Statins have been the standard treatment for hypercholesterolemia and the prevention of cardiovascular disease for more than 20 years. They function as competitive inhibitors of the HMG-CoA reductase, the rate-limiting enzyme in the synthesis of cholesterol. Although effective in lowering cholesterol levels, statin users experience side effects that are primarily associated with muscle pain and weakness. Evidence suggests that sarcoplasmic reticulum (SR) Ca2+ homeostasis is altered in statin-treated skeletal muscle fibres (1, 2), however, the reasons why statin toxicity is reported in skeletal but not cardiac muscle are not understood. To examine whether simvastatin, a commonly prescribed statin, can directly modulate RyR channel function, we incorporated single sheep cardiac RyR2 or mouse skeletal RyR1 into planar phospholipid bilayers under voltage-clamp conditions as previously described (3). Solutions were 250 mM HEPES, 80 mM Tris, 10 mM free Ca2+, pH 7.2, on the cis (cytoplasmic) side and 250 mM glutamic acid, 10 mM HEPES, pH to 7.2 with Ca(OH)2 (free [Ca2+] approximately 50 mM) on the trans (luminal) side of the bilayer. RyR1 open probability (Po) significantly increased after cytosolic addition of 1 µM simvastatin from 0.016±0.011 in control conditions to 0.064±0.021 (mean ± S.E.M., n=14, Student’s t-test, p<0.05). 10 µM cytosolic simvastatin produced further RyR1 activation (0.224±0.059, mean ± S.E.M., n=16, p<0.001). The increase in RyR1 Po was readily reversed to control values after washout of the cytosolic chamber (0.028±0.025, mean ± S.E.M., n=7). Simvastatin did not affect single-channel conductance under these conditions nor were significant changes in channel Po observed when simvastatin was added to the luminal side of RyR1. Unexpectedly, we found that 1 µM simvastatin appeared to inhibit cardiac RyR2 channels and that 10 µM simvastatin had no observable effect on RyR2 activity. Our data indicate that simvastatin can directly modulate RyR channel function although it may exert opposing actions at low concentrations, by inhibiting cardiac RyR2 and activating skeletal RyR1 channels. In line with these results, in permeabilised cardiac and skeletal myocytes, 10 µM simvastatin increased the frequency of Ca2+ sparks in skeletal cells but decreased frequency in cardiac myocytes (see Lotteau et al. this meeting). These actions of simvastatin may contribute to the reported muscular side effects and help to explain why these are of skeletal rather than cardiac origin. Since statins are prescribed to patients with a history of heart disease, it will be important to investigate the interactions between statin molecules and cardiac RyR2 in more detail in order to better understand the cardioprotective actions of statins. Funded by the British Heart Foundation.