RT Journal Article
SR Electronic
T1 Simvastatin Inhibits Catecholamine Secretion and Synthesis Induced by Acetylcholine via Blocking Na<sup>+</sup> and Ca<sup>2+</sup> Influx in Bovine Adrenal Medullary Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 130
OP 136
DO 10.1124/jpet.108.139659
VO 327
IS 1
A1 Taeko Matsuda
A1 Yumiko Toyohira
A1 Susumu Ueno
A1 Masato Tsutsui
A1 Nobuyuki Yanagihara
YR 2008
UL http://jpet.aspetjournals.org/content/327/1/130.abstract
AB Simvastatin, an inhibitor of HMG-CoA reductase, is a potent inhibitor of cholesterol biosynthesis and has beneficial effects in the primary and secondary prevention of cardiovascular diseases. In this study, we report the effects of simvastatin on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells used as a model of sympathetic neurons. Simvastatin inhibited catecholamine secretion induced by acetylcholine, an agonist of the nicotinic acetylcholine receptor; by veratridine, an activator of voltage-dependent Na+ channels; and by high K+, an activator of voltage-dependent Ca2+ channels (IC50 = 3.8, 7.8, and 6.1 μM, respectively). Simvastatin also suppressed acetylcholine-induced 22Na+ influx (IC50 = 4.3 μM) and 45Ca2+ influx (IC50 = 6.1 μM), veratridine-induced 22Na+ influx (IC50 = 6.6 μM) and 45Ca2+ influx (IC50 = 12 μM), and high K+-induced 45Ca2+ influx (IC50 = 11 μM). The reduction of catecholamine secretion caused by simvastatin was not overcome by increasing the concentration of acetylcholine or by treatment with mevalonate, the first metabolite of HMG-CoA. The inhibitory effect of simvastatin on histamine-induced secretion of catecholamines was observed in the presence of extracellular Ca2+, but not in a Ca2+-free medium, suggesting that simvastatin does not interfere with histamine receptors nonselectively. Simvastatin also suppressed acetylcholine-induced [14C]catecholamine synthesis from [14C]tyrosine as well as tyrosine hydroxylase activity. These findings suggest that simvastatin inhibits catecholamine secretion and synthesis induced by acetylcholine through suppression of Na+ and Ca2+ influx in the adrenal medulla and probably in the sympathetic neurons. The American Society for Pharmacology and Experimental Therapeutics