Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions
Open accessAbstract
Objectives We tested the hypothesis that pravastatin (PRA) activates endothelial nitric oxide synthase (eNOS).Background Pravastatin has been found to have clinical benefits beyond those predicted by its actions in reducing plasma low density lipoprotein cholesterol (LDL). Both PRA and simvastatin (SIM) are equally effective in reducing LDL, but only PRA reduces platelet aggregation and is an effective vasodilator. Nitric oxide (NO) also inhibits platelet aggregation and vasodilates.Methods We determined PRA and SIM effects on vasorelaxation in aortic rings and NO production by cultured bovine aortic endothelial cells. Nitric oxide was measured by using a NO electrode and by an assay for conversion of hemoglobin to methemoglobin. Specificity of NOS activation was tested by using the NOS inhibitor nitro-L-arginine methyl ester (L-NAME, 1 mmol/liter) in the presence or absence of excess L-arginine (L-ARG, 1 mmol/liter).Results Endothelium-dependent vasorelaxation was maximal with acetylocholine (ACH, 100%), followed by PRA (62.8%) and then SIM (37.1%). Direct measurement of NO confirmed that vasorelaxation is due to NO release and showed that PRA and ACH had similar dose-dependent effects on NO production, while SIM was only 25% to 30% as effective. Methemoglobin assay confirmed these results and demonstrated their specificity for NOS activity. The L-NAME blunted the responses to 45% of initial values. Excess L-ARG reversed this effect and potentiated NO production to 133% of initial levels.Conclusions Both PRA and SIM activate eNOS, but SIM is much less effective. Clinical benefits with PRA not explained by LDL reductions may be the result of an independent action of PRA on eNOS activation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Sacks, F. M., Pfeffer, M. A., Moye, L. A., Rouleau, J. L., Rutherford, J. D., Cole, T. G., Brown, L., Warnica, J. W., Arnold, J. M. O., Wun, C.-C., et al. (1996) · New England Journal of Medicine · doi:10.1056/nejm199610033351401 · Cited by 7,439 · see citing works
Biochemistry of nitric oxide and its redox-activated forms
Stamler, J. S., Singel, D. J., & Loscalzo, J. (1992) · Science · doi:10.1126/science.1281928 · Cited by 2,744 · see citing works
Steinberg, H. O., Brechtel, G., Johnson, A., Fineberg, N. S., & Baron, A. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117433 · Cited by 1,216 · see citing works
Tatti, P., Pahor, M., Byington, R. P., Mauro, P. D., Guarisco, R., Strollo, G., & Strollo, F. (1998) · Diabetes Care · doi:10.2337/diacare.21.4.597 · Cited by 843 · see citing works
Pedersen, T. R., OLSSON, A. G., Færgeman, O., KJEKSHUS, J. K., Wedel, H., Berg, K., Wilhelmsen, L., Haghfelt, T. H., Þorgeirsson, G., Pyörälà, K., et al. (1998) · Circulation · doi:10.1161/01.cir.97.15.1453 · Cited by 618 · see citing works
Collins, P. D., Rosano, G. M. C., Sarrel, P. M., Ulrich, L. G., Adamopoulos, S. N., Beale, C. M., McNeill, J. G., & Poole-Wilson, P. A. (1995) · Circulation · doi:10.1161/01.cir.92.1.24 · Cited by 530 · see citing works
Pritchard, K. A., Groszek, L., Smalley, D. M., Sessa, W. C., Wu, M., Villalon, P., Wolin, M. S., & Stemerman, M. B. (1995) · Circulation Research · doi:10.1161/01.res.77.3.510 · Cited by 471 · see citing works
Hamelin, B. A. (1998) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(97)01147-4 · Cited by 468 · see citing works
Williams, J. K., Sukhova, G., Herrington, D., & Libby, P. (1998) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(97)00537-8 · Cited by 401 · see citing works
Laufs, U., Fata, V. L., & Liao, J. K. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.50.31725 · Cited by 384 · see citing works
Sacks, F. M., Moyé, L. A., Davis, B. R., Cole, T. G., Rouleau, J. L., Nash, D. T., Pfeffer, M. A., & D, E. B. M. (1998) · Circulation · doi:10.1161/01.cir.97.15.1446 · Cited by 373 · see citing works
Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism.
Cockcroft, J. R., Chowienczyk, P., Brett, S., Chen, C., Dupont, A. G., Nueten, L. V., Wooding, S. J., & Ritter, J. M. (1995) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)10549-1 · Cited by 324 · see citing works
Reduction in Cardiovascular Events During Pravastatin Therapy
Byington, R. P., Jukema, J. W., Salonen, J. T., Pitt, B., Bruschke, A. V. G., Hoen, H. M., Furberg, C. D., & Mancini, G. B. J. (1995) · Circulation · doi:10.1161/01.cir.92.9.2419 · Cited by 282 · see citing works
Amlodipine Releases Nitric Oxide From Canine Coronary Microvessels
Zhang, X., & Hintze, T. H. (1998) · Circulation · doi:10.1161/01.cir.97.6.576 · Cited by 268 · see citing works
Böger, R. H., Bode-Böger, S. M., Mügge, A., Kienke, S., Brandes, R., Dwenger, A., & Frölich, J. C. (1995) · Atherosclerosis · doi:10.1016/0021-9150(95)05582-h · Cited by 252 · see citing works
ACE Inhibitors Promote Nitric Oxide Accumulation to Modulate Myocardial Oxygen Consumption
Zhang, X., Xie, Y.-W., Nasjletti, A., Xu, X., Wolin, M. S., & Hintze, T. H. (1997) · Circulation · doi:10.1161/01.cir.95.1.176 · Cited by 181 · see citing works
Dietary l-Arginine Supplementation Normalizes Platelet Aggregation in Hypercholesterolemic Humans
Wolf, A., Zalpour, C., Theilmeier, G., Wang, B., Ma, A. O., Anderson, B. E., Tsao, P. S., & Cooke, J. P. (1997) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(97)00523-8 · Cited by 171 · see citing works
Feelisch, M., & Kelm, M. (1991) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(05)81290-2 · Cited by 162 · see citing works
Effects of Lipid-Lowering Agents in the Dahl Salt-Sensitive Rat
Wilson, T. W., Alonso‐Galicia, M., & Roman, R. J. (1998) · Hypertension · doi:10.1161/01.hyp.31.1.225 · Cited by 108 · see citing works
Yokokawa, K., Tahara, H., Kohno, M., Mandal, A. K., Yanagisawa, M., & Takeda, T. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116805 · Cited by 101 · see citing works
Effect of atorvastatin on plasma fibrinogen
Wierzbicki, A. S., Lumb, P. J., Seinra, Y. K., & Crook, M. A. (1998) · The Lancet · doi:10.1016/s0140-6736(05)78556-1 · Cited by 94 · see citing works
van Vliet, A. K., van Thiel, G. C. F., Huisman, R. H., Moshage, H. J., Yap, S. H., & Cohen, L. (1995) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(94)00176-y · Cited by 87 · see citing works
Direct measurement of nitric oxide release from vascular endothelial cells
Guo, J. P., Murohara, T., Buerke, M., Scalia, R. G., & Lefer, A. M. (1996) · Journal of Applied Physiology · doi:10.1152/jappl.1996.81.2.774 · Cited by 82 · see citing works
Muramatsu, J. (1997) · Atherosclerosis · doi:10.1016/s0021-9150(96)06024-8 · Cited by 74 · see citing works
Amidative peptide processing and vascular function
Oldham, C. D., Li, C., Feng, J. X., Scott, R. O., Wang, W. Z., Moore, A. B., Girard, P. R., Huang, J., Caldwell, R. B., Caldwell, R. W., et al. (1997) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1997.273.6.c1908 · Cited by 55 · see citing works
Contribution of nitric oxide to the endothelium‐dependent hyperpolarization in rat aorta.
Vanheel, B., de Voorde, J. V., & Leusen, I. R. (1994) · The Journal of Physiology · doi:10.1113/jphysiol.1994.sp020068 · Cited by 49 · see citing works
Jay, M. T., Chirico, S., Siow, R., Bruckdorfer, K. R., Jacobs, M., Leake, D. S., Pearson, J. D., & Mann, G. E. (1997) · Experimental Physiology · doi:10.1113/expphysiol.1997.sp004030 · Cited by 48 · see citing works
Suzuki, Y., Tateishi, N., SOUTANI, M., & Maeda, N. (2008) · International Journal of Microcirculation · doi:10.1159/000179172 · Cited by 46 · see citing works
Lacoste, L., & Lam, J. Y. T. (1996) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(96)82590-3 · Cited by 38 · see citing works
Keh, D., Gerlach, M., rer, I. K., Seiler, S., Kerner, T., Falke, K. J., & Gerlach, H. (1996) · Blood Coagulation & Fibrinolysis · doi:10.1097/00001721-199609000-00007 · Cited by 37 · see citing works
Delyani, J. A., Nossuli, T. O., Scalia, R. G., Thomas, G., Garvey, D. S., & Lefer, A. M. (1996) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)21274-5 · Cited by 29 · see citing works
Endothelium-dependent relaxation of rat thoracic aorta by amrinone-induced nitric oxide release
Mori, K. J., Takeuchi, S., Moritoki, H., Tsuchiya, K., Nakaya, Y., Matsuoka, S., & Kuroda, Y. (1996) · European Heart Journal · doi:10.1093/oxfordjournals.eurheartj.a014850 · Cited by 25 · see citing works
Califf, R. M., & Granger, C. B. (1998) · Diabetes Care · doi:10.2337/diacare.21.4.655 · Cited by 22 · see citing works
Ma, L., Morita, I., & Murota, S. (1994) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1994.2331 · Cited by 12 · see citing works
L-arginine in the development and reversal of tolerance to nitroglycerin
Abou-Mohamed, G. (1996) · American Journal of Hypertension · doi:10.1016/0895-7061(96)81543-3 · Cited by 3 · see citing works
Abou-Mohamed, G., Kaesemeyer, W., Papapetropoulos, A., Catravas, J. D., & Caldwell, R. W. (1996) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(96)80631-0 · Cited by 2 · see citing works
Flagged first, then by citations
1 of the 38 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Kaesemeyer WH, Abou-Mohamed G, Crute TD, Caldwell RW. Nitrates supplemented with L-arginine for the reversal and treatment of nitrate tolerance: two case reports. Appl Cardiopulmon Pathophys 1997;6:255-62.
Cited by
Sorted by citations
Statins and the risk of dementia
Jick, H., Zornberg, G. L., Jick, S. S., Seshadri, S. S., & Drachman, D. (2000) · The Lancet · doi:10.1016/s0140-6736(00)03155-x · Cited by 1,748 · see citing works
Kureishi, Y., Luo, Z., Shiojima, I., Bialik, A., Fulton, D. J., Lefer, D. J., Sessa, W. C., & Walsh, K. X. (2000) · Nature Medicine · doi:10.1038/79510 · Cited by 1,438 · see citing works
Drug Treatment of Lipid Disorders
Knopp, R. H. (1999) · New England Journal of Medicine · doi:10.1056/nejm199908123410707 · Cited by 846 · see citing works
New insights into the pharmacodynamic and pharmacokinetic properties of statins
Corsini, A., Bellosta, S., Baetta, R., Fumagalli, R., Paoletti, R., & Bernini, F. (1999) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(99)00045-5 · Cited by 796 · see citing works
Statin effects beyond lipid lowering—are they clinically relevant?
Bonetti, P. O. (2003) · European Heart Journal · doi:10.1016/s0195-668x(02)00419-0 · Cited by 524 · see citing works
“80 Importantly, this effect was associated with an upregulation of vascular eNOS protein levels and a consecutive increase in NO bioavailability, indicating again an antiinflammatory role for NO.”
InfluentialFulton, D. J., Gratton, J., & Sessa, W. C. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)29198-9 · Cited by 495 · see citing works
Withdrawal of Statins Increases Event Rates in Patients With Acute Coronary Syndromes
Heeschen, C., Hamm, C. W., Laufs, U., Snapinn, S. M., Böhm, M., & White, H. D. (2002) · Circulation · doi:10.1161/01.cir.0000012530.68333.c8 · Cited by 480 · see citing works
Féron, O., Dessy, C., Desager, J., & Balligand, J. (2001) · Circulation · doi:10.1161/01.cir.103.1.113 · Cited by 418 · see citing works
Non-lipid-related effects of statins
Bellosta, S., Fed, N., Bernini, F., Paoletti, R., & Corsini, A. (2000) · Annals of Medicine · doi:10.3109/07853890008998823 · Cited by 332 · see citing works
Statin treatment withdrawal in ischemic stroke
Blanco, M., Nombela, F., Castellanos, M., Rodríguez‐Yáñez, M., García-Gil, M., Leira, R., Lizasoaín, I., Serena, J. L., Vivancos, J., Moro, M. Á., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000269789.09277.47 · Cited by 330 · see citing works
Antidepressant-Induced Sexual Dysfunction
Gregorian, R. S., Golden, K. A., Bahce, A., Goodman, C., Kwong, W. J., & Khan, Z. M. (2002) · Annals of Pharmacotherapy · doi:10.1345/aph.1a195 · Cited by 320 · see citing works
Pathophysiological implications of insulin resistance on vascular endothelial function
Wheatcroft, S. B., Williams, I. L., Shah, A. M., & Kearney, M. T. (2003) · Diabetic Medicine · doi:10.1046/j.1464-5491.2003.00869.x · Cited by 307 · see citing works
Statin treatment after onset of sepsis in a murine model improves survival.
Merx, M. W., Liehn, E. A., Graf, J., van de Sandt, A., Schaltenbrand, M., Schrader, J., Hanrath, P., & Weber, C. (2005) · Circulation · doi:10.1161/circulationaha.104.502195 · Cited by 287 · see citing works
Laufs, U., Gertz, K. R., Dirnagl, U., Böhm, M., Nickenig, G., & Endres, M. (2002) · Brain Research · doi:10.1016/s0006-8993(02)02649-5 · Cited by 279 · see citing works
Glorioso, N., Troffa, C., Filigheddu, F., Dettori, F., Soro, A., Parpaglia, P. P., Collatina, S., & Pahor, M. (1999) · Hypertension · doi:10.1161/01.hyp.34.6.1281 · Cited by 278 · see citing works
Beyond lipid lowering: the role of statins in vascular protection
Liao, J. K. (2002) · International Journal of Cardiology · doi:10.1016/s0167-5273(02)00195-x · Cited by 261 · see citing works
Laufs, U., Endres, M., Custodis, F., Gertz, K. R., Nickenig, G., Liao, J. K., & Böhm, M. (2000) · Circulation · doi:10.1161/01.cir.102.25.3104 · Cited by 261 · see citing works
Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities
Rosenson, R. S. (2003) · Atherosclerosis · doi:10.1016/s0021-9150(03)00239-9 · Cited by 260 · see citing works
Lefer, A. M. (2001) · Cardiovascular Research · doi:10.1016/s0008-6363(00)00247-9 · Cited by 248 · see citing works
Low-density lipoprotein-independent effects of statins
Davignon, J., & Laaksonen, R. (1999) · Current Opinion in Lipidology · doi:10.1097/00041433-199912000-00010 · Cited by 244 · see citing works
Implications of Early Structural-Functional Changes in the Endothelium for Vascular Disease
Simionescu, M. (2006) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000253884.13901.e4 · Cited by 240 · see citing works
Claudio Napoli, A., & Ignarro, L. J. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140226 · Cited by 216 · see citing works
Glutathione-S-Transferase M1, Obesity, Statins, and Autonomic Effects of Particles
Schwartz, J. D., Park, S. K., O’Neill, M. S., Vokonas, P., Sparrow, D., Weiss, S. T., & Kelsey, K. T. (2005) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200412-1698oc · Cited by 211 · see citing works
“In addition to lowering C-reactive protein concentrations (34), statins have been shown to decrease superoxide production (35), increase release of nitric oxide (NO) (36), which is an antioxidant as well as a vasodilator, and reduce markers of oxidative stress in APOE 1/ 1 mice (37).”
BackgroundRegulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs
Li, H., Wallerath, T., Münzel, T. F., & Förstermann, U. (2002) · Nitric Oxide · doi:10.1016/s1089-8603(02)00111-8 · Cited by 205 · see citing works
Tan, K. C. B., Chow, W.-S., Tam, S., Ai, V. H. G., Lam, C. H. L., & Lam, K. S. L. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.2.8249 · Cited by 202 · see citing works
Lefkou, E. E., Mamopoulos, A. M., Dagklis, T., Vosnakis, C., Rousso, D., & Girardi, G. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86957 · Cited by 192 · see citing works
“It is tempting to speculate that pravastatin might increase placental blood flow by its antiatherogenic effects and by stimulating the release of vasoactive substances from the endothelium, such as nitric oxide or carbon monoxide (42, 43).”
BackgroundHajjar, I. M., Schumpert, J., Hirth, V., Wieland, D. M., & Eleazer, G. P. (2002) · The Journals of Gerontology Series A · doi:10.1093/gerona/57.7.m414 · Cited by 188 · see citing works
Beyond lipid-lowering: effects of statins on endothelial nitric oxide
Laufs, U. (2003) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-002-0556-0 · Cited by 185 · see citing works
“In contrast, another study has shown pravastatin to be more effective than simvastatin at releasing NO from cultured bovine endothelial cells and producing NOmediated vasorelaxation of endothelium-intact rat aortic rings [50].”
BackgroundMethodResultParizadeh, S. M. R., Azarpazhooh, M. R., Moohebati, M., Nematy, M., Ghayour‐Mobarhan, M., Tavallaie, S., Rahsepar, A. A., Amini, M., Sahebkar, A., Mohammadi, M., et al. (2011) · Lipids · doi:10.1007/s11745-010-3517-x · Cited by 182 · see citing works
“It is also reported that statins can increase the release of NO [32], and also several statins have the ability to increase eNOS expression in the blood vessels of treated animals [33], resulting in the restoration of endothelial function.”
BackgroundBenefits of statin treatment in cardiac syndrome-X
Kayikcioglu, M. (2003) · European Heart Journal · doi:10.1016/s0195-668x(03)00478-0 · Cited by 173 · see citing works
Stokes, K. Y., Dugas, T. R., Tang, Y., Garg, H., Guidry, E., & Bryan, N. S. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01291.2008 · Cited by 171 · see citing works
“Interestingly, one of the most widely prescribed class of drugs for hypercholesterolemia, statins, not only reduces cholesterol levels but protects against many inflammatory facets of cardiovascular disease through the activation of eNOS (35), further supporting the concept that therapies designed to maintain/increase…”
BackgroundImpaired endothelial function in arterial hypertension and hypercholesterolemia
John, S., & Schmieder, R. E. (2000) · Journal of Hypertension · doi:10.1097/00004872-200018040-00002 · Cited by 165 · see citing works
Statins and cognitive function in the elderly
Bernick, C. B., Katz, R., Smith, N. L., Rapp, S., Bhadelia, R. A., Carlson, M. C., & Kuller, L. H. (2005) · Neurology · doi:10.1212/01.wnl.0000182897.18229.ec · Cited by 157 · see citing works
Early vascular benefits of statin therapy
Tsiara, S., Elisaf, M., & Mikhailidis, D. P. (2003) · Current Medical Research and Opinion · doi:10.1185/030079903125002225 · Cited by 157 · see citing works
Napoli, P. D. (2001) · Cardiovascular Research · doi:10.1016/s0008-6363(01)00306-6 · Cited by 154 · see citing works
Ray, B., & Lahiri, D. K. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.06.012 · Cited by 152 · see citing works
“Statins can increase cerebrovascular perfusion by upregulating eNOS [32] that might decrease the inflammation related to Ab deposition.”
BackgroundPleiotropic effects of statins
Farmer, J. A. (2000) · Current Atherosclerosis Reports · doi:10.1007/s11883-000-0022-3 · Cited by 151 · see citing works
John, S., Schneider, M. P., Delles, C., Jacobi, J., & Schmieder, R. E. (2005) · American Heart Journal · doi:10.1016/j.ahj.2004.06.027 · Cited by 145 · see citing works
Reduction in Blood Pressure With Statins Results From the UCSD Statin Study, a Randomized Trial
Golomb, B. A. (2008) · Archives of Internal Medicine · doi:10.1001/archinte.168.7.721 · Cited by 145 · see citing works
Use of Statins and Blood Pressure Control in Treated Hypertensive Patients with Hypercholesterolemia
Borghi, C., Prandin, M. G., Costa, F. V., Bacchelli, S., Esposti, D. D., & Ambrosioni, E. (2000) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-200004000-00006 · Cited by 143 · see citing works
BIRNBAUM, Y., Ye, Y., Rosanio, S., Tavackoli, S., Hu, Z.-Q., SCHWARZ, E., & Uretsky, B. F. (2004) · Cardiovascular Research · doi:10.1016/j.cardiores.2004.10.018 · Cited by 142 · see citing works
Atar, S., Ye, Y., Lin, Y., Freeberg, S. Y., Nishi, S. P. E., Rosanio, S., Huang, M.-H., Uretsky, B. F., Perez-Polo, J. R., & Birnbaum, Y. (2005) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01137.2005 · Cited by 142 · see citing works
“The infarct size (IS) limiting effect of statins is probably independent of their lipid-lowering properties (3; 4; 29; 30; 37; 45; 50; 52; 53) and may be mediated by enhancement of nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) (1; 3; 22; 31; 34-36; 53).”
Pravastatin Improves Cerebral Vasomotor Reactivity in Patients With Subcortical Small-Vessel Disease
Sterzer, P., Meintzschel, F., Rösler, A., Lanfermann, H., Steinmetz, H., & Sitzer, M. (2001) · Stroke · doi:10.1161/hs1201.099663 · Cited by 129 · see citing works
Tong, X.-K., Nicolakakis, N., Fernandes, P., Ongali, B., Brouillette, J., Quirion, R., & Hamel, E. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.06.003 · Cited by 122 · see citing works
Statins and their role in vascular protection
Mason, J. C. (2003) · Clinical Science · doi:10.1042/cs20030148 · Cited by 117 · see citing works
Terblanche, M., Almog, Y., Rosenson, R. S., Smith, T. S., & Hackam, D. G. (2006) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(06)70439-x · Cited by 117 · see citing works
Harris, M. B., Blackstone, M. A., Sood, S. G., Li, C., Goolsby, J. M., Venema, V. J., Kemp, B. E., & Venema, R. C. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00214.2004 · Cited by 117 · see citing works
“The first study to demonstrate that acute statin treatment of endothelial cells results in rapid NO release was conducted by measuring NO release with a NO electrode and by a methemoglobin technique (13).”
BackgroundMethodResultInfluentialInorganic nitrite therapy: historical perspective and future directions
Kevil, C. G., Kolluru, G. K., Pattillo, C. B., & Giordano, T. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.04.042 · Cited by 113 · see citing works
Therapeutic potential of statins in Alzheimer's disease
Kandiah, N., & Feldman, H. (2009) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2009.02.352 · Cited by 113 · see citing works
“Statins up regulate endothelial nitric oxide synthase (eNOS) [43,44], and reduce endothelin-1 [45] thereby resulting in relaxation of vascular smooth muscles and leading to vasodilatation.”
BackgroundWolfrum, S., Dendorfer, A., Schütt, M., Weidtmann, B., Heep, A., Tempel, K., Klein, H. H., Dominiak, P., & Richardt, G. (2004) · Journal of Cardiovascular Pharmacology · doi:10.1097/01.fjc.0000137162.14735.30 · Cited by 113 · see citing works
John, S., Delles, C., Jacobi, J., Schlaich, M. P., Schneider, M. P., Schmitz, G., & Schmieder, R. E. (2001) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(01)01128-7 · Cited by 110 · see citing works
“(25) and to decrease superoxide formation (26) by decreas-”
BackgroundLi, X.-H., Li, X.-H., Zhang, Y.-Y., Wang, M., & Wang, D. (2013) · Clinical Interventions in Aging · doi:10.2147/cia.s40405 · Cited by 108 · see citing works
“In addition, statins can also increase endothelial nitric oxide synthase (eNOS), and reduce endothelin-1, thereby resulting in relaxation of vascular smooth muscles and leading to vasodilatation.(13,14) Interestingly, inflammatory response has been demonstrated to be involved in the activation of plaque-associated mic…”
Miyahara, S., Kiryu, J., Yamashiro, K., Miyamoto, K., Hirose, F., Tamura, H., Katsuta, H., Nishijima, K., Tsujikawa, A., & Honda, Y. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63728-5 · Cited by 103 · see citing works
High-Sensitivity C-Reactive Protein and Atherosclerosis: From Theory to Therapy
Yu, H., & Rifai, N. (2000) · Clinical Biochemistry · doi:10.1016/s0009-9120(00)00186-7 · Cited by 102 · see citing works
Long-term effects of statins on arterial pressure and stiffness of hypertensives
Ichihara, A., Hayashi, M., Koura, Y., Tada, Y., Kaneshiro, Y., & Saruta, T. (2004) · Journal of Human Hypertension · doi:10.1038/sj.jhh.1001786 · Cited by 101 · see citing works
Antioxidative effects of statins
Adam, O., & Laufs, U. (2008) · Archives of Toxicology · doi:10.1007/s00204-008-0344-4 · Cited by 99 · see citing works
“Upregulation of eNOS expression is independent of cholesterol levels (Feron et al. 2001; Amin-Hanjani et al. 2001; Wagner et al. 2000; Laufs et al. 1999; Tannous et al. 1999; Kaesemeyer et al. 1999; Hernandez-Perera et al. 1998; Williams et al. 1998; Laufs et al. 1998).”
Isoprenoid metabolism and the pleiotropic effects of statins
Laufs, U., & Liao, J. K. (2003) · Current Atherosclerosis Reports · doi:10.1007/s11883-003-0008-z · Cited by 99 · see citing works
“Statins have been shown to increase NO production in humans [ 29 ].”
BackgroundHMG‐CoA reductase inhibition protects the diabetic myocardium from ischemia‐reperfusion injury
Lefer, D. J., Scalia, R. G., Jones, S. P., Sharp, B. R., Hoffmeyer, M. R., Farvid, A., Gibson, M. F., & Lefer, A. M. (2001) · The FASEB Journal · doi:10.1096/fj.00-0819fje · Cited by 96 · see citing works
Su, X., Xie, X., Liu, L., Lv, J., Song, F., Perkovic, V., & Zhang, H. (2016) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2016.07.033 · Cited by 95 · see citing works
Short-Term Atorvastatin Treatment Improves Endothelial Function in Hypercholesterolemic Women
Marchesi, S., Lupattelli, G., Siepi, D., Schillaci, G., Vaudo, G., Roscini, A. R., Sinzinger, H. F., & Mannarino, E. (2000) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-200011000-00011 · Cited by 95 · see citing works
Li, Y., Liu, Y., Fu, L., Mei, C., & Dai, B. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034450 · Cited by 94 · see citing works
Effect of simvastatin on renal function in autosomal dominant polycystic kidney disease
van Dijk, M. A., Kamper, A. M., van Veen, S., Souverijn, J. H. M., & Blauw, G. J. (2001) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/16.11.2152 · Cited by 94 · see citing works
Effects of Atorvastatin on Coronary Flow Reserve in Patients with Slow Coronary Flow
Çalışkan, M., Erdoğan, D., Güllü, H., Topçu, S., Çiftçi, Ö., Yı́ldı́rı́r, A., & Müderrisoğlu, H. (2007) · Clinical Cardiology · doi:10.1002/clc.20140 · Cited by 91 · see citing works
Ellul, J., Archer, N. J., Foy, C. M. L., Poppe, M., Boothby, H., Nicholas, H., Brown, R. G., & Lovestone, S. (2006) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2006.104034 · Cited by 91 · see citing works
John, S., & Schmieder, R. E. (2003) · Current Hypertension Reports · doi:10.1007/s11906-003-0021-1 · Cited by 91 · see citing works
“In this context, statins increase NO availability by stimulating and upregulating endothelial NOS in vitro independent of their cholesterol-lowering actions [ 56 ].”
BackgroundPravastatin down-regulates inflammatory mediators in human monocytes in vitro
Grip, O., Janciauskiene, S. M., & Lindgren, S. C. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00870-0 · Cited by 91 · see citing works
Early Statin Use and the Progression of Alzheimer Disease
Lin, F.-C., Chuang, Y., Hsieh, H., Lee, T.-C., Chiu, K.-F., Liu, C., & Wu, M. (2015) · Medicine · doi:10.1097/md.0000000000002143 · Cited by 90 · see citing works
“reduce endothelin-1, leading to vasodilatation and increase in cerebral perfusion.(6,17) In the studies of in vitro or in vivo, statin was proposed to have some neuroprotective effects through the”
BackgroundStatins for the prevention of Alzheimer's disease and dementia
Scott, H. D., & Laake, K. (2001) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003160 · Cited by 91 · see citing works
Statin therapy and angiogenesis
Skaletz‐Rorowski, A., & Walsh, K. (2003) · Current Opinion in Lipidology · doi:10.1097/00041433-200312000-00008 · Cited by 88 · see citing works
Gao, F., Linhartova, L., Johnston, A. M., & Thickett, D. R. (2008) · British Journal of Anaesthesia · doi:10.1093/bja/aem406 · Cited by 83 · see citing works
Skaletz‐Rorowski, A. (2002) · Cardiovascular Research · doi:10.1016/s0008-6363(02)00618-1 · Cited by 79 · see citing works
Wolfrum, S., Grimm, M. F., Heidbreder, M., Dendorfer, A., Katus, H. A., Liao, J. K., & Richardt, G. (2003) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-200303000-00017 · Cited by 77 · see citing works
“Statins increase eNOS expression (10,11) by stabilizing eNOS mRNA (12).”
BackgroundJoyce, M., Kelly, C. J., Winter, D. C., Chen, G., Leahy, A. L., & Bouchier‐Hayes, D. M. (2001) · Journal of Surgical Research · doi:10.1006/jsre.2001.6256 · Cited by 77 · see citing works
“This time period was chosen from in vivo and in vitro experiments, which showed that 72 h was a sufficient time period to enable protein production with an increase in the basal levels of ecNOS [19, 20, 46].”
BackgroundMethodCholesterol oxides as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus
Ferderbar, S., Pereira, E. C., Apolinário, E., Bertolami, M. C., Faludi, A. Á., Monte, O., Calliari, L. E., Sales, J. E. D. S., Gagliardi, A. R. D. T., Xavier, H. T., et al. (2006) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.645 · Cited by 76 · see citing works
“It also leads to an increase in the activity of paraoxonase – an antioxidant enzyme linked to HDL [27] and upregulates eNOS gene expression, which increases the production of nitric oxide [28,29].”
BackgroundRuiz, J. C., de Sotomayor, M. Á., Pérez‐Guerrero, C., Jimenez, L., Herrera, M. D., Pamies, E., Mv, M.-S., Stiefel, P., Miranda, M. L., Bravo, L. E., et al. (2002) · Journal of Hypertension · doi:10.1097/00004872-200203000-00018 · Cited by 75 · see citing works
Statins and the Role of Nitric Oxide in Chronic Heart Failure
von Haehling, S., Anker, S. D., & Bassenge, E. (2003) · Heart Failure Reviews · doi:10.1023/a:1022103222857 · Cited by 73 · see citing works
“For example, in vitro pravastatin appears to have an effect superior to simvastatin [ 40 ].”
Backgroundvan Etten, R. W., de Koning, E. J. P., Honing, M. L. H., Stroes, E. S. G., Gaillard, S., & Rabelink, T. J. (2002) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000015330.64968.c4 · Cited by 72 · see citing works
Kane, A. D., Herrera, E. A., Hansell, J. A., & Giussani, D. A. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.217968 · Cited by 70 · see citing works
“Normally Rho has direct negative effects on endothelial nitric oxide synthase (eNOS) mRNA activity or indirect inhibition of eNOS activity through inhibition of Akt which is known to activate eNOS through phosphorylation.”
BackgroundChen, W., Chen, C.-H., Hsu, M., Chang, R.-W., Wang, C., & Lee, T. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116192 · Cited by 70 · see citing works
Simvastatin Improves Diabetes-Induced Coronary Endothelial Dysfunction
Tawfik, H. E., El‐Remessy, A. B., Matragoon, S., Ma, G., Caldwell, R. B., & Caldwell, R. W. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.106823 · Cited by 70 · see citing works
“In addition, statins may activate eNOS by a mechanism unrelated to HMG-CoA reductase inhibition (Kaesemeyer et al., 1999; Harris et al., 2004).”
BackgroundResultVincenzi, B., Stock, S., Borba, C. P. C., Cleary, S. M., Oppenheim, C. E., Petruzzi, L. J., Fan, X., Copeland, P. M., Freudenreich, O., Cather, C., et al. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2014.08.021 · Cited by 67 · see citing works
“We chose to use pravastatin, one of the most extensively studied statins in both primary and secondary prevention trials (del Sol and Nanayakkara, 2008), available in generic form, because it appears to have fewer side effects than other statins such as simvastatin (Kaesemeyer et al., 1999; Ridker et al., 2005a, 2005b…”
BackgroundMethodMiida, T., Takahashi, A., & Ikeuchi, T. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.09.003 · Cited by 66 · see citing works
Tousoulis, D., Antoniades, C., Bosinakou, E., Kotsopoulou, M., Tsioufis, C., Tentolouris, C., Trikas, A., Pitsavos, C., & Stefanadis, C. (2004) · Heart · doi:10.1136/hrt.2003.027110 · Cited by 66 · see citing works
Pluripotential Mechanisms of Cardioprotection with HMG-CoA Reductase Inhibitor Therapy
Rosenson, R. S. (2001) · American Journal of Cardiovascular Drugs · doi:10.2165/00129784-200101060-00001 · Cited by 64 · see citing works
de Sotomayor, M. Á., Herrera, M. D., Marhuenda, E., & Andriantsitohaina, R. (2000) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0703668 · Cited by 64 · see citing works
“Indeed, such an e ect has been previously reported for another HMG-CoA reductase inhibitor, pravastatin (Kaesemeyer et al., 1999).”
BackgroundRole of L ‐arginine in the vascular actions and development of tolerance to nitroglycerin
Abou-Mohamed, G., Kaesemeyer, W., Caldwell, R. B., & Caldwell, R. W. (2000) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0703293 · Cited by 63 · see citing works
“Pravastatin, a lipid-lowering agent, is also a vasodilator and a NOS agonist (Kaesemeyer et al., 1999).”
BackgroundNon—Lipid-lowering effects of statins on atherosclerosis
Rosenson, R. S. (1999) · Current Cardiology Reports · doi:10.1007/s11886-999-0027-7 · Cited by 61 · see citing works
Nitric oxide: an emerging role in cardioprotection?
Rakhit, R. D., & Marber, M. S. (2001) · Heart · doi:10.1136/heart.86.4.368 · Cited by 60 · see citing works
Andreadou, I., Farmakis, D. T., Prokovas, E., Sigala, F., Ζώγα, Α., Spyridaki, K., Papalois, A. E., Papapetropoulos, A., ANASTASIOU‐NANA, M. I., Kremastinos, D. T., et al. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs121 · Cited by 59 · see citing works
Bioerodible devices for intermittent release of simvastatin acid
JEON, J., THOMAS, M., & Puleo, D. A. (2007) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2007.03.007 · Cited by 56 · see citing works
“Therefore, the approach used for enhancing simvastatin solubility was hydrolysis to cleave the lactone ring and convert the molecule to its β-hydroxyacid form (Kaesemeyer et al., 1999).”
MethodInfluentialAsymmetric dimethylarginine (ADMA) modulates endothelial function - therapeutic implications
Böger, R. H. (2003) · Vascular Medicine · doi:10.1191/1358863x03vm501ed · Cited by 55 · see citing works
Guérard, P., Rakotoniaina, Z., Goirand, F., Rochette, L., Dumas, M., Lirussi, F., & Bardou, M. (2006) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-006-0082-1 · Cited by 54 · see citing works
“This finding of an effect on both endothelial cells and vascular wall is in partial agreement with previous work where pravastatin increased endothelial-dependent dilation of preconstricted aortic rings, but had no effect on vascular smooth muscle cell proliferation or apoptosis (Kaesemeyer et al. 1999; Sindermann et…”
ResultNagaoka, T., Hein, T. W., Yoshida, A., & Kuo, L. (2007) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.06-0856 · Cited by 54 · see citing works
Yamanouchi, D., Banno, H., Nakayama, M., Sugimoto, M., Fujita, H., Kobayashi, M., Kuwano, H., & Komori, K. (2005) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2005.05.041 · Cited by 53 · see citing works
Effects of statins on vascular function of endothelin‐1
Mraiche, F., Cena, J., Das, D., & Vollrath, B. (2005) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706114 · Cited by 53 · see citing works
“…enhance endothelial nitric oxide synthase (eNOS) ability to generate NO in endothelial cells, and upregulate eNOS by inhibition of geranylgeranylation of a monomeric G protein Rho, which acts as a negative regulator of the enzyme mRNA stability (Laufs & Liao, 1998; Kaesemeyer et al., 1999).”
BackgroundResultBeishuizen, E. D., Tamsma, J. T., Jukema, J. W., van de Ree, M. A., van der Vijver, J. C. M., Meinders, A. E., & Huisman, M. V. (2005) · Diabetes Care · doi:10.2337/diacare.28.7.1668 · Cited by 52 · see citing works
Statins and blood pressure regulation
Borghi, C., Veronesi, M., Prandin, M. G., Dormi, A., & Ambrosioni, E. (2001) · Current Hypertension Reports · doi:10.1007/s11906-001-0090-y · Cited by 52 · see citing works
“This upregulation has been described in experimental conditions, particularly with pravastatin and simvastatin, and could help modulate the peripheral vascular tone regardless of the reduction in plasma cholesterol levels [ 41 ].”
MethodOxysterol species: reliable markers of oxidative stress in diabetes mellitus
Samadi, A., Gürlek, A., Şendur, S. N., Karahan, S., Akbıyık, F., & Lay, İ. (2018) · Journal of Endocrinological Investigation · doi:10.1007/s40618-018-0873-5 · Cited by 51 · see citing works
Current Understanding on the Role of Lipids in Macrophages and Associated Diseases
Florance, I., & Seenivasan, R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010589 · Cited by 50 · see citing works
Yin, Q., & Xiong, Y. (2005) · Journal of Cardiovascular Pharmacology · doi:10.1097/01.fjc.0000159642.44523.7f · Cited by 50 · see citing works
“Similar results have been shown in normocholesterolemic subjects with coronary artery disease.(20,34) In addition to increasing synthesis of NO, the present study provides important evidence that pravastatin up-regulated vascular DDAH activity.”
Result
- Authors
- Kaesemeyer, W. H., Caldwell, R. B., Huang, J., & Caldwell, R. W.
- Affiliations
- Augusta University (US)
- Corresponding author
- Kaesemeyer, Wayne H.
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 1999-01
- Volume
- 33
- Issue
- 1
- Pages
- 234-241
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2169537677
- Cited by
- 343
- References
- 38
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 6 · 2017: 8 · 2016: 8 · 2015: 7 · 2014: 8 · 2013: 10 · 2012: 9
- FWCI
- 19.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- pravastatin, simvastatin, endothelial nitric oxide synthase, nitric oxide, endothelium-dependent relaxation, platelet aggregation, vasodilation, L-NAME, L-arginine, statins, LDL cholesterol lowering, aortic endothelial cells
- MeSH terms
- Animals, Anticholesteremic Agents, Cattle, Endothelium, Vascular, Enzyme Activation, Cholesterol, LDL, Male, Platelet Aggregation, Vasodilation, Pravastatin, Rats, Sprague-Dawley, Nitric Oxide Synthase, Culture Techniques, Rats, Nitric Oxide Synthase Type III
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
