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) reductase inhibitor, simvastatin, were studied in conductance (aorta) and resistance vessels (branch II or III of superior mesenteric artery, SMA) of the rat (12 - 14 weeks old). 2. Simvastatin produced relaxation of both aorta and SMA, with and without functional endothelium. These responses were inhibited by the product of HMG-CoA reductase, mevalonate (1 mmol l(-1)). 3. In vessels with functional endothelium, the NO-synthase inhibitor, L-N(G)-nitroarginine (L-NOARG, 30 micromol l(-1)), inhibited simvastatin-induced relaxation. In the presence of L-NOARG, relaxation to simvastatin was lower in vessels with endothelium than in endothelium-denuded arteries without L-NOARG. 4. The cyclo-oxygenase inhibitor, indomethacin (10 micromol l(-1)), abolished endothelium-dependent component of the response to simvastatin in both arteries. The combination of L-NOARG plus indomethacin did not produce further inhibition. The T(p) receptor antagonist, GR 32191B (3 micromol l(-1)), did not affect relaxation in aorta but it reduced response to low concentrations of simvastatin in SMA. However, the inhibitory effect of L-NOARG was less marked 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 inhibitor, genistein (30 micromol l(-1)) in the two arteries. 6. The present study shows that simvastatin produces relaxation of conductance and small arteries through mevalonate-sensitive pathway. The endothelium-dependent relaxation to simvastatin involves both NO and vasodilator eicosanoids by a mechanism sensitive to SOD, and to genistein. Also, the results highlighted participation in the aorta of endothelial vasoconstrictor eicosanoids acting on the T(p) receptor after blockage of NO synthase only.