Modulation by simvastatin of iberiotoxin-sensitive, Ca ²⁺- activated K ⁺ channels of porcine coronary artery smooth muscle cells

Background and Purpose: Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors) have been demonstrated to reduce cardiovascular mortality. It is unclear how the expression level of HMG CoA reductase in cardiovascular tissues compares with that in cells derived from the liver. We hypothesized that this enzyme exists in different cardiovascular tissues, and simvastatin modulates the vascular iberiotoxin-sensitive Ca ²⁺- activated K ⁺ (BK _Ca) channels. Experimental Approaches: Expression of HMG CoA reductase in different cardiovascular preparations was measured. Effects of simvastatin on BK _Ca channel gatings of porcine coronary artery smooth muscle cells were evaluated. Key Results: Western immunoblots revealed the biochemical existence of HMG CoA reductase in human cardiovascular tissues and porcine coronary artery. In porcine coronary artery smooth muscle cells, extracellular simvastatin (1, 3 and 10 μM) (hydrophobic), but not simvastatin Na ⁺ (hydrophilic), inhibited the BK _Ca channels with a minimal recovery upon washout. Isopimaric acid (10 μM)-mediated enhancement of the BK _Ca amplitude was reversed by external simvastatin. Simvastatin Na ⁺ (10 μM, applied internally), markedly attenuated isopimaric acid (10 μM)-induced enhancement of the BK _Ca amplitude. Reduced glutathione (5 mM; in the pipette solution) abolished simvastatin -elicited inhibition. Mevalonolactone (500 μM) and geranylgeranyl pyrophosphate (20 μM) only prevented simvastatin (1 and 3 μM)-induced responses. simvastatin (10 μM) caused a rottlerin (1 μM)-sensitive (cycloheximide (10 μM)-insensitive) increase of PKC-δ protein expression. Conclusions and Implications: Our results demonstrated the biochemical presence of HMG CoA reductase in different cardiovascular tissues, and that simvastatin inhibited the BK _Ca channels of the arterial smooth muscle cells through multiple intracellular pathways.