Abstract
Treatment of cultured bovine adrenal medullary cells with carbamazepine (CBZ) for 5 days caused an increase in catecholamine secretion induced by veratridine, an activator of voltage-dependent Na+channels. However, no increase was stimulated by carbachol, an agonist of nicotinic receptors, or by 56 mM K+, a depolarizing agent that activates voltage-dependent Ca++ channels. CBZ (30 μg/ml) treatment enhanced veratridine-induced catecholamine secretion in a time-dependent manner (increases of 25%, 65% and 70% for 3, 5 and 7 days of treatment, respectively). CBZ treatment (5 days) increased veratridine-induced catecholamine secretion in a concentration-dependent manner (increases of 27%, 36%, 45% and 55% at 10, 15, 20 and 30 μg/ml of CBZ, respectively). CBZ treatment also increased 22Na+ influx and45Ca++ influx stimulated by veratridine. The stimulatory effect of CBZ treatment on catecholamine secretion was blocked by either actinomycin D or cycloheximide, an inhibitor of protein synthesis. Additive responses of catecholamine secretion and22Na+ influx induced by veratridine were associated with combined exposure of the cells to CBZ and dibutyryl cyclic AMP. CBZ treatment (30 μg/ml, 5 days) significantly increased the specific binding of [3H]saxitoxin to cell membranes. A Scatchard analysis of [3H]saxitoxin binding revealed that CBZ increased the Bmax value without any change in the dissociation constant. These findings suggest that CBZ up-regulates the density and activity of voltage-dependent Na+ channels.
Footnotes
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Send reprint requests to: Dr. Nobuyuki Yanagihara, Department of Pharmacology, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
- Abbreviations:
- CBZ
- carbamazepine
- dbc AMP
- dibutyryl cyclic AMP
- H89
- N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide
- KRP
- Krebs-Ringer phosphate
- STX
- saxitoxin
- TTX
- tetrodotoxin
- Kd
- dissociation constant
- GABA
- γ-aminobutyric acid
- NMDA
- N-methyl-d-aspartate
- Eagle’s MEM
- Eagle’s minimum essential medium
- DMSO
- dimethyl sulfoxide
- Received September 30, 1997.
- Accepted April 30, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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