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  • Title: Enhanced alpha2A-autoreceptor reserve for clonidine induced by reserpine and cholinomimetic agents in the rat vas deferens.
    Author: Pineda J, Ugedo L, García-Sevilla JA.
    Journal: Br J Pharmacol; 1997 Nov; 122(5):833-40. PubMed ID: 9384498.
    Abstract:
    1. The adaptive changes in the functional parameters of the presynaptic alpha2A-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 alpha2-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 alpha2A-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 (pK(A) = 7.10). The analysis of the occupancy-effect relation for clonidine revealed a large receptor reserve at alpha2A-adrenoceptors. 4. Acute, short-term and chronic treatments with reserpine increased the sensitivity of alpha2A-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 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 alpha2A-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 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 alpha2A-adrenoceptors induced by reserpine, pilocarpine or neostigmine treatments in the rat vas deferens.
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