EFFECTS OF IMIDAZOLINES ON NORADRENALINE RELEASE IN BRAIN - AN INVESTIGATION INTO THEIR RELATIONSHIP TO IMIDAZOLINE, ALPHA(2) AND H-3 RECEPTORS

The present study was carried out to clarify whether the imidazolines clonidine, moxonidine and cirazoline as well as the guanidine aganodin e inhibit noradrenaline release in the rat and rabbit brain via imidaz oline receptors, alpha(2)-adrenoceptors and/or histamine H-3 receptors . Slices or synaptosomes from the rat or the rabbit brain were incubat ed with H-3-noradrenaline and exposed to phenoxybenzamine, which irrev ersibly blocks presynaptic alpha(2)-adrenoceptors and, at considerably lower potency, imidazoline receptors. Tritium overflow in the superfu sed preparations was evoked electrically (3 Hz; slices) or by K+ 15 mm ol/l (synaptosomes). Noradrenaline and rauwolscine, which possess low affinity, if any, for imidazoline receptors, were used as reference dr ugs. The evoked overflow in rat brain cortex slices and synaptosomes a nd in rat medulla oblongata slices, not exposed to phenoxybenzamine, w as inhibited by clonidine, moxonidine and noradrenaline. Phenoxybenzam ine markedly attenuated the effect of each drug to about the same exte nt. In rabbit brain cortex slices, not exposed to phenoxybenzamine, th e evoked overflow was inhibited by clonidine, moxonidine, aganodine an d noradrenaline, facilitated by BDF 6143 -chloro-2-(2-imidazoline-2-yl -amino)-isoindoline), idazoxan and rauwolscine and not affected by cir azoline. In slices exposed to phenoxybenzamine, the inhibitory effects of the imidazolines, of aganodine and of noradrenaline were again att enuated by about the same high degree, the facilitatory effects of BDF 6143, idazoxan and rauwolscine were abolished and cirazoline produced a slight inhibition of the evoked overflow. The latter effect was not affected by high concentrations of rauwolscine and idazoxan (at which these drugs act antagonistic at imidazoline receptors in other models ). The specific binding of H-3-N-alpha-methylhistamine to H-3 receptor s in rat brain cortex membranes was displaced only by high concentrati ons of moxonidine (pK(i) = 6.16) and at even lower affinity by aganodi ne, BDF 6143, cirazoline, clonidine and idazoxan (pK(i) < 5). Histamin e, which was used as a reference drug, proved to be very potent (pK(i) = 8.20). In conclusion, imidazolines affect noradrenaline release in the rat and rabbit brain cortex and medulla oblongata via alpha(2)-adr enoceptors but not via imidazoline receptors resembling the presynapti c imidazoline receptors previously identified in peripheral tissues of the rabbit. In addition, the involvement of I-1- or I-2-imidazoline b inding sites or of H-3 receptors is very improbable in view of the low affinity of aganodine, moxonidine and/or clonidine for these recognit ion sites and/or incompatibility of the rank order of their affinities with the potencies of the drugs in inhibiting noradrenaline release. Copyright (C) 1996 Elsevier Science Ltd.