Effects of statins on vascular function of endothelin-1.

1. Although statins have been reported to inhibit the prepro-endothelin-1 (ET-1) gene transcription in endothelial cells, their effects on the vascular function of ET-1 have not been explored. We, therefore, examined the effects of statins on contraction and DNA synthesis mediated by ET-1 in vascular smooth muscle. The effects of statins on contraction induced by ET-1 were compared to those mediated by noradrenaline (NA) and KCl. 2. Simvastatin (SV) induced a concentration-dependent relaxation of tonic contraction mediated by ET-1 (10 nM) (IC50 value of 1.3 microM). The relaxation was also observed in rings precontracted with NA (0.1 microM) and KCl (60 mM). In contrast, pravastatin did not have any effect on the contractions. 3. Endothelial denudation or pretreatment with L-NAME did not prevent the relaxation, but did reduce the relaxant activity of SV. 4. SV prevented Rho activation caused by ET-1 and KCl in aortic homogenates, as assessed by a Rho pulldown assay. 5. The Rho kinase inhibitor HA-1077 mimicked the effects of SV on tonic contractions induced by ET-1, NA and KCl. 6. Pretreatment with the Kv channels inhibitor, 4-aminopyridine, attenuated the ability of SV to relax contractions mediated by ET-1 and NA. 7. In quiescent VSM cells, SV significantly inhibited DNA synthesis and Rho translocation stimulated by ET-1, as assessed by [3H]thymidine incorporation and Western blot, respectively. 8. Inhibition of Rho geranylgeranylation by GGTI-297, or treatment with HA-1077, mimicked the effects of SV on DNA synthesis stimulated by ET-1. 9. The results show that the statin potently inhibits both ET-1-mediated contraction and DNA synthesis via multiple mechanisms. Clinical benefits of statins may result, in part, from their effects on vascular function of ET-1.