Skip to main content
SpringerLink
Log in

Endothelial nitric oxide synthase genotype modulates the improvement of coronary blood flow by pravastatin: a placebo-controlled PET study

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The objective was to study whether coronary blood flow or its response to pravastatin are affected by genetic variation in the endothelial nitric oxide synthase (eNOS) gene. Vascular endothelial nitric oxide maintains endothelium-dependent vasodilatation and also mediates antithrombotic actions. Its formation is catalyzed by eNOS, a constitutive enzyme, which has a polymorphic site in intron 4 (4a/b). Some clinical studies have suggested an association of the rare a-allele of eNOS with coronary artery disease and myocardial infarction. We carried out a double-blind placebo-controlled study involving 43 men (aged 35±4 years), who were randomized to receive either 40 mg/day pravastatin (n=21) or placebo (n=22) for 6 months. Myocardial blood flow was measured by positron emission tomography (PET) using 15O-labeled water. PET was performed at rest and after stimulation by adenosine infusion. PET and lipid analyses were carried out at baseline and after 6 months. eNOS genotyping was done by PCR. At baseline there were no differences in basal or adenosine-stimulated coronary blood flow between subjects with either eNOS bb or ba genotypes. At the end of the study genotypes reacted differently between pravastatin and placebo groups with respect to the change in adenosine-stimulated flow (ANCOVA P=0.008). More specifically, after pravastatin treatment the adenosine-stimulated flow increased by 54.5% in men with the eNOS ba genotype, whereas in the men with the bb genotype no significant change in flow was observed (P=0.002 for ba versus bb). In the placebo group there were no significant changes in blood flow from the baseline values (P=0.916 for ba versus bb). After pravastatin treatment both genotype groups showed a similar decrease in serum total cholesterol and low-density lipoprotein cholesterol (P<0.00001 for both). Our results suggest that adenosine-stimulated myocardial perfusion improves after treatment with pravastatin in subjects with the eNOS ba genotype but not in those with the bb genotype. This effect is not dependent on the decrease of serum cholesterol.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.

Similar content being viewed by others

Abbreviations

ANCOVA: :

Analysis of covariance

eNOS: :

Endothelial nitric oxide synthase

BMI: :

Body mass index

CAD: :

Coronary artery disease

LDL: :

Low density lipoprotein

PET: :

Positron emission tomography

References

  1. Moncada S, Higgs A (1993) The l-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012

    CAS  PubMed  Google Scholar 

  2. Vallance P, Chan N (2001) Endothelial function and nitric oxide: clinical relevance. Heart 85:342–350

    CAS  PubMed  Google Scholar 

  3. Govers R, Rabelink TJ (2001) Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol 280:F193–F206

    CAS  PubMed  Google Scholar 

  4. Ludmer PL SA, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P (1986) Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 315:1046–1051

    CAS  PubMed  Google Scholar 

  5. Baller D, Notohamiprodjo G, Gleichmann U, Holzinger J, Weise R, Lehmann J (1999) Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis. Circulation 99:2871–2875

    CAS  PubMed  Google Scholar 

  6. Treasure CB, Klein JL, Weintraub WS, Talley JD, Stillabower ME, Kosinski AS, Zhang J, Boccuzzi SJ, Cedarholm JC, Alexander RW (1995) Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 332:481–487

    Google Scholar 

  7. Gould KL, Martucci J, Goldberg DI, Hess MJ, Edens RP, Latifi R, Dudrick SJ (1994) Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease. A potential noninvasive marker of healing coronary endothelium. Circulation 89:1530–1538

    CAS  PubMed  Google Scholar 

  8. Laufs U, La Fata V, Plutzky J, Liao JK (1998) Upregulation of endothelial nitric oxide synthase by HMC CoA reductase inhibitors. Circulation 97:1129–1135

    CAS  PubMed  Google Scholar 

  9. Mital S, Zhang X, Zhao G, Bernstein RD, Smith CJ, Fulton DL, Sessa WC, Liao JK, Hintze TH (2000) Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs. Am J Physiol Heart Circ Physiol 279:H2649–2657

    CAS  PubMed  Google Scholar 

  10. Dayanikli F, Grambow D, Muzik O, Mosca L, Rubenfire M, Schwaiger M (1994) Early detection of abnormal coronary flow reserve in asymptomatic men at high risk for coronary artery disease using positron emission tomography. Circulation 90:808–817

    CAS  PubMed  Google Scholar 

  11. Buus NH, Bottcher M, Hermansen F, Sander M, Nielsen TT, Mulvany MJ (2001) Influence of nitric oxide synthase and adrenergic inhibition on adenosine-induced myocardial hyperemia. Circulation 104:2305–2310

    CAS  PubMed  Google Scholar 

  12. Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD (1990) Effects of adenosine on human coronary arterial circulation. Circulation 82:1595–1600

    CAS  PubMed  Google Scholar 

  13. Pitkanen OP, Nuutila P, Raitakari OT, Porkka K, Iida H, Nuotio I, Ronnemaa T, Viikari J, Taskinen MR, Ehnholm C, Knuuti J (1999) Coronary flow reserve in young men with familial combined hyperlipidemia. Circulation 99:1678–1684

    PubMed  Google Scholar 

  14. Pitkanen OP, Nuutila P, Raitakari OT, Ronnemaa T, Koskinen PJ, Iida H, Lehtimaki TJ, Laine HK, Takala T, Viikari JS, Knuuti J (1998) Coronary flow reserve is reduced in young men with IDDM. Diabetes 47:248–254

    CAS  PubMed  Google Scholar 

  15. Laine H, Raitakari O, Niinikoski H, Pitkanen OP, Iida H, Viikari J, Nuutila P, Knuuti J (1998) Early impairment of coronary flow reserve in young men with borderline hypertension. J Am Coll Cardiol 32:147–153

    Article  CAS  Google Scholar 

  16. Wang XL, Sim AS, Badenhop RF, McCredie RM, Wilcken DE (1996) A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene. Nat Med 2:41–45

    CAS  PubMed  Google Scholar 

  17. Ichihara S, Yamada Y, Fujimura T, Nakashima N, Yokota M (1998) Association of a polymorphism of the endothelial constitutive nitric oxide synthase gene with myocardial infarction in the Japanese population. Am J Cardiol 81:83–86

    CAS  PubMed  Google Scholar 

  18. Hooper WC, Lally C, Austin H, Benson J, Dilley A, Wenger NK, Whitsett C, Rawlins P, Evatt BL (1999) The relationship between polymorphisms in the endothelial cell nitric oxide synthase gene and the platelet GPIIIa gene with myocardial infarction and venous thromboembolism in African Americans. Chest 116:880–886

    CAS  PubMed  Google Scholar 

  19. Hibi K, Ishigami T, Tamura K, Mizushima S, Nyui N, Fujita T, Ochiai H, Kosuge M, Watanabe Y, Yoshii Y, Kihara M, kimura K, Ishii M, Unemura S (1998) Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. Hypertension 32:521–526

    CAS  PubMed  Google Scholar 

  20. Sigusch HH, Suber R, Lehmann MH, Surber S, Weber J, Henke A, Reinhardt D, Hoffmann A, Figulla HR (2000) Lack of association between 27-bp repeat polymorphism in intron 4 of the endothelial nitric oxide synthase gene and the risk of coronary artery disease. Scand J Clin Lab Invest 60:229–235

    CAS  PubMed  Google Scholar 

  21. Pulkkinen A,Viitanen L, Kareinen A, Lehto S, Vauhkonen I, Laakso M (2000) Intron 4 polymorphism of the endothelial nitric oxide synthase gene is associated with elevated blood pressure in type 2 diabetic patients with coronary heart disease. J Mol Med 78:372–379

    CAS  PubMed  Google Scholar 

  22. Granath B Taylor R, van Bockxmeer FM, Mamotte CD (2001) Lack of evidence for association between endothelial nitric oxide synthase gene polymorphisms and coronary artery disease in the Australian Caucasian population. J Cardiovasc Risk 8:235–241

    Article  CAS  PubMed  Google Scholar 

  23. Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502

    CAS  PubMed  Google Scholar 

  24. Iida H, Kanno I, Takahashi A, et al (1988) Measurement of absolute myocardial blood flow with H215O and dynamic positron-emission tomography. Strategy for quantification in relation to the partial-volume effect. Circulation 78:104–115

    CAS  PubMed  Google Scholar 

  25. Iida H, Takahashi A, Tamura Y, Ono Y, Lammertsma AA (1995) Myocardial blood flow: comparison of oxygen-15-water bolus injection, slow infusion and oxygen-15-carbon dioxide slow inhalation. J Nucl Med 36:78–85

    CAS  PubMed  Google Scholar 

  26. Sommerschild HT, Kirkeboen KA (2000) Adenosine and cardioprotection during ischaemia and reperfusion—an overview. Acta Anaesthesiol Scand 44:1038–1055

    Article  CAS  PubMed  Google Scholar 

  27. Masumoto A, Horooka Y, Hironaga K, Eshima K, Setoguchi S, Egashira K, Takeshita A (2001) Effect of pravastatin on endothelial function in patients with coronary artery disease (cholesterol independent effect of pravastatin). Am J Cardiol 88:1291–1294

    Article  CAS  PubMed  Google Scholar 

  28. Feron O, Dessy C, Desager JP, Balligand JL (2001) Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes activation through a decrease in caveolin abundance. Circulation 103:113–118

    CAS  PubMed  Google Scholar 

  29. Laufs U, Endres M, Custodis F, Gertz K, Nickenig G, Liao JK, Bohm M (2000) Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription. Circulation 102:3104–3110

    CAS  PubMed  Google Scholar 

  30. Kunnas TA, Ilveskoski E, Niskakangas T, Laippala P, Kajander OA, Mikkelsson J, Goebeler S, Penttilä A, Perola M, Nikkari S, Karhunen PJ (2002) Association of the endothelial nitric oxide synthase gene polymorphism with risk of coronary artery disease and myocardial infarction in middle-aged men. J Mol Med 80:605–609

    Google Scholar 

  31. Wang XL, Wang J (2000) Endothelial nitric oxide synthase gene sequence variations and vascular disease. Mol Genet Metab 70:241–251

    CAS  PubMed  Google Scholar 

  32. Wang XL, Mahaney MC, Sim AS, Wang J, WangJ, Blancero J, Almasy K, Badenhop RB, Wilcken DE (1997) Genetic contribution of the endothelial conctitutive nitric oxide synthase gene to plasma nitric oxide levels. Arterioscler Thromb Vasc Biol 17:3147–3153

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study has received financial support from the Medical Research Grants of the Turku University Central Hospital, the Academy of Finland, Helsinki, the Medical Research Foundation of the Tampere University Hospital, Tampere, the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, and the Yrjö Jahnsson Foundation. Bristol-Myers Squibb Finland provided the drugs used in the study free of charge.

Author information

Authors and Affiliations

  1. Department of Clinical Chemistry, Center for Laboratory Medicine, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland

    Tarja A. Kunnas, Terho Lehtimäki, Reijo Laaksonen, Erkki Ilveskoski, Pekka J. Karhunen & Seppo T. Nikkari

  2. Department of Medical Biochemistry, University of Tampere Medical School, University of Tampere, 33014, Tampere, Finland

    Seppo T. Nikkari

  3. Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland

    Reijo Laaksonen

  4. Turku PET Center, University of Turku, Turku, Finland

    Tuula Janatuinen, Risto Vesalainen, Pirjo Nuutila & Juhani Knuuti

  5. Department of Medicine, Turku University Central Hospital, Turku, Finland

    Risto Vesalainen

  6. Department of Internal Medicine, University of Turku, Turku, Finland

    Pirjo Nuutila

Authors
  1. Tarja A. Kunnas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Terho Lehtimäki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reijo Laaksonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erkki Ilveskoski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tuula Janatuinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Risto Vesalainen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pirjo Nuutila
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pekka J. Karhunen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Juhani Knuuti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Seppo T. Nikkari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seppo T. Nikkari.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kunnas, T.A., Lehtimäki, T., Laaksonen, R. et al. Endothelial nitric oxide synthase genotype modulates the improvement of coronary blood flow by pravastatin: a placebo-controlled PET study. J Mol Med 80, 802–807 (2002). https://doi.org/10.1007/s00109-002-0398-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-002-0398-3

Keywords

Search

Navigation