Plasma membrane ion channels and mitochondrial electron transport complexes (mETC) are recognised "off-targets" for certain drugs. Simvastatin is one such drug, a lipophilic statin used to treat hypercholesterolaemia, but which is also associated with adverse effects like myopathy and increased risk of glucose intolerance. Such myopathy is thought to arise through adverse actions of simvastatin on skeletal muscle mETC and mitochondrial respiration. In this study we investigated whether the glucose intolerance associated with simvastatin is also mediated via adverse effects on mETC in pancreatic beta-cells since mitochondrial respiration underlies insulin secretion from these cells, an effect in part mediated by promotion of Ca 2+ influx via opening of voltage-gated Ca 2+ channels (VGCCs).We used murine pancreatic beta-cells to investigate these ideas. Mitochondrial membrane potential, oxygen consumption and ATP-sensitive-K + -channel activity were monitored as markers of mETC activity, respiration and cellular ATP/ADP ratio respectively; Ca 2+ channel activity and Ca 2+ influx were also measured. In intact beta-cells, simvastatin inhibited oxidative respiration (IC50 ~ 3 µM) and mETC (1< IC50 < 10 µM), effects expected to impair VGCC opening. Consistent with this idea simvastatin > 0.1 µM reversed activation of VGCCs by glucose but had no significant effect in the sugar's absence. The VGCC effects were mimicked by rotenone which also decreased respiration and ATP/ADP. This study demonstrates modulation of beta-cell VGCC activity by mitochondrial respiration and their sensitivity to mETC inhibitors. This reveals a novel outcome for the action of drugs like simvastatin for which mETC is an "off target".
Statins are a chemically related group used as lipid-lowering agents, studies confirmed that statins have additional pleiotropic, cholesterol independent, effects mediated by inhibition of isoprenoid synthesis with subsequent inhibition of the downstream signaling molecules like Rho, Rac, and Ras. However, different statin members might have a distinctive effect on the immune system; thereby having different peripheral and cardiovascular actions, such extra-hepatic effects impose the preferences of one statin over another. The present study aimed to identify the role of the short-term utilization of atorvastatin on leukocyte concentration as a representative in vivo marker for immunomodulation. Two widely used statin agents were included in the study- the lipophilic (atorvastatin) versus the hydrophilic (rosuvastatin) for comparison. Blood samples were withdrawn from the two statin groups, before and after therapy, and an automated differential white blood cell count was performed to determine the difference between the studied samples. The results showed that short-term use of atorvastatin, but not rosuvastatin, was associated with a selective reduction of lymphocyte count (p<0.0001). The study concluded that lymphocyte levels were reduced significantly after short-term use of atorvastatin; an effect which might need to be considered in certain immunological disease associated with cardiac ones.
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