Characterization of endothelial factors involved in the vasodilatory effect of simvastatin in aorta and small mesenteric artery of the rat

1 Vascular effects of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) r eductase inhibitor, simvastatin, were studied in conductance (aorta) and re sistance vessels (branch II or III of superior mesenteric artery, SMA) of t he rat (12-14 weeks old). 2 Simvastatin produced relaxation of both aorta and SMA, with and without f unctional endothelium. These responses were inhibited by the product of HMG -CoA reductase, mevalonate (1 mmol(-1)). 3 In vessels with functional endothelium, the NO-synthase inhibitor, L-NG-n itroarginine (L-NOARG, 30 mu mol l(-1)), inhibited simvastatin-induced rela xation. In the presence of L-NOARG, relaxation to simvastatin was lower in vessels with endothelium than in endothelium-denuded arteries without L-NOA RG. 4 The cyclo-oxygenase inhibitor, indomethacin (10 mu mol l(-1)), abolished endothelium-dependent component of the response to simvastatin in both arte ries. The combination of L-NOARG plus indomethacin did not produce further inhibition. The T-p receptor antagonist, GR32191B (3 mu mol l(-1)), did not affect relaxation in aorta but it reduced response to low concentrations o f simvastatin in SMA. However, the inhibitory effect of L-NOARG was less ma rked in the presence of GR 32191B in aorta but not in SMA. 5 The endothelium-dependent relaxation to simvastatin was inhibited by the superoxide dismutase (SOD, 100 u ml(-1)) or by the tyrosine kinase inhibito r, genistein (30 mu mol l(-1)) in the two arteries. 6 The present study shows that simvastatin produces relaxation of conductan ce and small arteries through mevalonate-sensitive pathway. The endothelium -dependent relaxation to simvastatin involves both NO and vasodilator eicos anoids by a mechanism sensitive to SOD, and to genistein. Also, the results highlighted participation in the aorta of endothelial vasoconstrictor eico sanoids acting on the T-p receptor after blockage of NO synthase only.