Differential effects of short and prolonged exposure to carvedilol on voltage-dependent Na(+) channels in cultured bovine adrenal medullary cells.
We examined the effects of short and prolonged exposure to carvedilol, an antihypertensive and beta-adrenoceptor blocking drug, on voltage-dependent Na(+) channels in cultured bovine adrenal medullary cells. Carvedilol (1-100 microM) reduced (22)Na(+) influx induced by veratridine, an activator of voltage-dependent Na(+) channels. Carvedilol also suppressed veratridine-induced (45)Ca(2+) influx and catecholamine secretion in a concentration-dependent manner similar to that of (22)Na(+) influx. Prolonged exposure of the cells to 10 microM carvedilol increased [(3)H]saxitoxin ([(3)H]STX) binding, which reached a plateau at 12 h and was still observed at 48 to 72 h. Scatchard analysis of [(3)H]STX binding revealed that carvedilol increased the B(max) value (control, 14.9 +/- 0.9 fmol/10(6) cells; carvedilol, 23.8 +/- 1.2 fmol/10(6) cells) (n = 3, P < 0.05) without altering the K(d) value, suggesting a rise in the number of cell surface Na(+) channels. The increase in [(3)H]STX binding by carvedilol was prevented by cycloheximide, an inhibitor of protein synthesis, whereas carvedilol changed neither alpha- nor beta(1)-subunit mRNA levels of Na(+) channels. The carvedilol-induced increase of [(3)H]STX binding was abolished by brefeldin A and H-89, inhibitors of intracellular vesicular trafficking of proteins from the trans-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.
Kajiwara
Koji
K
Second Department of Internal Medicine, School of Medicine, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu 807-8555, Japan.
Yanagita
Toshihiko
T
Nakashima
Yasuhide
Y
Wada
Akihiko
A
Izumi
Futoshi
F
Yanagihara
Nobuyuki
N
D000313:Adrenal Medulla / Q000187:drug effects / Q000378:metabolism*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077261:Carvedilol; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004591:Electrophoresis, Polyacrylamide Gel; D004594:Electrophysiology; D007700:Kinetics; D011412:Propanolamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012530:Saxitoxin / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000096:biosynthesis / Q000187:drug effects*; D014701:Veratridine / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D002395:Catecholamines; D011412:Propanolamines; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D015222:Sodium Channels; D000077261:Carvedilol; D012530:Saxitoxin; D014701:Veratridine; D012964:Sodium; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium