PT  - JOURNAL ARTICLE
AU  - Ernô Sántha
AU  - Beáta Sperlágh
AU  - Tibor Zelles
AU  - Gabriella Zsilla
AU  - Péter T. Tóth
AU  - Balázs Lendvai
AU  - Mária Baranyi
AU  - E. Sylvester Vizi
TI  - Multiple Cellular Mechanisms Mediate the Effect of Lobeline on the Release of Norepinephrine
DP  - 2000 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 302--307
VI  - 294
IP  - 1
4099  - http://jpet.aspetjournals.org/content/294/1/302.short
4100  - http://jpet.aspetjournals.org/content/294/1/302.full
SO  - J Pharmacol Exp Ther2000 Jul 01; 294
AB  - The complex effect of lobeline on [3H]norepinephrine ([3H]NE) release was investigated in this study. Lobeline-induced release of [3H]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 μM), it increased the release and at high concentration (100 and 300 μM), the evoked release of [3H]NE was abolished. The effect of lobeline on the basal release was [Ca2+]-independent, insensitive to mecamylamine, a nicotinic acetylcholine receptor antagonist, and to desipramine, a noradrenaline uptake inhibitor. However, lobeline-induced release was temperature-dependent: at low temperature (12°C), at which the membrane carrier proteins are inhibited, lobeline failed to increase the basal release. Lobeline dose dependently inhibited the uptake of [3H]NE into rat hippocampal synaptic vesicles and purified synaptosomes with IC50 values of 1.19 ± 0.11 and 6.53 ± 1.37 μM, respectively. Lobeline also inhibited Ca2+ influx induced by KCl depolarization in sympathetic neurons measured with the Fura-2 technique. In addition, phenylephrine, an α1-adrenoceptor agonist, contracted the smooth muscle of the vas deferens and enhanced stimulation-evoked contraction. Both effects were inhibited by lobeline. Our results can be best explained as a reversal of the monoamine uptake by lobeline that is facilitated by the increased intracellular NE level after lobeline blocks vesicular uptake. At high concentrations, lobeline acts as a nonselective Ca2+ channel antagonist blocking pre- and postjunctional Ca2+ channels serving as a counterbalance for the multiple transmitter releasing actions. The American Society for Pharmacology and Experimental Therapeutics