Inhibitory presynaptic imidazoline receptors on sympathetic nerves in the rabbit aorta differ from I sub(1)- and I sub(2)-imidazoline binding sites

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 351; no. 5; pp. 507 - 516
• Main Authors: Molderings, G J, Goethert, M
• Format: Journal Article
• Language: English
• Published: 01-01-1995
• ISSN: 0028-1298

The involvement of imidazoline receptors in modulation of noradrenaline release was investigated in the rabbit aorta preincubated with [ super(3)H]noradrenaline and superfused with physiological salt solution containing cocaine, corticosterone and propranolol. After blockade of alpha sub(2)-autoreceptors by rauwolscine, the electrically evoked tritium overflow 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)-isoindoline) > BDF 6100 [2-(2-imidazolin-2-ylamino)-isoindoline] > clonidine > ST587 (2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine nitrate) greater than or equal to cirazoline > tolazoline > idazoxan > phentolamine. Comparison of the potencies of these drugs with those previously found for the presynaptic imidazoline receptors in the rabbit pulmonary artery revealed a very good correlation. In contrast, no positive correlation was found with their affinities for the I sub(1)- and I sub(2)-imidazoline binding sites in bovine adrenal medullary membranes and with their lipophilicity (log P values). The electrically evoked tritium overflow was also inhibited by the recently identified endogenous imidazoline 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-acetic 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 clonidine, BDF 6143 and cirazoline (apparent pA sub(2) 6.48-7.32) than in antagonizing that of oxymetazoline and moxonidine (apparent pA sub(2) 8.33 and 8.12, respectively). In a final series of experiments, BDF 6143 (under the conditions applied a selective agonist at presynaptic imidazoline receptors) proved to be considerably less potent in inhibiting tritium overflow evoked by high K super(+) than by electrical stimulation, whereas moxonidine (in rabbit aorta a selective agonist at presynaptic alpha sub(2)-adrenoceptors) exhibited similar potency in inhibiting the overflow evoked by both methods of stimulation. It is concluded that noradrenaline release in the rabbit aorta is inhibited via both alpha sub(2)-autoceptors and presynaptic imidazoline receptors which can be activated by the endogenous imidazoline receptor ligand agmatine. The occurrence of such an alpha sub(2)-adrenoceptor-independent mechanism is compatible with the ability of K super(+) ions to attenuate the inhibitory effect of an imidazoline receptor agonist but not of an alpha sub(2)-adrenoceptor agonist, since susceptibility to K super(+) ions has been suggested to be a typical feature of imidazoline recognition sites. The presynaptic imidazoline receptor in rabbit aorta appears to be identical with the previously characterized presynaptic imidazoline receptor in rabbit pulmonary artery, but differs clearly from the I sub(1) and I sub(2) binding sites in the bovine adrenal medulla.