Received for publication April 2, 2008.
Revised June 27, 2008.
Accepted for publication June 30, 2008.

Simvastatin inhibits catecholamine secretion and synthesis induced by acetylcholine via blocking Na⁺ and Ca²⁺ influx in bovine adrenal medullary cells

Abstract

Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, is a potent inhibitor of cholesterol biosynthesis and has beneficial effects in the primary and secondary prevention of cardiovascular diseases. Here, 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 non-selectively. 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.

Key words: Adrenal medulla, Cattecholamine, Nicotinic acetylcholine receptor, Secretion, Simvastatin, Synthesis