Endothelin blocking drugs have vasodilator effects mediated at least in part via the nitric oxide system. Hypercholesterolaemia is associated with vascular dysfunction manifest as impaired nitric oxide-mediated vasodilatation and arterial stiffness. Treatment with HMG CoA reductase inhibitors (statins) has proven mortality benefits in a range of patient populations. Subjects (n = 5) received either placebo or 800 mug cerivastatin for an 8-week period in a double-blind, placebo-controlled, cross-over study. Cerivastatin reduced the total plasma cholesterol compared with baseline by 27% (5.4 +/- 0.4 mmol/L versus 7.3 +/- 0.4 mmol/L, P = 0.04). Selective endothelin-A receptor blockade caused an increase in forearm blood flow (FBF) (18.0 +/- 7.2%, P = 0.04). Compared with placebo, cerivastatin therapy caused a trend towards a further increase in FBF (18.0 +/- 7.2% versus 52.0 +/- 19.0%, P = 0.06). Selective endothelin-B receptor blockade reduced FBF (-11.0 +/- 3.9%, P = 0.02) with no difference between placebo and cerivastatin therapy (-11.0 +/- 3.9% versus -13.0 +/- 3.6%, P = 0.9). Combined endothelin-A/endothelin-B receptor blockade increased FBF (39.8 +/- 13.4%, P < 0.01) with no difference between placebo and cerivastatin therapy (39.8 +/- 13.4% versus 42.4 +/- 19.0%, P = 0.7). There was a trend towards a reduction in the augmentation index between cerivastatin and placebo (6.2 +/- 2.7 versus 9.1 +/- 2.4, n = 5, P = 0.4) compared with baseline (7.2 +/- 1.0). In conclusion, statin therapy may decrease large artery stiffness and increase the vasodilating effects of endothelin-A receptor blockade.