Effects of imidazolines in noradrenaline release in brain: An investigation into their relationship to imidazoline, α2 and H 3 receptors

Abstract

The present study was carried out to clarify whether the imidazolines clonidine, moxonidine and cirazoline as well as the guanidine aganodine inhibit noradrenaline release in the rat and rabbit brain via imidazoline receptors, α 2-adrenoceptors and/or histamine H 3 receptors. Slices or synaptosomes from the rat or the rabbit brain were incubated with 3H-noradrenaline and exposed to phenoxybenzamine, which irreversibly blocks presynaptic α 2-adrenoceptors and, at considerably lower potency, imidazoline receptors. Tritium overflow in the superfused preparations was evoked electrically (3 Hz; slices) or by K + 15 mmol/1 (synaptosomes). Noradrenaline and rauwolscine, which possess low affinity, if any, for imidazoline receptors, were used as reference drugs. The evoked overflow in rat brain cortex slices and synaptosomes and in rat medulla oblangata slices, not exposed to phenoxybenzamine, was inhibited by clonidine, moxonidine and noradrenaline. Phenoxybenzamine markedly attenuated the effect of each drug to about the same extent. In rabbit brain cortex slices, not exposed to phenoxybenzamine, the evoked overflow was inhibited by clonidine, aganodine and noradrenaline, facilitated by BDF 6143 (4-chloro-2-(2-imidazoline-2-yl-amino)-isoindoline), idazoxan and rauwolscine and not affected by cirazoline. In slices exposed to phenoxybenzamine, the inhibitory effects of the imidazolines, of aganodine and of noradrenaline were again attenuated 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 3H-N α -methylhistamine to H 3 receptors in rat brain cortex membranes was displaced only by high concentrations of moxonidine (pK i=6.16) and at even lower affinity by aganodine, BDF 6143, cirazoline, clonidine and idazoxan (pK i<5). Histamine, 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 oblangata via α 2-adrenoceptors but not via imidazoline receptors resembling the presynaptic imidazoline receptors previously identified in peripheral tissues of the rabbit. In addition, the involvement of I 1- or I 2-imidazoline binding sites or of H 3 receptors is very improbable in view of the low affinity of aganodine, moxonidine and/or clonidine for these recognition sites and/or incompatibility of the rank order of their affinities with the potencies of the drugs in inhibiting noradrenaline release.