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
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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
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↵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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