Endothelial dysfunction: a strategic target in the treatment of hypertension?

Cardiovascular Physiology
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Abstract

Endothelial dysfunction is a common feature of hypertension, and it results from the imbalanced release of endothelium-derived relaxing factors (EDRFs; in particular, nitric oxide) and endothelium-derived contracting factors (EDCFs; angiotensin II, endothelins, uridine adenosine tetraphosphate, and cyclooxygenase-derived EDCFs). Thus, drugs that increase EDRFs (using direct nitric oxide releasing compounds, tetrahydrobiopterin, or l-arginine supplementation) or decrease EDCF release or actions (using cyclooxygenase inhibitor or thromboxane A2/prostanoid receptor antagonists) would prevent the dysfunction. Many conventional antihypertensive drugs, including angiotensin-converting enzyme inhibitors, calcium channel blockers, and third-generation β-blockers, possess the ability to reverse endothelial dysfunction. Their use is attractive, as they can address arterial blood pressure and vascular tone simultaneously. The severity of endothelial dysfunction correlates with the development of coronary artery disease and predicts future cardiovascular events. Thus, endothelial dysfunction needs to be considered as a strategic target in the treatment of hypertension.

Keywords

Endothelium Prostaglandin Contraction Free radical Hypertensive rats 
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References

  1. 1.
    Félétou M, Vanhoutte PM (2006) Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol 291:H985–H1002PubMedCrossRefGoogle Scholar
  2. 2.
    Susic D (1997) Hypertension, aging, and atherosclerosis. The endothelial interface. Med Clin North Am 81:1231–1240PubMedCrossRefGoogle Scholar
  3. 3.
    Flavahan NA, Vanhoutte PM (1990) G-proteins and endothelial responses. Blood Vessels 27:218–229PubMedGoogle Scholar
  4. 4.
    Shibano T, Codina J, Birnbaumer L, Vanhoutte PM (1994) Pertussis toxin-sensitive G proteins in regenerated endothelial cells of porcine coronary artery. Am J Physiol 267:H979–H981PubMedGoogle Scholar
  5. 5.
    Tang EH, Vanhoutte PM (2009) Prostanoids and reactive oxygen species: team players in endothelium-dependent contractions. Pharmacol Ther 122:140–149PubMedCrossRefGoogle Scholar
  6. 6.
    Vanhoutte PM, Shimokawa H, Tang EH, Feletou M (2009) Endothelial dysfunction and vascular disease. Acta Physiol (Oxf) 196:193–222CrossRefGoogle Scholar
  7. 7.
    Michel FS, Man GS, Man RY, Vanhoutte PM (2008) Hypertension and the absence of EDHF-mediated responses favour endothelium-dependent contractions in renal arteries of the rat. Br J Pharmacol 155:217–226PubMedCrossRefGoogle Scholar
  8. 8.
    Sekiguchi F, Nakahira T, Kawata K, Sunano S (2002) Responses to endothelium-derived factors and their interaction in mesenteric arteries from Wistar Kyoto and stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 29:1066–1074PubMedCrossRefGoogle Scholar
  9. 9.
    Yang D, Gluais P, Zhang JN, Vanhoutte PM, Félétou M (2004) Endothelium-dependent contractions to acetylcholine, ATP and the calcium ionophore A 23187 in aortas from spontaneously hypertensive and normotensive rats. Fundam Clin Pharmacol 18:321–326PubMedCrossRefGoogle Scholar
  10. 10.
    Lee J, Choi KC, Yeum CH, Kim W, Yoo K, Park JW, Yoon PJ (1995) Impairment of endothelium-dependent vasorelaxation in chronic two-kidney, one-clip hypertensive rats. Nephrol Dial Transplant 10:619–623PubMedGoogle Scholar
  11. 11.
    Stankevicius E, Martinez AC, Mulvany MJ, Simonsen U (2002) Blunted acetylcholine relaxation and nitric oxide release in arteries from renal hypertensive rats. J Hypertens 20:1571–1579PubMedCrossRefGoogle Scholar
  12. 12.
    Cordellini S (1999) Endothelial dysfunction in DOCA-salt hypertension: possible involvement of prostaglandin endoperoxides. Gen Pharmacol 32:315–320PubMedCrossRefGoogle Scholar
  13. 13.
    Zhou MS, Kosaka H, Tian RX, Abe Y, Chen QH, Yoneyama H, Yamamoto A, Zhang L (2001) l-Arginine improves endothelial function in renal artery of hypertensive Dahl rats. J Hypertens 19:421–429PubMedCrossRefGoogle Scholar
  14. 14.
    Zhou MS, Nishida Y, Chen QH, Kosaka H (1999) Endothelium-derived contracting factor in carotid artery of hypertensive Dahl rats. Hypertension 34:39–43PubMedGoogle Scholar
  15. 15.
    Linder L, Kiowski W, Bühler FR, Lüscher TF (1990) Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation 81:1762–1767PubMedGoogle Scholar
  16. 16.
    Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE (1990) Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 323:22–27PubMedCrossRefGoogle Scholar
  17. 17.
    Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA (1993) Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 87:1468–1474PubMedGoogle Scholar
  18. 18.
    Félétou M, Vanhoutte PM (2006) Endothelium-derived hyperpolarizing factor: where are we now? Arterioscler Thromb Vasc Biol 26:1215–1225PubMedCrossRefGoogle Scholar
  19. 19.
    Higashi Y, Sasaki S, Nakagawa K, Fukuda Y, Matsuura H, Oshima T, Chayama K (2002) Tetrahydrobiopterin enhances forearm vascular response to acetylcholine in both normotensive and hypertensive individuals. Am J Hypertens 15:326–332PubMedCrossRefGoogle Scholar
  20. 20.
    Sessa WC (2005) Regulation of endothelial derived nitric oxide in health and disease. Mem Inst Oswaldo Cruz 100:15–18PubMedCrossRefGoogle Scholar
  21. 21.
    Cooke JP (2000) Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol 20:2032–2037PubMedGoogle Scholar
  22. 22.
    Gryglewski RJ, Palmer RM, Moncada S (1986) Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 320:454–456PubMedCrossRefGoogle Scholar
  23. 23.
    Mehta JL, Lopez LM, Chen L, Cox OE (1994) Alterations in nitric oxide synthase activity, superoxide anion generation, and platelet aggregation in systemic hypertension, and effects of celiprolol. Am J Cardiol 74:901–905PubMedCrossRefGoogle Scholar
  24. 24.
    Sagar S, Kallo IJ, Kaul N, Ganguly NK, Sharma BK (1992) Oxygen free radicals in essential hypertension. Mol Cell Biochem 111:103–108PubMedCrossRefGoogle Scholar
  25. 25.
    Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A (1998) Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 97:2222–2229PubMedGoogle Scholar
  26. 26.
    Vanhoutte PM, Tang EH (2008) Endothelium-dependent contractions: when a good guy turns bad! J Physiol 586:5295–304PubMedCrossRefGoogle Scholar
  27. 27.
    Ferder L, Inserra E, Martinez-Maldonado M (2006) Inflammation and the metabolic syndrome: role of angiotensin II and oxidative stress. Curr Hypertens Rep 8:191–198PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang H, Schmeisser A, Garlichs CD, Plötze K, Damme U, Mügge A, Daniel WG (1999) Angiotensin II-induced superoxide anion generation in human vascular endothelial cells: role of membrane-bound NADH-/NADPH-oxidases. Cardiovasc Res 44:215–222PubMedCrossRefGoogle Scholar
  29. 29.
    Dohi Y, Hahn AW, Boulanger CM, Bühler FR, Lüscher TF (1992) Endothelin stimulated by angiotensin II augments contractility of spontaneously hypertensive rat resistance arteries. Hypertension 19:131–137PubMedGoogle Scholar
  30. 30.
    Pollock DM, Keith TL, Highsmith RF (1995) Endothelin receptors and calcium signaling. FASEB J 9:1196–1204PubMedGoogle Scholar
  31. 31.
    Hoffman A, Abassi ZA, Brodsky S, Ramadan R, Winaver J (2000) Mechanisms of big endothelin-1-induced diuresis and natriuresis: role of ET(B) receptors. Hypertension 35:732–739PubMedGoogle Scholar
  32. 32.
    Asano H, Shimizu K, Muramatsu M, Iwama Y, Toki Y, Miyazaki Y, Okumura K, Hashimoto H, Ito T (1994) Prostaglandin H2 as an endothelium-derived contracting factor modulates endothelin-1-induced contraction. J Hypertens 12:383–390PubMedCrossRefGoogle Scholar
  33. 33.
    Auch-Schwelk W, Vanhoutte PM (1992) Contractions to endothelin in normotensive and spontaneously hypertensive rats: role of endothelium and prostaglandins. Blood Press 1:45–49PubMedCrossRefGoogle Scholar
  34. 34.
    Taddei S, Vanhoutte PM (1993) Role of endothelium in endothelin-evoked contractions in the rat aorta. Hypertension 21:9–15PubMedGoogle Scholar
  35. 35.
    Jankowski V, Tolle M, Vanholder R, Schonfelder G, van der Giet M, Henning L, Schluter H, Paul M, Zidek W, Jankowski J (2005) Uridine adenosine tetraphosphate: a novel endothelium- derived vasoconstrictive factor. Nat Med 11:223–227PubMedCrossRefGoogle Scholar
  36. 36.
    Hirao A, Kondo K, Takeuchi K, Inui N, Umemura K, Ohashi K, Watanabe H (2008) Cyclooxygenase-dependent vasoconstricting factor(s) in remodelled rat femoral arteries. Cardiovasc Res 79:161–168PubMedCrossRefGoogle Scholar
  37. 37.
    Park SJ, Lee JJ, Vanhoutte PM (1999) Endothelin-1 releases endothelium-derived endoperoxides and thromboxane A2 in porcine coronary arteries with regenerated endothelium. Acta Pharmacol Sin 20:872–878Google Scholar
  38. 38.
    Lüscher TF, Vanhoutte PM (1986) Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 8:344–348PubMedGoogle Scholar
  39. 39.
    Gao YJ, Lee RM (2005) Hydrogen peroxide is an endothelium-dependent contracting factor in rat renal artery. Br J Pharmacol 146:1061–1068PubMedCrossRefGoogle Scholar
  40. 40.
    Nishimura Y, Usui H, Kurahashi K, Suzuki A (1995) Endothelium-dependent contraction induced by acetylcholine in isolated rat renal arteries. Eur J Pharmacol 275:217–221PubMedCrossRefGoogle Scholar
  41. 41.
    Taddei S, Virdis A, Mattei P, Salvetti A (1993) Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension 21:929–933PubMedGoogle Scholar
  42. 42.
    Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S (2009) Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol 157:527–536PubMedCrossRefGoogle Scholar
  43. 43.
    Tang EH, Leung FP, Huang Y, Feletou M, So KF, Man RY, Vanhoutte PM (2007) Calcium and reactive oxygen species increase in endothelial cells in response to releasers of endothelium-derived contracting factor. Br J Pharmacol 151:15–23PubMedCrossRefGoogle Scholar
  44. 44.
    Félétou M, Verbeuren TJ, Vanhoutte PM (2009) Endothelium-dependent contractions in SHR: a tale of prostanoid TP and IP receptors. Br J Pharmacol 156:563–574PubMedCrossRefGoogle Scholar
  45. 45.
    Ge T, Hughes H, Junquero DC, Wu KK, Vanhoutte PM, Boulanger CM (1995) Endothelium-dependent contractions are associated with both augmented expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin H2 in the SHR aorta. Circ Res 76:1003–1010PubMedGoogle Scholar
  46. 46.
    Gluais P, Lonchampt M, Morrow JD, Vanhoutte PM, Feletou M (2005) Acetylcholine-induced endothelium-dependent contractions in the SHR aorta: the Janus face of prostacyclin. Br J Pharmacol 146:834–845PubMedCrossRefGoogle Scholar
  47. 47.
    Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, Lipsky PE (1998) Cyclooxygenase in biology and disease. FASEB J 12:1063–1073PubMedGoogle Scholar
  48. 48.
    Yang D, Félétou M, Levens N, Zhang JN, Vanhoutte PM (2003) A diffusible substance(s) mediates endothelium-dependent contractions in the aorta of SHR. Hypertension 41:143–148PubMedCrossRefGoogle Scholar
  49. 49.
    Tang EH, Ku DD, Tipoe GL, Feletou M, Man RY, Vanhoutte PM (2005) Endothelium-dependent contractions occur in the aorta of wild-type and COX2−/− knockout but not COX1−/− knockout mice. J Cardiovasc Pharmacol 46:761–765PubMedCrossRefGoogle Scholar
  50. 50.
    Wong SL, Leung FP, Lau CW, Au CL, Yung LM, Yao X, Chen ZY, Vanhoutte PM, Gollasch M, Huang Y (2009) Cyclooxygenase-2-derived prostaglandin F2alpha mediates endothelium-dependent contractions in the aortae of hamsters with increased impact during aging. Circ Res 104:228–235PubMedCrossRefGoogle Scholar
  51. 51.
    Shi Y, Man RY, Vanhoutte PM (2008) Two isoforms of cyclooxygenase contribute to augmented endothelium-dependent contractions in femoral arteries of 1-year-old rats. Acta Pharmacol Sin 29:185–192PubMedCrossRefGoogle Scholar
  52. 52.
    Tang EH, Vanhoutte PM (2008) Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension. Physiol Genomics 32:409–418PubMedGoogle Scholar
  53. 53.
    Numaguchi Y, Harada M, Osanai H, Hayashi K, Toki Y, Okumura K, Ito T, Hayakawa T (1999) Altered gene expression of prostacyclin synthase and prostacyclin receptor in the thoracic aorta of spontaneously hypertensive rats. Cardiovasc Res 41:682–688PubMedCrossRefGoogle Scholar
  54. 54.
    Gluais P, Paysant J, Badier-Commander C, Verbeuren T, Vanhoutte PM, Félétou M (2006) In SHR aorta, calcium ionophore A-23187 releases prostacyclin and thromboxane A2 as endothelium-derived contracting factors. Am J Physiol Heart Circ Physiol 291:H2255–H2264PubMedCrossRefGoogle Scholar
  55. 55.
    Gluais P, Vanhoutte PM, Félétou M (2007) Mechanisms underlying ATP-induced endothelium-dependent contractions in the SHR aorta. Eur J Pharmacol 556:107–114PubMedCrossRefGoogle Scholar
  56. 56.
    Zou MH, Leist M, Ullrich V (1999) Selective nitration of prostacyclin synthase and defective vasorelaxation in atherosclerotic bovine coronary arteries. Am J Pathol 154:1359–1365PubMedGoogle Scholar
  57. 57.
    Zou MH, Shi C, Cohen RA (2002) High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H(2) receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes 51:198–203PubMedCrossRefGoogle Scholar
  58. 58.
    Bachschmid M, Thurau S, Zou MH, Ullrich V (2003) Endothelial cell activation by endotoxin involves superoxide/NO-mediated nitration of prostacyclin synthase and thromboxane receptor stimulation. FASEB J 17:914–916PubMedGoogle Scholar
  59. 59.
    Dai FX, Skopec J, Diederich A, Diederich D (1992) Prostaglandin H2 and thromboxane A2 are contractile factors in intrarenal arteries of spontaneously hypertensive rats. Hypertension 19:795–798PubMedGoogle Scholar
  60. 60.
    Auch-Schwelk W, Katusic ZS, Vanhoutte PM (1990) Thromboxane A2 receptor antagonists inhibit endothelium-dependent contractions. Hypertension 15:699–703PubMedGoogle Scholar
  61. 61.
    Kato T, Iwama Y, Okumura K, Hashimoto H, Ito T, Satake T (1990) Prostaglandin H2 may be the endothelium-derived contracting factor released by acetylcholine in the aorta of the rat. Hypertension 15:475–481PubMedGoogle Scholar
  62. 62.
    Yang D, Félétou M, Boulanger CM, Wu HF, Levens N, Zhang JN, Vanhoutte PM (2002) Oxygen-derived free radicals mediate endothelium-dependent contractions to acetylcholine in aortas from spontaneously hypertensive rats. Br J Pharmacol 136:104–110PubMedCrossRefGoogle Scholar
  63. 63.
    Tang EH, Jensen BL, Skott O, Leung GP, Feletou M, Man RY, Vanhoutte PM (2008) The role of prostaglandin E and thromboxane-prostanoid receptors in the response to prostaglandin E2 in the aorta of Wistar Kyoto rats and spontaneously hypertensive rat. Cardiovasc Res 78:130–138PubMedCrossRefGoogle Scholar
  64. 64.
    Rapoport RM, Williams SP (1996) Role of prostaglandins in acetylcholine-induced contraction of aorta from spontaneously hypertensive and Wistar-Kyoto rats. Hypertension 28:64–75PubMedGoogle Scholar
  65. 65.
    Shi Y, Feletou M, Ku DD, Man RY, Vanhoutte PM (2007) The calcium ionophore A23187 induces endothelium-dependent contractions in femoral arteries from rats with streptozotocin-induced diabetes. Br J Pharmacol 150:624–632PubMedCrossRefGoogle Scholar
  66. 66.
    Auch-Schwelk W, Katusic ZS, Vanhoutte PM (1989) Contractions to oxygen-derived free radicals are augmented in aorta of the spontaneously hypertensive rat. Hypertension 13:859–864PubMedGoogle Scholar
  67. 67.
    Li J, Li W, Li W, Altura BT, Altura BM (2004) Mechanisms of hydroxyl radical-induced contraction of rat aorta. Eur J Pharmacol 499:171–178PubMedCrossRefGoogle Scholar
  68. 68.
    Rodriguez-Martinez MA, Garcia-Cohen EC, Baena AB, Gonzalez R, Salaices M, Marin J (1998) Contractile responses elicited by hydrogen peroxide in aorta from normotensive and hypertensive rats. Endothelial modulation and mechanism involved. Br J Pharmacol 125:1329–1335PubMedCrossRefGoogle Scholar
  69. 69.
    Yang Z, Zheng T, Zhang A, Altura BT, Altura BM (1998) Mechanisms of hydrogen peroxide-induced contraction of rat aorta. Eur J Pharmacol 344:169–181PubMedCrossRefGoogle Scholar
  70. 70.
    Tang EH, Vanhoutte PM (2008) Gap junction inhibitors reduce endothelium-dependent contractions in the aorta of spontaneously hypertensive rats. J Pharmacol Exp Ther 327:148–153PubMedCrossRefGoogle Scholar
  71. 71.
    Katusic ZS, Vanhoutte PM (1989) Superoxide anion is an endothelium-derived contracting factor. Am J Physiol 257:H33–H37PubMedGoogle Scholar
  72. 72.
    Neunteufl T, Katzenschlager R, Hassan A, Klaar U, Schwarzacher S, Glogar D, Bauer P, Weidinger F (1997) Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 129:111–118PubMedCrossRefGoogle Scholar
  73. 73.
    Sayed N, Kim DD, Fioramonti X, Iwahashi T, Durán WN, Beuve A (2008) Nitroglycerin-induced S-nitrosylation and desensitization of soluble guanylyl cyclase contribute to nitrate tolerance. Circ Res 103:606–614PubMedCrossRefGoogle Scholar
  74. 74.
    Sydow K, Daiber A, Oelze M, Chen Z, August M, Wendt M, Ullrich V, Mülsch A, Schulz E, Keaney JF Jr, Stamler JS, Münzel T (2004) Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance. J Clin Invest 113:482–489PubMedGoogle Scholar
  75. 75.
    Katusic ZS (2001) Vascular endothelial dysfunction: does tetrahydrobiopterin play a role? Am J Physiol Heart Circ Physiol 281:H981–H986PubMedGoogle Scholar
  76. 76.
    Vásquez-Vivar J (2009) Tetrahydrobiopterin, superoxide, and vascular dysfunction. Free Radic Biol Med 47:1108–1119PubMedCrossRefGoogle Scholar
  77. 77.
    Gokce N (2004) l-Arginine and hypertension. J Nutr 134:2807S–2811SPubMedGoogle Scholar
  78. 78.
    Lekakis JP, Papathanassiou S, Papaioannou TG, Papamichael CM, Zakopoulos N, Kotsis V, Dagre AG, Stamatelopoulos K, Protogerou A, Stamatelopoulos SF (2002) Oral l-arginine improves endothelial dysfunction in patients with essential hypertension. Int J Cardiol 86:317–323PubMedCrossRefGoogle Scholar
  79. 79.
    Miller AL (2006) The effects of sustained-release l-arginine formulation on blood pressure and vascular compliance in 29 healthy individuals. Altern Med Rev 11:23–29PubMedGoogle Scholar
  80. 80.
    Auch-Schwelk W, Katusić ZS, Vanhoutte PM (1992) Nitric oxide inactivates endothelium-derived contracting factor in the rat aorta. Hypertension 19:442–445PubMedGoogle Scholar
  81. 81.
    Feletou M, Tang EH, Vanhoutte PM (2008) Nitric oxide the gatekeeper of endothelial vasomotor control. Front Biosci 13:4198–4217PubMedCrossRefGoogle Scholar
  82. 82.
    Tang EH, Feletou M, Huang Y, Man RY, Vanhoutte PM (2005) Acetylcholine and sodium nitroprusside cause long-term inhibition of EDCF-mediated contractions. Am J Physiol Heart Circ Physiol 289:H2434–2440PubMedCrossRefGoogle Scholar
  83. 83.
    Yang D, Gluais P, Zhang JN, Vanhoutte PM, Félétou M (2004) Nitric oxide and inactivation of the endothelium-dependent contracting factor released by acetylcholine in spontaneously hypertensive rat. J Cardiovasc Pharmacol 43:815–820PubMedCrossRefGoogle Scholar
  84. 84.
    Mancini GB, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Lüscher TF, Klibaner MI, Haber HE, Uprichard AC, Pepine CJ, Pitt B (1996) Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation 94:258–265PubMedGoogle Scholar
  85. 85.
    Taddei S, Virdis A, Ghiadoni L, Sudano I, Salvetti A (2002) Effects of antihypertensive drugs on endothelial dysfunction: clinical implications. Drugs 62:265–284PubMedCrossRefGoogle Scholar
  86. 86.
    Godfraind T (2005) Antioxidant effects and the therapeutic mode of action of calcium channel blockers in hypertension and atherosclerosis. Philos Trans R Soc Lond B Biol Sci 360:2259–2272PubMedCrossRefGoogle Scholar
  87. 87.
    Batova S, DeWever J, Godfraind T, Balligand JL, Dessy C, Feron O (2006) The calcium channel blocker amlodipine promotes the unclamping of eNOS from caveolin in endothelial cells. Cardiovasc Res 71:478–485PubMedCrossRefGoogle Scholar
  88. 88.
    Lenasi H, Kohlstedt K, Fichtlscherer B, Mülsch A, Busse R, Fleming I (2003) Amlodipine activates the endothelial nitric oxide synthase by altering phosphorylation on Ser1177 and Thr495. Cardiovasc Res 59:844–853PubMedCrossRefGoogle Scholar
  89. 89.
    van Amsterdam FT, Roveri A, Maiorino M, Ratti E, Ursini F (1992) Lacidipine: a dihydropyridine calcium antagonist with antioxidant activity. Free Radic Biol Med 12:183–187PubMedCrossRefGoogle Scholar
  90. 90.
    Kalinowski L, Dobrucki LW, Szczepanska-Konkel M, Jankowski M, Martyniec L, Angielski S, Malinski T (2003) Third-generation beta-blockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation 107:2747–2752PubMedCrossRefGoogle Scholar
  91. 91.
    Moncada S, Vane JR (1997) The role of prostacyclin in vascular tissue. Fed Proc 38:66–71Google Scholar
  92. 92.
    Salinas G, Rangasetty UC, Uretsky BF, Birnbaum Y (2007) The cycloxygenase 2 (COX-2) story: it's time to explain, not inflame. J Cardiovasc Pharmacol Ther 12:98–111PubMedCrossRefGoogle Scholar
  93. 93.
    Belhassen L, Pelle G, Dubois-Rande J, Adnot S (2003) Improved endothelial function by the thromboxane a2 receptor antagonist S18886 in patients with coronary artery disease treated with aspirin. J Am Coll Cardiol 41:1198–1204PubMedCrossRefGoogle Scholar
  94. 94.
    Behm DJ, Ogbonna A, Wu C, Burns-Kurtis CL, Douglas SA (2009) Epoxyeicosatrienoic acids function as selective, endogenous antagonists of native thromboxane receptors: identification of a novel mechanism of vasodilation. J Pharmacol Exp Ther 328:231–239PubMedCrossRefGoogle Scholar

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© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Division of Cardiovascular Medicine, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  2. 2.Department Pharmacology and Pharmacy, Li Ka Shing Faculty of MedicineUniversity of Hong KongHong KongChina
  3. 3.Department BIN Fusion TechnologyChonbuk National UniversityJeonjuKorea

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