Simvastatin preserves coronary endothelial function in hypercholesterolemia in the absence of lipid lowering

Recent evidence suggests that some benefit from the 3-hydroxy-3-methylgluta ryl coenzyme A reductase inhibitors may occur independent of lipid lowering . We aimed to determine the effect Of simvastatin on coronary endothelial f unction, endothelial NO synthase (eNOS) expression, and oxidative stress in experimental hypercholesterolemia (HC) in the absence of cholesterol lower ing. Pigs were randomized to 3 experimental groups: normal diet (N group), high cholesterol diet (HC group), and HC diet with simvastatin (HC+S group) for 12 weeks. Low density lipoprotein cholesterol was similarly increased in the HC and HCS-S groups compared with the N group. In vitro analysis of coronary large- and small-vessel endothelium-dependent vasorelaxation was p erformed. The mean vasorelaxation of epicardial vessels to bradykinin was s ignificantly attenuated in the HC group compared with the N group (32.3+/-1 .2% versus 42.9+/-1.6%, respectively; P<0.0001), This attenuation was signi ficantly reversed in the HC+S group (38.7+/-1.5%, P<0.005 versus HC group). The maximal vasorelaxation to substance P was significantly attenuated in the HC group compared with the N group (50.5+/-11.9% versus 79.3+/-5.3%, re spectively; P<0.05). This attenuated response was normalized in the HC+S gr oup (74.9+/-4.1%, P<0.05 versus PIC group). The maximal arteriolar vasorela xation to bradykinin was also significantly attenuated in the HC group comp ared with the N group (71.9+/-4.9% versus 96.8+/-1.34%, respectively; P<0.0 05), This was reversed in the HC+S group (98.4+/-0.6%, P<0.0001 versus HC g roup). Western blotting of coronary tissue homogenates for eNOS demonstrate d a decrease in protein levels in the HC group compared with the N group, w ith normalization in the HC+S group. Elevation of plasma F-2-isoprostanes a nd thiobarbituric acid-reactive substances, markers of oxidative stress, oc curred in the PIC compared with the N group. These changes were reversed in the HC+S group. Tn summary, simvastatin preserves endothelial function in coronary epicardial vessels and arterioles in experimental HC tin the absen ce of cholesterol lowering) in association with an increase in coronary eNO S levels and a decrease in oxidative stress, These alterations may play a r ole in the reduction in cardiac events after treatment with 3-hydroxy-3-met hylglutaryl coenzyme A reductase inhibitors.