Enhanced α 2A ‐autoreceptor reserve for clonidine induced by reserpine and cholinomimetic agents in the rat vas deferens

1 The adaptive changes in the functional parameters of the presynaptic α 2A ‐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 α 2 ‐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 n M ) was used to block partially the α 2A ‐adrenoceptor‐mediated effect of clonidine. 3 In control (untreated) animals, clonidine inhibited concentration‐dependently the twitch response of the vas deferens (pEC 50 =8.66) with a maximal effect near 100%. The apparent affinity constant for clonidine was estimated with the nested hyperbolic methodology (p K A =7.10). The analysis of the occupancy‐effect relation for clonidine revealed a large receptor reserve at α 2A ‐adrenoceptors. 4 Acute, short‐term and chronic treatments with reserpine increased the sensitivity of α 2A ‐adrenoceptors to clonidine (decreased the EC 50 ) by about 3, 4 and 9 fold, respectively, and also increased the pool of receptor reserve for this agonist (decreased the K E ) 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 α 2A ‐adrenoceptors to clonidine (decreased the EC 50 ) by about 3 and 2 fold, respectively, and also increased the pool of receptor reserve for this agonist (decreased the K E ) 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 α 2A ‐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