Current Cardiology Reports

, Volume 12, Issue 6, pp 472–480 | Cite as

Advances in Pharmacologic Modulation of Nitric Oxide in Hypertension

  • Yoshiko Mizuno
  • Robert F. Jacob
  • R. Preston MasonEmail author


A number of structural and functional mechanisms have been identified in the pathogenesis of hypertensive vascular disease, each of which requires effective therapy to reduce global cardiovascular risk. Hypertension, together with other cardiovascular risk factors, promotes endothelial dysfunction as evidenced by decreased nitric oxide (NO) release and reduced vascular responsiveness to normal vasodilatory stimuli. In addition, the mechanical forces inherent in hypertension activate neurohormonal mechanisms, including the renin-angiotensin system, which modulate vessel wall structure and function. Antihypertensive drugs may have class-specific hemodynamic and physiologic effects that attenuate these vascular disease processes. Pharmacologic approaches that enhance endothelial NO bioavailability have been shown to restore vasodilation while reducing clinical events. These agents improve NO bioavailability by increasing endogenous production through enzymatic mechanisms or by promoting the direct release of NO by its redox congeners in a spontaneous fashion. In this article, we review the basic mechanisms of endothelial dysfunction along with the use and comparative therapeutic benefits of various pharmacologic interventions, with particular emphasis on antihypertensive agents.


Antihypertensives Nitric oxide Endothelial function Central aortic pressure 

Clinical Trial Acronyms


Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension


African American Heart Failure Trial


Anglo-Scandinavian Cardiac Outcomes Trial


Conduit Artery Function Evaluation


Elevation of Nifedipine and Cerivastatin on Recovery of Endothelial Function


Randomized Aldactone Evaluation Study.



Dr. R. Preston Mason has received preclinical research funding from Astra Zeneca, Daiichi Sankyo, Forest Research Institute, NicOx, Novartis, Pfizer, and Sanofi Aventis. No other potential conflicts of interest relevant to this article were reported.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Weber T, Auer J, O’Rourke MF, et al.: Arterial stiffness, wave reflections, and the risk of coronary artery disease. Circulation 2004, 109:184–189.CrossRefPubMedGoogle Scholar
  2. 2.
    Williams B, Lacy PS, Thom SM, et al.: Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006, 113:1213–1225.CrossRefPubMedGoogle Scholar
  3. 3.
    Harrison DG: Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 1997, 100:2153–2157.CrossRefPubMedGoogle Scholar
  4. 4.
    Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE: Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990, 323:22–27.CrossRefPubMedGoogle Scholar
  5. 5.
    Kinoshita H, Milstien S, Wambi C, Katusic ZS: Inhibition of tetrahydrobiopterin biosynthesis impairs endothelial dependent relaxation in canine basilar artery. Am J Physiol 1997, 273:H718–H724.PubMedGoogle Scholar
  6. 6.
    Landmesser U, Dikalov S, Price SR, et al.: Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 2003, 111:1201–1209.PubMedGoogle Scholar
  7. 7.
    Landmesser U, Cai H, Dikalov S, et al.: Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 2002, 40:511–515.CrossRefPubMedGoogle Scholar
  8. 8.
    • Mason RP, Kubant R, Jacob RF, et al.: Loss of arterial and renal nitric oxide bioavailability in hypertensive rats with diabetes: effect of beta-blockers. Am J Hypertens 2009, 22:1160–1166. This is an original article showing the effect of multiple risk factors on endothelial dysfunction and metabolic disease.CrossRefPubMedGoogle Scholar
  9. 9.
    Mason RP, Kalinowski L, Jacob RF, et al.: Nebivolol reduces nitroxidative stress and restores nitric oxide bioavailability in endothelium of black Americans. Circulation 2005, 112:3795–3801.CrossRefPubMedGoogle Scholar
  10. 10.
    Campia U, Choucair WK, Bryant MB, et al.: Reduced endothelium-dependent and -independent dilation of conductance arteries in African Americans. J Am Coll Cardiol 2002, 40:754–760.CrossRefPubMedGoogle Scholar
  11. 11.
    Redon J, Oliva MR, Tormos C, et al.: Antioxidant activities and oxidative stress byproducts in human hypertension. Hypertension 2003, 41:1096–1101.CrossRefPubMedGoogle Scholar
  12. 12.
    Rodriguez-Iturbe B, Zhan CD, Quiroz Y, et al.: Antioxidant-rich diet relieves hypertension and reduces renal immune infiltration in spontaneously hypertensive rats. Hypertension 2003, 41:341–346.CrossRefPubMedGoogle Scholar
  13. 13.
    •• Cooper SA, Whaley-Connell A, Habibi J, et al.: Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance. Am J Physiol Heart Circ Physiol 2007, 293:H2009–H2023. This is a comprehensive review on oxidative stress, cardiovascular insulin resistance, and the contribution of Ang II to insulin/IGF-1 signaling pathways.CrossRefPubMedGoogle Scholar
  14. 14.
    Laursen JB, Rajagopalan S, Galis Z, et al.: Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 1997, 95:588–593.PubMedGoogle Scholar
  15. 15.
    Thai H, Wollmuth J, Goldman S, Gaballa M: Angiotensin subtype 1 receptor (AT1) blockade improves vasorelaxation in heart failure by up-regulation of endothelial nitric-oxide synthase via activation of the AT2 receptor. J Pharmacol Exp Ther 2003, 307:1171–1178.CrossRefPubMedGoogle Scholar
  16. 16.
    Takemoto M, Egashira K, Usui M, et al.: Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats. J Clin Invest 1997, 99:278–287.CrossRefPubMedGoogle Scholar
  17. 17.
    • Gradman AH, Kad R: Renin inhibition in hypertension. J Am Coll Cardiol 2008, 51:519–528. This is an insightful review focusing on the structure and function of renin and prorenin along with the efficacy of aliskiren.CrossRefPubMedGoogle Scholar
  18. 18.
    • O’Brien E, Barton J, Nussberger J, et al.: Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. Hypertension 2007, 49:276–284. This is a clinical study describing the effects of aliskiren on plasma renin activity in combination therapy with other RAS-directed treatments.CrossRefPubMedGoogle Scholar
  19. 19.
    • Imanishi T, Tsujioka H, Ikejima H, et al.: Renin inhibitor aliskiren improves impaired nitric oxide bioavailability and protects against atherosclerotic changes. Hypertension 2008, 52:563–572. This is a recent study showing an antioxidant effect of combined treatment with aldosterone antagonist and ACE inhibitor.CrossRefPubMedGoogle Scholar
  20. 20.
    Nguyen G, Danser AH: The (pro)renin receptor: therapeutic consequences. Expert Opin Investig Drugs 2006, 15:1131–1135.CrossRefPubMedGoogle Scholar
  21. 21.
    Schiffrin EL: Effects of aldosterone on the vasculature. Hypertension 2006, 47:312–318.CrossRefPubMedGoogle Scholar
  22. 22.
    Pitt B, Zannad F, Remme WJ, et al.: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999, 341:709–717.CrossRefPubMedGoogle Scholar
  23. 23.
    Farquharson CA, Struthers AD: Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 2000, 101:594–597.PubMedGoogle Scholar
  24. 24.
    Virdis A, Neves MF, Amiri F, et al.: Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension 2002, 40:504–510.CrossRefPubMedGoogle Scholar
  25. 25.
    Nagata D, Takahashi M, Sawai K, et al.: Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity. Hypertension 2006, 48:165–171.CrossRefPubMedGoogle Scholar
  26. 26.
    •• Imanishi T, Ikejima H, Tsujioka H, et al.: Addition of eplerenone to an angiotensin-converting enzyme inhibitor effectively improves nitric oxide bioavailability. Hypertension 2008, 51:734–741. This is the initial study describing the effects of aliskiren on NO bioavailability.CrossRefPubMedGoogle Scholar
  27. 27.
    Oberleithner H, Callies C, Kusche-Vihrog K, et al.: Potassium softens vascular endothelium and increases nitric oxide release. Proc Natl Acad Sci U S A 2009, 106:2829–2834.CrossRefPubMedGoogle Scholar
  28. 28.
    Liu SL, Schmuck S, Chorazcyzewski JZ, et al.: Aldosterone regulates vascular reactivity: short-term effects mediated by phosphatidylinositol 3-kinase-dependent nitric oxide synthase activation. Circulation 2003, 108:2400–2406.CrossRefPubMedGoogle Scholar
  29. 29.
    McTavish D, Campoli-Richards D, Sorkin EM: Carvedilol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1993, 45:232–258.Google Scholar
  30. 30.
    Lee J, Lee M, Kim JU, et al.: Carvedilol reduces plasma 8-hydroxy-2′-deoxyguanosine in mild to moderate hypertension: a pilot study. Hypertension 2005, 45:986–990.CrossRefPubMedGoogle Scholar
  31. 31.
    Yoshioka T, Iwamoto N, Tsukahara F, et al.: Anti-NO action of carvedilol in cell-free system and in vascular endothelial cells. Br J Pharmacol 2000, 129:1530–1535.CrossRefPubMedGoogle Scholar
  32. 32.
    Van de Water A, Xhonneux R, Reneman RS, Janssen PA: Cardiovascular effects of dl-nebivolol and its enantiomers—a comparison with those of atenolol. Eur J Pharmacol 1988, 156:95–103.CrossRefPubMedGoogle Scholar
  33. 33.
    Troost R, Schwedhelm E, Rojczyk S, et al.: Nebivolol decreases systemic oxidative stress in healthy volunteers. Br J Pharmacol 2000, 50:377–379.Google Scholar
  34. 34.
    Mollnau H, Schulz E, Daiber A, et al.: Nebivolol prevents vascular NOS III uncoupling in experimental hyperlipidemia and inhibits NADPH oxidase activity in inflammatory cells. Arterioscler Thromb Vasc Biol 2003, 23:615–621.CrossRefPubMedGoogle Scholar
  35. 35.
    Kalinowski L, Dobrucki LW, Szczepanska-Konkel M, et al.: Third-generation beta-blockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation 2003, 107:2747–2752.CrossRefPubMedGoogle Scholar
  36. 36.
    Dessy C, Saliez J, Ghisdal P, et al.: Endothelial beta3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation beta-blocker nebivolol. Circulation 2005, 112:1198–1205.CrossRefPubMedGoogle Scholar
  37. 37.
    Perez-Reyes E: Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 2003, 83:117–161.PubMedGoogle Scholar
  38. 38.
    Kojda G, Klaus W, Werner G, Fricke U: Reduced responses of nitrendipine in PGF2 alpha-precontracted porcine isolated arteries after pretreatment with methylene blue. Basic Res Cardiol 1990, 85:461–466.CrossRefPubMedGoogle Scholar
  39. 39.
    Brovkovych VV, Kalinowski L, Muller-Peddinghaus R, Malinski T: Synergistic antihypertensive effects of nifedipine on endothelium: concurrent release of NO and scavenging of superoxide. Hypertension 2001, 37:34–39.PubMedGoogle Scholar
  40. 40.
    Taddei S, Virdis A, Ghiadoni L, et al.: Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension. Hypertension 2001, 37:943–948.PubMedGoogle Scholar
  41. 41.
    Effect of nifedipine and cerivastatin on coronary endothelial function in patients with coronary artery disease: the ENCORE I Study (Evaluation of Nifedipine and Cerivastatin On Recovery of coronary Endothelial function) [no authors listed]. Circulation 2003, 107:422–428.Google Scholar
  42. 42.
    Kobayashi N, Yanaka H, Tojo A, et al.: Effects of amlodipine on nitric oxide synthase mRNA expression and coronary microcirculation in prolonged nitric oxide blockade-induced hypertensive rats. J Cardiovasc Pharmacol 1999, 34:173–181.CrossRefPubMedGoogle Scholar
  43. 43.
    Zhang X, Hintze TH: Amlodipine releases nitric oxide from canine coronary microvessels: an unexpected mechanism of action of a calcium channel-blocking agent. Circulation 1998, 97:576–580.PubMedGoogle Scholar
  44. 44.
    Jamerson K, Weber MA, Bakris GL, et al.: Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008, 359:2417–2428.CrossRefPubMedGoogle Scholar
  45. 45.
    Ignarro LJ, Napoli C, Loscalzo J: Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview. Circ Res 2002, 90:21–28.CrossRefPubMedGoogle Scholar
  46. 46.
    Mason RP, Cockcroft JR: Targeting nitric oxide with drug therapy. J Clin Hypertens 2006, 8:40–52.CrossRefGoogle Scholar
  47. 47.
    Taylor AL, Ziesche S, Yancy C, et al.: Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004, 351:2049–2057.CrossRefPubMedGoogle Scholar
  48. 48.
    Stokes GS, Bune AJ, Huon N, Barin ES: Long-term effectiveness of extended-release nitrate for the treatment of systolic hypertension. Hypertension 2005, 45:380–384.CrossRefPubMedGoogle Scholar
  49. 49.
    Zhao L, Mason NA, Strange JW, et al.: Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic Peptide activity. Circulation 2003, 107:234–237.CrossRefPubMedGoogle Scholar
  50. 50.
    Bivalacqua TJ, Usta MF, Champion HC, et al.: Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats. Int J Impot Res 2004, 16:21–29.CrossRefPubMedGoogle Scholar
  51. 51.
    Kim D, Aizawa T, Wei H, et al.: Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: a mechanism by which angiotensin II antagonizes cGMP signaling. J Mol Cell Cardiol 2005, 38:175–184.CrossRefPubMedGoogle Scholar
  52. 52.
    MacPherson JD, Gillespie TD, Dunkerley HA, et al.: Inhibition of phosphodiesterase 5 selectively reverses nitrate tolerance in the venous circulation. J Pharmacol Exp Ther 2006, 317:188–195.CrossRefPubMedGoogle Scholar
  53. 53.
    Ferrannini E, Natali A, Capaldo B, et al.: Insulin resistance, hyperinsulinemia, and blood pressure: role of age and obesity. European Group for the Study of Insulin Resistance (EGIR). Hypertension 1997, 30:1144–1149.PubMedGoogle Scholar
  54. 54.
    Saad MF, Rewers M, Selby J, et al.: Insulin resistance and hypertension: the Insulin Resistance Atherosclerosis study. Hypertension 2004, 43:1324–1331.CrossRefPubMedGoogle Scholar
  55. 55.
    Zeng G, Nystrom FH, Ravichandran LV, et al.: Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 2000, 101:1539–1545.PubMedGoogle Scholar
  56. 56.
    Abe H, Yamada N, Kamata K, et al.: Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin receptor substrate-1. J Clin Invest 1998, 101:1784–1788.CrossRefPubMedGoogle Scholar
  57. 57.
    Wei Y, Sowers JR, Nistala R, et al.: Angiotensin II-induced NADPH oxidase activation impairs insulin signaling in skeletal muscle cells. J Biol Chem 2006, 281:35137–35146.CrossRefPubMedGoogle Scholar
  58. 58.
    Andreozzi F, Laratta E, Sciacqua A, et al.: Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells. Circ Res 2004, 94:1211–1218.CrossRefPubMedGoogle Scholar
  59. 59.
    •• Wei Y, Whaley-Connell AT, Chen K, et al.: NADPH oxidase contributes to vascular inflammation, insulin resistance, and remodeling in the transgenic (mRen2) rat. Hypertension 2007, 50:384–391. This is an influential paper demonstrating the crucial role of Ang II/NAD(P)H oxidase in insulin resistance and endothelial dysfunction.CrossRefPubMedGoogle Scholar
  60. 60.
    Taniyama Y, Hitomi H, Shah A, et al.: Mechanisms of reactive oxygen species-dependent downregulation of insulin receptor substrate-1 by angiotensin II. Arterioscler Thromb Vasc Biol 2005, 25:1142–1147.CrossRefPubMedGoogle Scholar
  61. 61.
    Hitomi H, Kiyomoto H, Nishiyama A, et al.: Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells. Hypertension 2007, 50:750–755.CrossRefPubMedGoogle Scholar
  62. 62.
    Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003, 26(Suppl 1):S5–S20.Google Scholar
  63. 63.
    • Lastra-Lastra G, Sowers JR, Restrepo-Erazo K, et al.: Role of aldosterone and angiotensin II in insulin resistance: an update. Clin Endocrinol 2009, 71:1–6. This is a recent review describing the role of Ang II and aldosterone in the pathogenesis of insulin resistance.CrossRefGoogle Scholar
  64. 64.
    Ryan MJ, Didion SP, Mathur S, et al.: PPAR(gamma) agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic mice. Hypertension 2004, 43:661–666.CrossRefPubMedGoogle Scholar
  65. 65.
    Fujishima S, Ohya Y, Nakamura Y, et al.: Troglitazone, an insulin sensitizer, increases forearm blood flow in humans. Am J Hypertens 1998, 11:1134–1137.CrossRefPubMedGoogle Scholar
  66. 66.
    Nolan JJ, Ludvik B, Beerdsen P, et al.: Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994, 331:1188–1193.CrossRefPubMedGoogle Scholar
  67. 67.
    Benson SC, Pershadsingh HA, Ho CI, et al.: Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 2004, 43:993–1002.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Yoshiko Mizuno
    • 1
    • 2
  • Robert F. Jacob
    • 2
  • R. Preston Mason
    • 1
    • 2
    Email author
  1. 1.Cardiovascular Division, Department of MedicineBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  2. 2.Elucida Research LLCBeverlyUSA

Personalised recommendations