It is known that moxonidine acts as an agonist at presynaptic ␣ 2 -adrenoceptors of the postganglionic sympathetic nerve terminals and leads to a reduction in noradrenaline release. In addition, it is conceivable that I 1 -binding sites located in other regions of the pre-and postganglionic sympathetic neurons are involved in this effect. Our aim was to investigate whether and to what extent activation of the I 1 -binding sites contributes to the moxonidine-induced inhibition of noradrenaline release. Noradrenaline release was induced in pithed spontaneously hypertensive rats (pretreated with phenoxybenzamine/desipramine at 10/0.5 mg/kg) by stimulation of sympathetic overflow from the spinal cord. Noradrenaline overflow was reduced using moxonidine (0.18, 0.6, and 1.8 mg/kg) by 39.4, 70.4, or 78.7%, respectively, even when all ␣ 1 -/␣ 2 -adrenoceptors were blocked effectively by phenoxybenzamine. In contrast, the I 1 -antagonist efaroxan (0.1, 1, and 3 mg/kg) increased noradrenaline overflow from 453 (control) to 1710, 1999, or 2754 pg/ml, suggesting an autoreceptor-like function of I 1 -binding sites. In consequence, moxonidine (0.18, 0.6, and 1.8 mg/kg) reduced the increase in noradrenaline overflow in efaroxan-treated animals (1 mg/kg) by 22.7, 41.7, and 50.5%, respectively. Agmatine (6 and 60 mg/kg), an endogenous agonist at I 1 -binding sites, reduced noradrenaline overflow (Ϫ36 or 53%), even under ␣ 2 -adrenoceptor blockade. When 2-endo-amino-3-exoisopropylbicyclo[2.2.1]heptane (AGN192403) (10 mg/kg) was injected, a selective blocker of I 1 -binding sites, noradrenaline overflow was not influenced by agmatine. It is concluded that moxonidine reduces noradrenaline overflow by acting at I 1 -binding sites in addition to its agonistic property at ␣ 2 -adrenoceptors. The exact location of the I 1 -binding sites on the pre-or postsynaptic sympathetic neurons is unknown, but the location in the pre-or postsynaptic membrane of the sympathetic ganglion is the most plausible explanation.Clonidine and the related compounds moxonidine and rilmenidine that induce inhibition of noradrenaline release from sympathetic neurons are second line antihypertensives. Recently, the presynaptic ␣ 2 -adrenoceptor mediating an inhibition of noradrenaline release from sympathetic nerves at which these compounds act was subclassified as the ␣ 2A -and ␣ 2C

In pithed spontaneous hypertensive rats, noradrenaline overflow was diminished by moxonidine even when alpha(2)-adrenoceptors were blocked quantitatively using phenoxybenzamine, suggesting an I(1)-receptor-mediated mechanism of noradrenaline release. This hypothesis was confirmed, since the noradrenaline overflow was (1) increased under alpha(2)-adrenoceptors blockade by the mixed I(1)/alpha(2)-antagonists efaroxan or idazoxan, (2) still reduced by moxonidine when both alpha(2)- and I(1)-receptors were blocked, and (3) diminished by agmatine after pretreatment with phenoxybenzamine, but not with AGN192403. An indirect ganglionic I(1)-receptor-mediated mechanism of noradrenaline release is supposed.

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