SEARCH

SEARCH BY CITATION

Keywords:

  • Presynaptic α2A-adrenoceptors;
  • clonidine;
  • EEDQ;
  • agonist affinities;
  • receptor reserve;
  • receptor occupancy;
  • rat vas deferens;
  • reserpine;
  • pilocarpine;
  • neostigmine
  • 1
    The adaptive changes in the functional parameters of the presynaptic α2A-adrenoceptors in rat vas deferens were examined after treatments with the monoamine depleter reserpine or with the direct/indirect cholinomimetic agents pilocarpine and neostigmine.
  • 2
    For this purpose, we studied the inhibition induced by the α2-adrenoceptor agonist clonidine on the twitch contraction of the vas deferens elicited by electrical field stimulation, in animals that had been treated with acute (single dose), short-term (for 4 days) and chronic (for 11 days) regimens of reserpine (0.25 mg kg−1, s.c., every 48 h), pilocarpine (10 mg kg−1, i.p., every 12 h) or neostigmine (0.1 mg kg−1, i.p., every 12 h). The irreversible receptor alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 300 nM) was used to block partially the α2A-adrenoceptor-mediated effect of clonidine.
  • 3
    In control (untreated) animals, clonidine inhibited concentration-dependently the twitch response of the vas deferens (pEC50=8.66) with a maximal effect near 100%. The apparent affinity constant for clonidine was estimated with the nested hyperbolic methodology (pKA=7.10). The analysis of the occupancy-effect relation for clonidine revealed a large receptor reserve at α2A-adrenoceptors.
  • 4
    Acute, short-term and chronic treatments with reserpine increased the sensitivity of α2A-adrenoceptors to clonidine (decreased the EC50) by about 3, 4 and 9 fold, respectively, and also increased the pool of receptor reserve for this agonist (decreased the KE) by 4, 10 and 10 fold, respectively. Receptor affinity values were not changed after treatments.
  • 5
    Short-term and chronic, but not acute, treatments with pilocarpine and neostigmine increased the sensitivity of α2A-adrenoceptors to clonidine (decreased the EC50) by about 3 and 2 fold, respectively, and also increased the pool of receptor reserve for this agonist (decreased the KE) by 2 and 3 fold, respectively. Receptor affinity values were not changed after these treatments.
  • 6
    These results indicate that an enhancement of the receptor reserve for clonidine might account for the supersensitivity of α2A-adrenoceptors induced by reserpine, pilocarpine or neostigmine treatments in the rat vas deferens.

British Journal of Pharmacology (1997) 122, 833–840; doi:10.1038/sj.bjp.0701455