Rosuvastatin improves basal nitric oxide activity of the renal vasculature in patients with hypercholesterolemia



      Impaired endothelium-dependent vasodilation represents an early manifestation of atherosclerosis. Prospective studies have demonstrated that impaired endothelial function in the peripheral circulation of hypercholesterolemic patients predicts CV events and can be restored by statin treatment. Whether this also holds true in the renal circulation has not yet been adequately addressed.


      In a double-blind, randomized, placebo-controlled cross-over trial, 40 hypercholesterolemic patients were randomly assigned to receive rosuvastatin (10 mg/day) and matching placebo. The primary objective of the study was to assess the effect of 6-week treatment with rosuvastatin on basal NOS activity of the renal vasculature, as assessed by measuring renal plasma flow (RPF) both before and after blockade of NOS with systemic infusion of NG-monomethyl-l-arginine (l-NMMA). In a subgroup of 20 patients we also studied the effects of a 3-day treatment regimen.


      Compared to placebo treatment, rosuvastatin decreased LDL-cholesterol levels both after 3 days and 6 weeks of treatment. The decrease in RPF in response to l-NMMA was significantly more pronounced after 6-week therapy with rosuvastatin compared to placebo (−13.7 ± 1.0% versus −11.3 ± 0.7%; p = 0.046), indicating increased basal NOS activity with rosuvastatin treatment. A trend towards improved basal NOS activity was already evident after 3-day treatment.


      Treatment with rosuvastatin improved basal NOS activity in the renal circulation of hypercholesterolemic patients, suggestive of a nephroprotective effect. In view of the close relation between altered renal function and cardiovascular events, these nephroprotective effects may contribute to the improved CV prognosis associated with statin treatment.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Vane J.R.
        • Anggard E.E.
        • Botting R.M.
        Regulatory functions of the vascular endothelium.
        N Engl J Med. 1990; 323: 27-36
        • Govers R.
        • Rabelink T.J.
        Cellular regulation of endothelial nitric oxide synthase.
        Am J Physiol Renal Physiol. 2001; 280: F193-F206
        • Wolfrum S.
        • Jensen K.S.
        • Liao J.K.
        Endothelium-dependent effects of statins.
        Arterioscler Thromb Vasc Biol. 2003; 23: 729-736
        • John S.
        • Schlaich M.
        • Langenfeld M.
        • et al.
        Increased bioavailability of nitric oxide after lipid-lowering therapy in hypercholesterolemic patients: A randomized, placebo-controlled, double-blind study.
        Circulation. 1998; 98: 211-216
        • Perticone F.
        • Ceravolo R.
        • Maio R.
        • et al.
        Effects of atorvastatin and vitamin C on endothelial function of hypercholesterolemic patients.
        Atherosclerosis. 2000; 152: 511-518
      1. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344(8934):1383–9.

        • Sacks F.M.
        • Pfeffer M.A.
        • Moye L.A.
        • et al.
        The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators.
        N Engl J Med. 1996; 335: 1001-1009
        • Laufs U.
        • La Fata V.
        • Plutzky J.
        • Liao J.K.
        Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors.
        Circulation. 1998; 97: 1129-1135
        • Fleischmann E.H.
        • Schlaich M.P.
        • Schmidt B.M.
        • Oehmer S.
        • Schmieder R.E.
        Hypercholesterolaemia and treatment with statins do not alter l-arginine-induced changes of renal haemodynamics.
        Nephrol Dial Transplant. 2002; 17: 1758-1765
        • John S.
        • Delles C.
        • Jacobi J.
        • et al.
        Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks.
        J Am Coll Cardiol. 2001; 37: 1351-1358
        • Hillege H.L.
        • Fidler V.
        • Diercks G.F.
        • et al.
        Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population.
        Circulation. 2002; 106: 1777-1782
        • Anavekar N.S.
        • McMurray J.J.
        • Velazquez E.J.
        • et al.
        Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.
        N Engl J Med. 2004; 351: 1285-1295
        • Arnlov J.
        • Evans J.C.
        • Meigs J.B.
        • et al.
        Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study.
        Circulation. 2005; 112: 969-975
        • de Zeeuw D.
        Albuminuria, not only a cardiovascular/renal risk marker, but also a target for treatment?.
        Kidney Int Suppl. 2004; 92: S2-S6
        • Cole B.R.
        • Giangiacomo J.
        • Ingelfinger J.R.
        • Robson A.M.
        Measurement of renal function without urine collection. A critical evaluation of the constant-infusion technic for determination of inulin and para-aminohippurate.
        N Engl J Med. 1972; 287: 1109-1114
        • Schmieder R.E.
        • Gatzka C.
        • Schobel H.
        • Schachinger H.
        • Weihprecht H.
        Renal hemodynamic response to stress is influenced by ACE-inhibitors.
        Clin Nephrol. 1994; 42: 381-388
        • Schmieder R.E.
        • Veelken R.
        • Schobel H.
        • et al.
        Glomerular hyperfiltration during sympathetic nervous system activation in early essential hypertension.
        J Am Soc Nephrol. 1997; 8: 893-900
        • Delles C.
        • Jacobi J.
        • Schlaich M.P.
        • John S.
        • Schmieder R.E.
        Assessment of endothelial function of the renal vasculature in human subjects.
        Am J Hypertens. 2002; 15: 3-9
        • Delles C.
        • Klingbeil A.U.
        • Schneider M.P.
        • et al.
        The role of nitric oxide in the regulation of glomerular haemodynamics in humans.
        Nephrol Dial Transplant. 2004; 19: 1392-1397
        • Schlaich M.P.
        • Jacobi J.
        • John S.
        • et al.
        Is l-arginine infusion an adequate tool to assess endothelium-dependent vasodilation of the human renal vasculature?.
        Clin Sci (Lond). 2000; 99: 293-302
        • Wierema T.K.
        • Houben A.J.
        • Kroon A.A.
        • et al.
        Nitric oxide dependence of renal blood flow in patients with renal artery stenosis.
        J Am Soc Nephrol. 2001; 12: 1836-1843
        • Jacobi J.
        • Schneider M.P.
        • John S.
        • Schmieder R.E.
        Impact of NO-synthase inhibition on renal hemodynamics in normotensive and hypertensive subjects.
        J Hypertens. 2002; 20: 525-530
        • John S.
        • Schneider M.P.
        • Delles C.
        • Jacobi J.
        • Schmieder R.E.
        Lipid-independent effects of statins on endothelial function and bioavailability of nitric oxide in hypercholesterolemic patients.
        Am Heart J. 2005; 149: 473
        • Boger R.H.
        • Bode-Boger S.M.
        • Szuba A.
        • et al.
        Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia.
        Circulation. 1998; 98: 1842-1847
        • Boger R.H.
        • Bode-Boger S.M.
        • Matsuoka H.
        • et al.
        Is asymmetric dimethylarginine a novel marker of atherosclerosis?.
        Circulation. 2000; 101: E160-E161
        • Lu T.M.
        • Ding Y.A.
        • Leu H.B.
        • et al.
        Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia.
        Am J Cardiol. 2004; 94: 157-161
        • Fried L.F.
        • Orchard T.J.
        • Kasiske B.L.
        Effect of lipid reduction on the progression of renal disease: a meta-analysis.
        Kidney Int. 2001; 59: 260-269
        • Vidt D.G.
        • Cressman M.D.
        • Harris S.
        • Pears J.S.
        • Hutchinson H.G.
        Rosuvastatin-induced arrest in progression of renal disease.
        Cardiology. 2004; 102: 52-60
        • Vidt D.G.
        • Harris S.
        • McTaggart F.
        • et al.
        Effect of short-term rosuvastatin treatment on estimated glomerular filtration rate.
        Am J Cardiol. 2006; 97: 1602-1606
        • Tonelli M.
        • Isles C.
        • Craven T.
        • et al.
        Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease.
        Circulation. 2005; 112: 171-178
        • Geluk C.A.
        • Asselbergs F.W.
        • Hillege H.L.
        • et al.
        Impact of statins in microalbuminuric subjects with the metabolic syndrome: a substudy of the PREVEND Intervention Trial.
        Eur Heart J. 2005; 26: 1314-1320