Vol. 294, Issue 1, 302-307, July 2000

Multiple Cellular Mechanisms Mediate the Effect of Lobeline on the Release of Norepinephrine¹

Ernô Sántha, Beáta Sperlágh, Tibor Zelles, Gabriella Zsilla, Péter T. Tóth, Balázs Lendvai, Mária Baranyi and E. Sylvester Vizi

Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary

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 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 Ca²⁺ channel antagonist blocking pre- and postjunctional Ca²⁺ channels serving as a counterbalance for the multiple transmitter releasing actions.