Semin Vasc Med 2004; 4(4): 367-375
DOI: 10.1055/s-2004-869593
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Statins and Hypertension

Michel Pelat1 J-L. Balligand1
  • 1Unit of Pharmacology and Therapeutics, FATH 5349 /UCL, Department of Medicine, Faculty of Medicine, Université Catholique de Louvain, Brussels, Belgium
Further Information

Publication History

Publication Date:
29 April 2005 (online)

ABSTRACT

Hypertension and dyslipidemia are frequently associated as risk factors for cardiovascular diseases. Statins are among the most potent drugs to correct hypercholesterolemia, and their use across a wide range of cardiovascular risk levels significantly reduced morbidity and mortality in large intervention trials. Aside from (or in addition to) reducing plasma cholesterol, statins also reduce blood pressure, another effect associated with cardiovascular risk reduction by other antihypertensive drugs. This review examines the proposition that a part of the statins’ beneficial effect in cardiovascular diseases may result from direct effects on blood pressure regulation, perhaps independent of lipid lowering. Potential molecular mechanisms are considered (e.g., “pleiotropic” effects on endothelial vasoactive mediators, oxidant stress, or inflammation), all of which may affect the central or peripheral control of blood pressure homeostasis, as well as modulate target organ damage. In particular, potential effects of statins on blood pressure and heart rate variability open new perspectives for a better tailoring of drug treatment in high-cardiovascular risk patients.

REFERENCES

  • 1 Sever P S, Dahlof B, Poulter N R et al.. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.  Lancet. 2003;  361 1149-1158
  • 2 Lloyd-Jones D M, Evans J C, Larson M G et al.. Cross-classification of JNC VI blood pressure stages and risk groups in the Framingham Heart Study.  Arch Intern Med. 1999;  159 2206-2212
  • 3 Pearson T A, Laurora I, Chu H et al.. The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals.  Arch Intern Med. 2000;  160 459-467
  • 4 Feron O, Dessy C, Moniotte S et al.. Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase.  J Clin Invest. 1999;  103 897-905
  • 5 Fielding C J, Bist A, Fielding P E. Caveolin mRNA levels are up-regulated by free cholesterol and down-regulated by oxysterols in fibroblast monolayers.  Proc Natl Acad Sci U S A. 1997;  94 3753-3758
  • 6 Nickenig G, Jung O, Strehlow K et al.. Hypercholesterolemia is associated with enhanced angiotensin AT1-receptor expression.  Am J Physiol. 1997;  272 H2701-H2707
  • 7 Warnholtz A, Nickenig G, Schulz E et al.. Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system.  Circulation. 1999;  99 2027-2033
  • 8 Jagla A, Schrezenmeir J. Postprandial triglycerides and endothelial function.  Exp Clin Endocrinol Diabetes. 2001;  109 S533-S547
  • 9 Bakker S J, Ijzerman R G, Teerlink T, Westerhoff H V, Gans R O, Heine R J. Cytosolic triglycerides and oxidative stress in central obesity: the missing link between excessive atherosclerosis, endothelial dysfunction, and beta-cell failure?.  Atherosclerosis. 2000;  148 17-21
  • 10 Igarashi K, Tsuji M, Nishimura M et al.. Improvement of endothelium-dependent coronary vasodilation after a single LDL apheresis in patients with hypercholesterolemia.  J Clin Apheresis. 2004;  19 11-16
  • 11 Tamai O, Matsuoka H, Itabe H et al.. Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans.  Circulation. 1997;  95 76-82
  • 12 Davignon J. The cardioprotective effects of statins.  Curr Atheroscler Rep. 2004;  6 27-35
  • 13 Wilson T W, Alonso-Galicia M, Roman R J. Effects of lipid-lowering agents in the Dahl salt-sensitive rat.  Hypertension. 1998;  31 225-231
  • 14 Jiang J, Sun C W, Alonso-Galicia M et al.. Lovastatin reduces renal vascular reactivity in spontaneously hypertensive rats.  Am J Hypertens. 1998;  11 1222-1231
  • 15 Jiang J, Roman R J. Lovastatin prevents development of hypertension in spontaneously hypertensive rats.  Hypertension. 1997;  30 968-974
  • 16 Susic D, Varagic J, Ahn J et al.. Beneficial pleiotropic vascular effects of rosuvastatin in two hypertensive models.  J Am Coll Cardiol. 2003;  42 1091-1097
  • 17 Straznicky N E, Howes L G, Lam W et al.. Effects of pravastatin on cardiovascular reactivity to norepinephrine and angiotensin II in patients with hypercholesterolemia and systemic hypertension.  Am J Cardiol. 1995;  75 582-586
  • 18 Abetel G, Poget P N, Bonnabry J P. Hypotensive effect of an inhibitor of cholesterol synthesis (fluvastatin). A pilot study.  Schweiz Med Wochenschr. 1998;  128 272-277
  • 19 Glorioso N, Troffa C, Filigheddu F et al.. Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia.  Hypertension. 1999;  34 1281-1286
  • 20 Sposito A C, Mansur A P, Coelho O R et al.. Additional reduction in blood pressure after cholesterol-lowering treatment by statins (lovastatin or pravastatin) in hypercholesterolemic patients using angiotensin-converting enzyme inhibitors (enalapril or lisinopril).  Am J Cardiol. 1999;  83 1497-1499
  • 21 Borghi C, Prandin M G, Costa F V et al.. Use of statins and blood pressure control in treated hypertensive patients with hypercholesterolemia.  J Cardiovasc Pharmacol. 2000;  35 549-555
  • 22 Nazzaro P, Manzari M, Merlo M et al.. Distinct and combined vascular effects of ACE blockade and HMG-CoA reductase inhibition in hypertensive subjects.  Hypertension. 1999;  33 719-725
  • 23 Leibovitz E, Hazanov N, Zimlichman R et al.. Treatment with atorvastatin improves small artery compliance in patients with severe hypercholesterolemia.  Am J Hypertens. 2001;  14 1096-1098
  • 24 Tonolo G, Melis M G, Formato M et al.. Additive effects of Simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients.  Eur J Clin Invest. 2000;  30 980-987
  • 25 Prasad G V, Ahmed A, Nash M M et al.. Blood pressure reduction with HMG-CoA reductase inhibitors in renal transplant recipients.  Kidney Int. 2003;  63 360-364
  • 26 Tsiara S, Elisaf M, Mikhailidis D P. Early vascular benefits of statin therapy.  Curr Med Res Opin. 2003;  19 540-556
  • 27 Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J et al.. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells.  J Clin Invest. 1998;  101 2711-2719
  • 28 Hernandez-Perera O, Perez-Sala D, Soria E et al.. Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells.  Circ Res. 2000;  87 616-622
  • 29 Ichiki T, Takeda K, Tokunou T et al.. Downregulation of angiotensin II type 1 receptor by hydrophobic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in vascular smooth muscle cells.  Arterioscler Thromb Vasc Biol. 2001;  21 1896-1901
  • 30 Wassmann S, Laufs U, Baumer A T et al.. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase.  Mol Pharmacol. 2001;  59 646-654
  • 31 Wassmann S, Hilgers S, Laufs U et al.. Angiotensin II type 1 receptor antagonism improves hypercholesterolemia-associated endothelial dysfunction.  Arterioscler Thromb Vasc Biol. 2002;  22 1208-1212
  • 32 Delbosc S, Morena M, Djouad F et al.. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are able to reduce superoxide anion production by NADPH oxidase in THP-1-derived monocytes.  J Cardiovasc Pharmacol. 2002;  40 611-617
  • 33 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
  • 34 Laufs U, Liao J K. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase.  J Biol Chem. 1998;  273 24266-24271
  • 35 Kureishi Y, Luo Z, Shiojima I et al.. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.  Nat Med. 2000;  6 1004-1010
  • 36 Feron O, Dessy C, Desager J P et al.. Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance.  Circulation. 2001;  103 113-118
  • 37 Pelat M, Dessy C, Massion P et al.. Rosuvastatin decreases caveolin-1 and improves nitric oxide-dependent heart rate and blood pressure variability in apolipoprotein E-/- mice in vivo.  Circulation. 2003;  107 2480-2486
  • 38 Drab M, Verkade P, Elger M et al.. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice.  Science. 2001;  293 2449-2452
  • 39 Frank P G, Lee H, Park D S et al.. Genetic ablation of caveolin-1 confers protection against atherosclerosis.  Arterioscler Thromb Vasc Biol. 2004;  24 98-105
  • 40 Bauersachs J, Galuppo P, Fraccarollo D et al.. Improvement of left ventricular remodeling and function by hydroxymethylglutaryl coenzyme a reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction.  Circulation. 2001;  104 982-985
  • 41 Takemoto M, Node K, Nakagami H et al.. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy.  J Clin Invest. 2001;  108 1429-1437
  • 42 Lee T M, Chou T F, Tsai C H. Association of pravastatin and left ventricular mass in hypercholesterolemic patients: role of 8-iso-prostaglandin f2alpha formation.  J Cardiovasc Pharmacol. 2002;  40 868-874
  • 43 Kontopoulos A G, Athyros V G, Pehlivanidis A N et al.. Long-term treatment effect of atorvastatin on aortic stiffness in hypercholesterolaemic patients.  Curr Med Res Opin. 2003;  19 22-27
  • 44 Ferrier K E, Muhlmann M H, Baguet J P et al.. Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension.  J Am Coll Cardiol. 2002;  39 1020-1025
  • 45 Taylor A J, Kent S M, Flaherty P J et al.. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness.  Circulation. 2002;  106 2055-2060
  • 46 Raison J, Rudnichi A, Safar M E. Effects of atorvastatin on aortic pulse wave velocity in patients with hypertension and hypercholesterolaemia: a preliminary study.  J Hum Hypertens. 2002;  16 705-710
  • 47 Youssef F, Seifalian A M, Jagroop I A et al.. The early effect of lipid-lowering treatment on carotid and femoral intima media thickness (IMT).  Eur J Vasc Endovasc Surg. 2002;  23 358-364
  • 48 Parati G, Pomidossi G, Albini F et al.. Relationship of 24-hour blood pressure mean and variability to severity of target-organ damage in hypertension.  J Hypertens. 1987;  5 93-98
  • 49 Frattola A, Parati G, Cuspidi C et al.. Prognostic value of 24-hour blood pressure variability.  J Hypertens. 1993;  11 1133-1137
  • 50 Mancia G, Parati G, Hennig M et al.. Relation between blood pressure variability and carotid artery damage in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis (ELSA).  J Hypertens. 2001;  19 1981-1989
  • 51 Sander D, Kukla C, Klingelhofer J et al.. Relationship between circadian blood pressure patterns and progression of early carotid atherosclerosis: a 3-year follow-up study.  Circulation. 2000;  102 1536-1541
  • 52 Parati G, Bilo G, Vettorello M et al.. Assessment of overall blood pressure variability and its different components.  Blood Press Monit. 2003;  8 155-159
  • 53 Mussalo H, Vanninen E, Ikaheimo R et al.. Short-term blood pressure variability in renovascular hypertension and in severe and mild essential hypertension.  Clin Sci (Lond). 2003;  105 609-614
  • 54 Frattola A, Parati G, Castiglioni P et al.. Lacidipine and blood pressure variability in diabetic hypertensive patients.  Hypertension. 2000;  36 622-628
  • 55 Liu J G, Xu L P, Chu Z X et al.. Contribution of blood pressure variability to the effect of nitrendipine on end-organ damage in spontaneously hypertensive rats.  J Hypertens. 2003;  21 1961-1967
  • 56 Stauss H M, Nafz B, Mrowka R et al.. Blood pressure control in eNOS knock-out mice: comparison with other species under NO blockade.  Acta Physiol Scand. 2000;  168 155-160
  • 57 Riahi S, Christensen J H, Toft E et al.. HMG-CoA reductase inhibitors improve heart rate variability in patients with a previous myocardial infarction.  Pharmacol Res. 2002;  45 479-483
  • 58 Horwich T B, MacLellan W R, Fonarow G C. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure.  J Am Coll Cardiol. 2004;  43 642-648
  • 59 Pehlivanidis A N, Athyros V G, Demitriadis D S et al.. Heart rate variability after long-term treatment with atorvastatin in hypercholesterolaemic patients with or without coronary artery disease.  Atherosclerosis. 2001;  157 463-469
  • 60 Welzig C M, Shin D G, Park H J et al.. Lipid lowering by pravastatin increases parasympathetic modulation of heart rate: Galpha(i2), a possible molecular marker for parasympathetic responsiveness.  Circulation. 2003;  108 2743-2746
  • 61 Pliquett R U, Cornish K G, Zucker I H. Statin therapy restores sympathovagal balance in experimental heart failure.  J Appl Physiol. 2003;  95 700-704
  • 62 Pliquett R U, Cornish K G, Peuler J D et al.. Simvastatin normalizes autonomic neural control in experimental heart failure.  Circulation. 2003;  107 2493-2498

Jean-Luc BalligandM.D. Ph.D. 

Unit of Pharmacology and Therapeutics, FATH 5349/Université Catholique de Louvain

53 Ave. Mounier, 1200 Brussels, Belgium

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