Fluvastatin attenuates nitrate tolerance in patients with ischemic heart disease complicating hypercholesterolemia

Background: Long-term administration of nitrates results in the development of tolerance. Nitrate tolerance is considered to occur in association with oxidative stress, although its underlying mechanisms are multi-factorial. Fluvastatin, a newly developed statin, is considered to have not only a cholesterol-lowering effect but also anti-oxidative properties. Methods: In this study, the effect of fluvastatin on nitrate tolerance was investigated in 12 dyslipidemic patients (nine men and three women, aged 63.5+/-6.7 years), who were complicated with ischemic heart disease and had received organic nitrates for a long period. Results: Four months after fluvastatin therapy, symptoms of angina were significantly reduced. Consumption of sublingual nitrates over 2 weeks significantly decreased (14.4+/-11.2 to 2.3+/-2.5 tablets, P<0.01). In exercise stress testing, exercise duration was significantly prolonged (275+/-73 to 360+/-86 s, P<0.01) and the blood pressure-heart rate products significantly increased (16 368+/-2246 to 18 381+/-1772, P<0.01). Both the percent change in forearm blood flow with reactive hyperemia (232+/-83 to 282+/-104%, P<0.05) and that after sublingual nitroglycerine (2.5+/-4.7 to 5.8+/-4.7%, P<0.05) were increased. Although the levels of total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol were unchanged, the serum anti-Ox-LDL titer (16.7+/-6.3 to 13.4+/-5.4 AcU/ml, P<0.05) and 8-OHdG level (1.11+/-0.34 to 0.73+/-0.34 ng/ml, P<0.05) decreased. Conclusions: Fluvastatin attenuated nitrate tolerance in dyslipidemic patients complicated with ischemic heart disease who had been receiving organic nitrates over long period. The anti-oxidative effect of fluvastatin may attenuate nitrate tolerance. (C) 2003 Elsevier Ireland Ltd. All rights reserved.