Download PDF
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)

    Permissions and Reprints

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.

KEYWORDS

Hypertension - blood pressure variability - endothelium - nitric oxide synthase - caveolin - statins

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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 8 Jagla A, Schrezenmeir J. Postprandial triglycerides and endothelial function.  Exp Clin Endocrinol Diabetes. 2001;  109 S533-S547
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 11 Tamai O, Matsuoka H, Itabe H et al.. Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans.  Circulation. 1997;  95 76-82
    PubMedGoogle Scholar
  • 12 Davignon J. The cardioprotective effects of statins.  Curr Atheroscler Rep. 2004;  6 27-35
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 15 Jiang J, Roman R J. Lovastatin prevents development of hypertension in spontaneously hypertensive rats.  Hypertension. 1997;  30 968-974
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 26 Tsiara S, Elisaf M, Mikhailidis D P. Early vascular benefits of statin therapy.  Curr Med Res Opin. 2003;  19 540-556
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 49 Frattola A, Parati G, Cuspidi C et al.. Prognostic value of 24-hour blood pressure variability.  J Hypertens. 1993;  11 1133-1137
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 54 Frattola A, Parati G, Castiglioni P et al.. Lacidipine and blood pressure variability in diabetic hypertensive patients.  Hypertension. 2000;  36 622-628
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar

Jean-Luc BalligandM.D. Ph.D. 

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

53 Ave. Mounier, 1200 Brussels, Belgium