Vol. 304, Issue 3, 1063-1071, March 2003

Modification of Noradrenaline Release in Pithed Spontaneously Hypertensive Rats by I₁-Binding Sites in Addition to ₂-Adrenoceptors

Walter Raasch, Britta Jungbluth, Ulrich Schäfer, Walter Häuser and Peter Dominiak

Institute of Experimental and Clinical Pharmacology and Toxicology Medical University of Lübeck, Lübeck, Germany

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 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 ₁-/₂-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 ₂-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 ₂-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.