Modification of noradrenaline release in pithed spontaneously hypertensive rats by I1-binding sites in addition to alpha2-adrenoceptors.
It is known that moxonidine acts as an agonist at presynaptic alpha(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 alpha(1)-/alpha(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 (-36 or 53%), even under alpha(2)-adrenoceptor blockade. When 2-endo-amino-3-exo-isopropylbicyclo[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 alpha(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.
Raasch
Walter
W
Institute of Experimental and Clinical Pharmacology, Lübeck, Germany. raasch@medinfo.mu-luebeck.de
Jungbluth
Britta
B
Schäfer
Ulrich
U
Häuser
Walter
W
Dominiak
Peter
P
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000376:Agmatine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D019329:Idazoxan / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010643:Phenoxybenzamine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*
D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D001572:Benzofurans; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; D010643:Phenoxybenzamine; D000376:Agmatine; C043482:moxonidine; C062597:efaroxan; D009638:Norepinephrine; D019329:Idazoxan