Abstract
We examined the effects of short and prolonged exposure to carvedilol, an antihypertensive and β-adrenoceptor blocking drug, on voltage-dependent Na+ channels in cultured bovine adrenal medullary cells. Carvedilol (1–100 μM) reduced22Na+ influx induced by veratridine, an activator of voltage-dependent Na+ channels. Carvedilol also suppressed veratridine-induced 45Ca2+influx and catecholamine secretion in a concentration-dependent manner similar to that of 22Na+ influx. Prolonged exposure of the cells to 10 μM carvedilol increased [3H]saxitoxin ([3H]STX) binding, which reached a plateau at 12 h and was still observed at 48 to 72 h. Scatchard analysis of [3H]STX binding revealed that carvedilol increased the Bmax value (control, 14.9 ± 0.9 fmol/106 cells; carvedilol, 23.8 ± 1.2 fmol/106 cells) (n = 3, P < 0.05) without altering theKd value, suggesting a rise in the number of cell surface Na+ channels. The increase in [3H]STX binding by carvedilol was prevented by cycloheximide, an inhibitor of protein synthesis, whereas carvedilol changed neither α- nor β1-subunit mRNA levels of Na+ channels. The carvedilol-induced increase of [3H]STX binding was abolished by brefeldin A and H-89, inhibitors of intracellular vesicular trafficking of proteins from thetrans-Golgi network and of cyclic AMP-dependent protein kinase (protein kinase A), respectively. The present findings suggest that short-term treatment with carvedilol reduces the activity of Na+ channels, whereas prolonged exposure to carvedilol up-regulates cell surface Na+ channels. This may add new pharmacological effects of carvedilol to our understanding in the treatment of heart failure and hypertension.
Footnotes
- Abbreviations:
- TTX
- tetrodotoxin
- STX
- saxitoxin
- PbTx-3
- Ptychodiscus brevis toxin-3
- hNE-Na
- human neuroendocrine-type Na+ channel α-subunit
- MEM
- minimum essential medium
- BFA
- brefeldin A
- DMSO
- dimethyl sulfoxide
- KRP
- Krebs-Ringer phosphate
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- SSC
- saline-sodium citrate
- S
- segment
- kb
- kilobase
- Received November 13, 2001.
- Accepted March 6, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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