Modification of noradrenaline release in pithed spontaneously hypertensive rats by I1-binding sites in addition to alpha2-adrenoceptors

J Pharmacol Exp Ther. 2003 Mar;304(3):1063-71. doi: 10.1124/jpet.102.044966.


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.

MeSH terms

  • Adrenergic alpha-Antagonists / pharmacology
  • Agmatine / pharmacology
  • Animals
  • Antihypertensive Agents / pharmacology
  • Benzofurans / pharmacology
  • Binding Sites
  • Blood Pressure / drug effects
  • Disease Models, Animal
  • Heart Rate / drug effects
  • Idazoxan / pharmacology
  • Imidazoles / pharmacology
  • Male
  • Norepinephrine / metabolism*
  • Phenoxybenzamine / pharmacology
  • Rats
  • Rats, Inbred SHR
  • Receptors, Adrenergic, alpha-2 / metabolism*


  • Adrenergic alpha-Antagonists
  • Antihypertensive Agents
  • Benzofurans
  • Imidazoles
  • Receptors, Adrenergic, alpha-2
  • Phenoxybenzamine
  • Agmatine
  • moxonidine
  • efaroxan
  • Norepinephrine
  • Idazoxan