Multiple Cellular Mechanisms Mediate the Effect of Lobeline on the Release of Norepinephrine

• Published in: The Journal of pharmacology and experimental therapeutics 2000-07, Vol.294 (1), p.302-307
• Main Authors: Sántha, E, Sperlágh, B, Zelles, T, Zsilla, G, Tóth, P T, Lendvai, B, Baranyi, M, Vizi, E S
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Calcium Channels - drug effects; Desipramine - pharmacology; Guinea Pigs; Lobeline - pharmacology; Male; Muscle Contraction - drug effects; Nicotinic Agonists - pharmacology; Norepinephrine - secretion; Rats; Vas Deferens - drug effects; Vas Deferens - physiology; Vas Deferens - secretion
• ISSN: 0022-3565; 1521-0103

The complex effect of lobeline on [ 3 H]norepinephrine ([ 3 H]NE) release was investigated in this study. Lobeline-induced release of [ 3 H]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 [ 3 H]NE was abolished. The effect of lobeline on the basal release was [Ca 2+ ]-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 [ 3 H]NE into rat hippocampal synaptic vesicles and purified synaptosomes with IC 50 values of 1.19 ± 0.11 and 6.53 ± 1.37 μM, respectively. Lobeline also inhibited Ca 2+ influx induced by KCl depolarization in sympathetic neurons measured with the Fura-2 technique. In addition, phenylephrine, an α 1 -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 Ca 2+ channel antagonist blocking pre- and postjunctional Ca 2+ channels serving as a counterbalance for the multiple transmitter releasing actions.