Abstract

It is known that moxonidine acts as an agonist at presynaptic α₂-adrenoceptors of the postganglionic sympathetic nerve terminals and leads to a reduction in noradrenaline release. In addition, it is conceivable that I₁-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 I₁-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 α₁-/α₂-adrenoceptors were blocked effectively by phenoxybenzamine. In contrast, the I₁-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 I₁-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 I₁-binding sites, reduced noradrenaline overflow (−36 or 53%), even under α₂-adrenoceptor blockade. When 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane (AGN192403) (10 mg/kg) was injected, a selective blocker of I₁-binding sites, noradrenaline overflow was not influenced by agmatine. It is concluded that moxonidine reduces noradrenaline overflow by acting at I₁-binding sites in addition to its agonistic property at α₂-adrenoceptors. The exact location of the I₁-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.