Effect of simvastatin on vascular smooth muscle responsiveness: involvement of Ca(2+) homeostasis.
This report is focused on the study of simvastatin-induced relaxation of rat aorta through its effects on vascular smooth muscle and Ca(2+) 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 Ca(2+) entry through voltage-operated Ca(2+) channels (VOCCs) by diltiazem abolished the endothelium-dependent and direct relaxation, whereas Ca(2+)-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(2) 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 Ca(2+)-free medium, which is mainly due to intracellular Ca(2+) 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) (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 Ca(2+) release from intracellular stores, which could promote activation of endothelial factors, and blockade of extracellular Ca(2+) entry, which promote relaxations independent of the presence of endothelium. This action on Ca(2+) could be related to the inhibition of isoprenoid synthesis, which subsequently affects the function of G-proteins involved in communication among intracellular Ca(2+) pools and capacitative Ca(2+) entry.
Department of Pharmacology, Faculty of Pharmacy, University of Seville, C/Profesor Garcia-Gonzalez s/n, 41012, Seville, Spain. aldesoto@fafar.us.es
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Alvarez de Sotomayor
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Pérez-Guerrero
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Herrera
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Marhuenda
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D004110:Diltiazem / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D014665:Vasodilator Agents; D019821:Simvastatin; D004110:Diltiazem; D008798:Mevalonic Acid; C000543:cyclopiazonic acid