New insights on mode of action of vasorelaxant activity of simvastatin.

Simvastatin is a semisynthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is used extensively to treat atherosclerotic cardiovascular disease. Apart from the lipid-lowering effect, simvastatin has been documented to offer impressive vasorelaxant activity. However, the mechanism associated with this vasorelaxant activity has yet not been substantially explored. Thus, the present study has aimed to elucidate the mechanism(s) associated with simvastatin-induced vasorelaxation using an established rat aortic ring model. The results from the study depicted that simvastatin caused significant relaxation in aortic rings pre-contracted with phenylephrine and potassium chloride (KCl). The vasorelaxant effect of simvastatin was attenuated by methylene blue (sGC-dependent cyclic guanosine monophosphate (cGMP) inhibitor), N-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor), 4-aminopyridine (K blocker), glibenclamide (K blocker), and barium chloride (K blocker). In addition, the vasorelaxant effect of simvastatin was slightly reduced by PD123319 (angiotensin II type 2 receptor (ATR) antagonist). However, indomethacin (COX inhibitor), 1H-[1,2,4]Ox adiazolol [4,3-α]quinoxalin-1-one (ODQ; selective soluble guanylate cyclase (sGC) inhibitor), losartan (angiotensin II type 1 receptor (ATR) antagonist), atropine (muscarinic receptor blocker), and tetraethyl ammonium (TEA; K blocker) did not affect the vasorelaxant effect of simvastatin. Furthermore, simvastatin was found to attenuate the release of calcium (Ca) from intracellular stores in the presence of ruthenium red (ryanodine receptor, RyR inhibitor) and extracellular stores via nifedipine (voltage-operated Ca channels, VOCC blocker) and SK&F96365 (receptor-operated Ca channel, ROCC blocker). Thus, it can be concluded that the vasorelaxant effect of simvastatin involves NO/cGMP pathways, ATR receptors, Ca channels, and K channels.