Stain pleiotropy: direct regulation of arterial contractility by simvastatin

Abstract

Long‐term use of simvastatin, an inhibitor HMG‐CoA reductase and cholesterol synthesis, has been reported to influence vascular function secondary to the reduction of cholesterol. However, direct effects of simvastatin application on fresh isolated arteries and its relevance for arterial contractility regulation are unclear. Here, we investigated direct regulation of vascular reactivity by therapeutic concentrations of simvastatin in an ex‐vivo preparation of rat thoracic aorta using a combination of wire myography, Western blotting, and arterial biotinylation techniques. Our wire myography data revealed that simvastatin stimulates reversible contraction of aorta at therapeutic concentrations (0.0001–0.1 μM), with 0.01 μM producing maximum response that is equivalent to ~60% of depolarization‐mediated aorta contraction induced by 60mM K+. Endothelium removal or co‐application of mevalonate with simvastatin did not alter simvastatin‐induced vasocontraction. In contrast, removing extracellular Ca2+ with EGTA or co‐application of nimodipine, a blocker of CaV1.2, each abolished simvastatin‐evoked contraction of aorta. Ryanodine, a blocker of ryanodine receptor‐mediated Ca2+ release from intracellular Ca2+ stores, did not alter aorta contraction by simvastatin. Arterial biotinylation data showed that CaV1.2 channel protein expression and relative cellular distribution remain unchanged by simvastatin for the time points covering duration of simvastatin application. In summary, our data suggest that simvastatin directly controls arterial smooth muscle cell [Ca2+]i and arterial contractility primarily by stimulating Ca2+ entry via CaV1.2 ion channel in arterial smooth muscle cells, which is independent of HMG‐CoA reductase inhibition by simvastatin. Our future studies will examine if simvastatin and other statins can alter arterial contractility and blood pressure in normotensive and hypertensive animals in which CaV1.2 is upregulated. Support or Funding Information This work was supported by a start‐up grant from the Mercer University College of Pharmacy to Dr. Raquibul Hasan