Multiple cellular mechanisms mediate the effect of lobeline on the releaseof norepinephrine

Citation
E. Santha et al., Multiple cellular mechanisms mediate the effect of lobeline on the releaseof norepinephrine, J PHARM EXP, 294(1), 2000, pp. 302-307
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
294
Issue
1
Year of publication
2000
Pages
302 - 307
Database
ISI
SICI code
0022-3565(200007)294:1<302:MCMMTE>2.0.ZU;2-A
Abstract
The complex effect of lobeline on [H-3] norepinephrine ([H-3]NE) release wa s investigated in this study. Lobeline-induced release of [H-3]NE from the vas deferens was strictly concentration-dependent. In contrast, electrical stimulation-evoked release was characterized by diverse effects of lobeline depending on the concentration used: at lower concentration (10 mu M), it increased the release and at high concentration (100 and 300 mu M), the evo ked release of [H-3]NE was abolished. The effect of lobeline on the basal r elease was [Ca2+]-independent, insensitive to mecamylamine, a nicotinic ace tylcholine receptor antagonist, and to desipramine, a noradrenaline uptake inhibitor. However, lobeline-induced release was temperature-dependent: at low temperature (12 degrees C), at which the membrane carrier proteins are inhibited, lobeline failed to increase the basal release. Lobeline dose dep endently inhibited the uptake of [H-3]NE into rat hippocampal synaptic vesi cles and purified synaptosomes with IC50 values of 1.19 +/- 0.11 and 6.53 /- 1.37 mu M, respectively. Lobeline also inhibited Ca2+ influx induced by KCl depolarization in sympathetic neurons measured with the Fura-2 techniqu e. In addition, phenylephrine, an alpha(1)-adrenoceptor agonist, contracted the smooth muscle of the vas deferens and enhanced stimulation-evoked cont raction. Both effects were inhibited by lobeline. Our results can be best e xplained as a reversal of the monoamine uptake by lobeline that is facilita ted by the increased intracellular NE level after lobeline blocks vesicular uptake. At high concentrations, lobeline acts as a nonselective Ca2+ chann el antagonist blocking pre- and postjunctional Ca2+ channels serving as a c ounterbalance for the multiple transmitter releasing actions.