Improvement of age-related endothelial dysfunction by simvastatin: effect on NO and COX pathways.

The effects of oral administration of the HMG-CoA reductase inhibitor, simvastatin (SV), on age-related endothelial dysfunction were investigated in the aorta of male Wistar rats. Adult (12-14 weeks) and old (60-80 weeks) rats were treated daily for 12 weeks with either vehicle or SV (1 mg kg(-1)). In old rats, SV treatment did not significantly affect systolic blood pressure and LDL-cholesterol, but it reduced plasma cholesterol, triglycerides and oxidised LDL though it did not affect total antioxidant status. SV improved endothelium-dependent relaxation to acetylcholine and A-23187 in vessels from aged, but not adult, rats. This effect was linked to a greater NO vasodilatation via an increased expression of endothelial NO-synthase. A mechanism sensitive to superoxide dismutase and catalase also accounts for enhanced endothelial vasodilatation. Finally, SV did not affect the release of prostacyclin, but it inhibited the generation of thromboxane (TX) A2 from COX-2 isoform. The effect of the latter was sensitive to the Tp receptor antagonist, ICI-192,605. The present study provides evidence that oral administration of SV improves endothelial dysfunction in the aorta from aged rats by mechanisms associated with enhanced NO vasodilatation, reduced release of TXA2 from cyclo-oxygenase, and increased antioxidant properties of the vessel wall. These data underscore a new therapeutic perspective for SV in age-related endothelial dysfunction.