidazole-4-acet ic acid and 1-benzylimidazole did not attenuate the inhibitory effect of BDF 6143 on the electrically evoked tritium overflow. In contrast, rauwolscine antagonized the inhibitory effect of various imidazolines; rauwolscine was clearly less potent in antagonizing the effect of clo nidine, BDF 6143 and cirazoline (apparent pA(2) 6.48-7.32) than in ant agonizing that of oxymetazoline and moxonidine (apparent pA(2) 8.33 an d 8.12, respectively). In a final series of experiments, BDF 6143 (und er the conditions applied a selective agonist at presynaptic imidazoli ne receptors) proved to be considerably less potent in inhibiting trit ium overflow evoked by high K+ than by electrical stimulation, whereas moxonidine (in rabbit aorta a selective agonist at presynaptic alpha( 2)-adrenoceptors) exhibited similar potency in inhibiting the overflow evoked by both methods of stimulation. It is concluded that noradrena line release in the rabbit aorta is inhibited via both alpha(2)-autoce ptors and presynaptic imidazoline receptors which can be activated by the endogenous imidazoline receptor ligand agmatine. The occurrence of such an alpha(2)-adrenoceptor-independent mechanism is compatible wit h the ability of K+ ions to attenuate the inhibitory effect of an imid azoline receptor agonist but not of an alpha(2)-adrenoceptor agonist, since susceptibility to K+ ions has been suggested to be a typical fea ture of imidazoline recognition sites. The presynaptic imidazoline rec eptor in rabbit aorta appears to be identical with the previously char acterized presynaptic imidazoline receptor in rabbit pulmonary artery, but differs clearly from the I-1 and I-2 binding sites in the bovine adrenal medulla.