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Research ArticleNEUROPHARMACOLOGY

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

Ernô Sántha, Beáta Sperlágh, Tibor Zelles, Gabriella Zsilla, Péter T. Tóth, Balázs Lendvai, Mária Baranyi and E. Sylvester Vizi
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 302-307;
Ernô Sántha
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Beáta Sperlágh
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Tibor Zelles
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Gabriella Zsilla
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Péter T. Tóth
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Balázs Lendvai
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Mária Baranyi
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E. Sylvester Vizi
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. E. Sylvester Vizi, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Szigony u. 43., H-1450 P.O. Box 67, Hungary. E-mail: esvizi{at}koki.hu

  • ↵1 This study was supported in part by the Hungarian Research Fund (OTKA) (T022450, T029859), Hungarian Medical Research Foundation (194/96, 195/96, 53/98), and a Philip Morris research grant.

  • Abbreviations:
    DA
    dopamine
    VDCC
    voltage-dependent Ca2+ channel
    NE
    norepinephrine
    FR
    fractional release
    TB
    tetrabenazine
    nAChR(s)
    nicotinic acetylcholine receptor(s)
    [Ca2+]i
    intracellular calcium concentration, DMI, desipramine
    DOPEG
    3,4-dihydroxyphenylethylene glycol
    • Received December 10, 1999.
    • Accepted April 3, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleNEUROPHARMACOLOGY

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

Ernô Sántha, Beáta Sperlágh, Tibor Zelles, Gabriella Zsilla, Péter T. Tóth, Balázs Lendvai, Mária Baranyi and E. Sylvester Vizi
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 302-307;

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Research ArticleNEUROPHARMACOLOGY

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

Ernô Sántha, Beáta Sperlágh, Tibor Zelles, Gabriella Zsilla, Péter T. Tóth, Balázs Lendvai, Mária Baranyi and E. Sylvester Vizi
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 302-307;
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