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

ABSTRACT: 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.

SUBMITTER: Alvarez De Sotomayor M

PROVIDER: S-EPMC1572427 | biostudies-other | 2000 Nov

REPOSITORIES: biostudies-other

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

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