Effect of simvastatin on vascular smooth muscle responsiveness:: involvement of Ca2+ homeostasis

This report is focused on the study of simvastatin-induced relaxation of rat aorta through its effects on vascular smooth muscle and Ca2+ signalling. The presence of endothelium affected only the simvastatin-induced relaxation of aortic rings precontracted with noradrenaline, but not by depolarization with KCl 80 mM. Blockade of Ca2+ entry through voltage-operated Ca2+ channels (VOCCs)by diltiazem abolished the endothelium-dependent and direct relaxation, whereas Ca2+-ATPase inhibition by cyclopiazonic acid (3 X 10(-5) M) only affected the endothelium-dependent relaxation. In KCl-depolarised arteries concentration-response curves for CaCl, were shifted to the right in the presence of simvastatin (3 x 10(-6) and 3 x 10(-5) M) or diltiazem (10(-6) and 10(-7) M). The transient contraction caused by noradrenaline in Ca2+-free medium, which is mainly due to intracellular Ca2+ release, was inhibited by simvastatin (3 X 10(-5) M) or cyclopiazonic acid (3 X 10(-5) M) and the contraction induced by CaCl, (2 X 10(-3) M) added after noradrenaline was inhibited by diltiazem and simvastatin. All the reported effects of simvastatin were inhibited by the product of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, mevalonate (10-3 M). These findings demonstrate that the Vascular effects of simvastatin may involve both Ca2+ release from intracellular stoles, which could promote activation of endothelial factors, and blockade of extracellular Ca2+ entry, which promote relaxations independent of the presence of endothelium. This action on Ca2+ could be related to the inhibition of isoprenoid synthesis, which subsequently affects the function of G-proteins involved in communication among intracellular Ca2+ pools and capacitative Ca2+ entry. (C) 2001 Elsevier Science B.V. All rights reserved.