Current Hypertension Reports

, Volume 2, Issue 1, pp 64–70 | Cite as

Antihypertensive drugs and reversing of endothelial dysfunction in hypertension

  • Stefano Taddei
  • Agostino Virdis
  • Lorenzo Ghiadoni
  • Isabella Sudano
  • Antonio Salvetti


Essential hypertension is associated with impaired endothelium-dependent vasodilation and is caused mainly by production of oxygen free radicals that can destroy nitric oxide (NO), impairing its beneficial and protective effects on the vessel wall. Antihypertensive drugs can improve or restore endothelium-dependent vasodilation depending on their ability to counteract the mechanisms that impair endothelial function. Although treatment with atenolol gives negative results in peripheral subcutaneous and muscle microcirculation, acute nebivolol exerts a modest vasodilating effect in the forearm circulation. Whether this compound can activate NO production in essential hypertensive patients is controversial. Calcium entry blockers, particularly the dihydropyridine-like drugs, can reverse impaired endothelium-dependent vasodilation in different vascular districts, including the subcutaneous, epicardial, and peripheral arteries and forearm circulation. In the forearm circulation, nifedipine and lacidipine can improve endothelial dysfunction by restoring NO availability. Angiotensin-converting enzyme (ACE) inhibitors, however, seem to improve endothelial function in subcutaneous, epicardial, and renal circulation, but are ineffective in potentiating the blunted response to acetylcholine in the forearm of patients with essential hypertension. Finally, recent evidence suggests angiotensin II receptor antagonists can restore endothelium-dependent vasodilation t acetylcholine in subcutaneous, but not in the forearm muscle, microcirculation. However, treatment with an angiotensin II receptor antagonist can improve basal NO release and decrease the vasoconstrictor effect of endogenous endothelin-1.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Luscher TF, Vanhoutte PM: The Endothelium: Modulator of Cardiovascular Function. Boca Raton, FL: CRC Press; 1990.Google Scholar
  2. 2.
    Miller VM, Vanhoutte PM: Endothelium-dependent contractions to arachidonic acid are mediated by products of cyclooxygenase. Am J Physiol 1985, 248:H432-H437.PubMedGoogle Scholar
  3. 3.
    Katusic ZS, Vanhoutte PM: Superoxide anion is an endothelium-derived contracting factor. Am J Physiol 1989, 257:H33-H37.PubMedGoogle Scholar
  4. 4.
    Gryglewski RJ, Palmer RMJ, Moncada S: Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 1986, 320:454–456.PubMedCrossRefGoogle Scholar
  5. 5.
    Taddei S, Virdis A, Ghiadoni L, Salvetti A: The role of endothelium in human hypertension. Curr Opin Nephrol Hypertens 1998, 7:203–209.PubMedGoogle Scholar
  6. 6.
    Taddei S, Virdis A, Ghiadoni L, et al.: Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 1998, 97:2222–2229.PubMedGoogle Scholar
  7. 7.
    Ruschitzka F, Noll G, Luscher TF: Angiotensin converting enzyme inhibitors and vascular protection in hypertension. J Cardiovasc Pharmacol 1999, 34(suppl 1):S3-S12.PubMedGoogle Scholar
  8. 8.
    Panza JA, Quyyumi AA, Callahan TS, Epstein SE: Effect of antihypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertension. J Am Coll Cardiol 1993, 21:1145–1151.PubMedCrossRefGoogle Scholar
  9. 9.
    Lyons D, Webster J, Benjamin N: The effect of antihypertensive therapy on responsiveness to local intra-arterial NG-monomethyl-L-arginine in patients with essential hypertension. J Hypertens 1994, 12:1047–1052.PubMedGoogle Scholar
  10. 10.
    Schiffrin LE, Deng LY: Structure and function of resistance arteries of hypertensive patients treated with a ß-blocker or a calcium channel antagonist. J Hypertens 1996, 14:1247–1255.PubMedCrossRefGoogle Scholar
  11. 11.
    Gao Y, Nagao T, Bond RA, et al.: Nebivolol induces endothelium-dependent relaxations of canine coronary arteries. J Cardiovasc Pharmacol 1991, 17:964–969.PubMedCrossRefGoogle Scholar
  12. 12.
    Cockcroft JR, Chowienczyk PJ, Brett SE, et al.: Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther 1995, 274:1067–1071.PubMedGoogle Scholar
  13. 13.
    Dawes M, Brett SE, Chowienczyk PJ, et al.: The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension. Br J Clin Pharmacol 1999, 48:460–463.PubMedCrossRefGoogle Scholar
  14. 14.
    Watanabe H, Nakagawa K: Carvedilol improves endothelial dysfunction in patients with essential hypertension. Circulation 1999, 100:I-104 (Abs).Google Scholar
  15. 15.
    Feuerstein GZ, Ruffolo RR: Carvedilol, a novel multiple action antihypertensive agent with antioxidant activity and the potential for myocardial and vascular protection. Eur Heart J 1995, 16(suppl F):38–42.PubMedGoogle Scholar
  16. 16.
    Vanhoutte PM: Vascular endothelium and Ca2+-antagonists. J Cardiovasc Pharmacol 1988, 12(suppl 6):21–28.Google Scholar
  17. 17.
    Tschudi MR, Criscione L, Novosel D, et al.: Antihypertensive therapy augments endothelium-dependent relaxations in coronary arteries of spontaneously hypertensive rats. Circulation 1994, 89:2212–2218. This major study evaluates the effect of different antihypertensive treatments on endothelial function in an experimental model of hypertension.PubMedGoogle Scholar
  18. 18.
    Takase H, Moreau P, Küng CF, et al.: Antihypertensive therapy prevents endothelial dysfunction in chronic nitric oxide deficiency. Effect of verapamil and trandolapril. Hypertension 1996, 27:25–31.PubMedGoogle Scholar
  19. 19.
    Frielingsdorf J, Seiler C, Kauffman P, et al.: Normalization of abnormal coronary vasomotion by calcium antagonists in patients with hypertension. Circulation 1996, 93:1380–1387. This major study first demonstrates that calcium antagonists can improve endothelial function in the coronary circulation of normotensive subjects with atherosclerotic lesions and essential hypertensive patients with and without atherosclerotic lesions.PubMedGoogle Scholar
  20. 20.
    Muiesan ML, Salvetti M, Monteduro C, et al.: Effect of treatment on flow-dependent vasodilation of the brachial artery in essential hypertension. Hypertension 1999, 33(pt 2):575–580.PubMedGoogle Scholar
  21. 21.
    Taddei S, Virdis A, Ghiadoni L, et al.: Lacidipine restores endothelium-dependent vasodilation in essential hypertensive patients. Hypertension 1997, 30:1606–1612.PubMedGoogle Scholar
  22. 22.
    Taddei S, Virdis A, Ghiadoni L, et al.: Nifedipine enhances endothelium-dependent relaxations and inhibits contractions to endothelin-1 and phenylephrine in human hypertension. Circulation 1997, 96(suppl I):I-762 (abs).Google Scholar
  23. 23.
    Luscher TF, Yang Z: Calcium antagonists and ACE-inhibitors: effect on endothelium and vascular smooth muscle cells. Drugs 1993, 46(suppl 2):121–132.PubMedCrossRefGoogle Scholar
  24. 24.
    Lupo E, Locher R, Weisse B, Vetter W: In vitro antioxidant activity of calcium antagonists against LDL oxidation compared with α-tocopherol. Biochem Biophys Res Comm 1994, 203:1803–1808.PubMedCrossRefGoogle Scholar
  25. 25.
    Mak TI, Boehme P, Weglicki WB: Antioxidant effects of calcium channel blockers against free radical injury in endothelial cells. Circ Res 1992, 70:1099–1103. This is an interesting study supporting the concept that calcium antagonists show antioxidant effects.PubMedGoogle Scholar
  26. 26.
    Virdis A, Taddei S, Buralli S, et al.: Nifedipine improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Am J Hypertens 1999, 12(n 4, pt 2):57A (Abs).Google Scholar
  27. 27.
    Taddei S, Virdis A, Ghiadoni L, et al.: Different effect of a calcium-antagonist and a beta-blocker on nitric oxide availability in essential hypertensive patients. J Hypertens 1999, 17:s129 (Abs).Google Scholar
  28. 28.
    Rajagopalan S, Kurz S, Munzel T, et al.: Angiotensin II mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alteration of vasomotor tone. J Clin Invest 1996, 97:1916–1923. This major study demonstrates the role of angiotensin II in causing endothelial dysfunction. This angiotensin II-mediated effect is related to AT-1 receptor activation.PubMedCrossRefGoogle Scholar
  29. 29.
    Schiffrin EL: Correction of remodeling and function of small arteries in human hypertension by cilazapril, an angiotensin I-converting enzyme inhibitor. J Cardiovasc Pharmacol 1996, 27(suppl 2):S13-S18.PubMedCrossRefGoogle Scholar
  30. 30.
    Schiffrin EL, Deng Li-Y: Comparison of effects of angiotensin I-converting enzyme inhibition and ß-blockade for 2 years on function of small arteries from hypertensive patients. Hypertension 1995, 25(pt 2):699–703.PubMedGoogle Scholar
  31. 31.
    Rizzoni D, Muiesan ML, Porteri E, et al.: Effects of long-term antihypertensive treatment with lisinopril on resistance arteries in hypertensive patients with left ventricular hypertrophy. J Hypertens 1997, 15:197–204.PubMedCrossRefGoogle Scholar
  32. 32.
    Antony I, Lerebours G, Nitenberg A: Angiotensin-converting enzyme inhibition restores flow-dependent and cold pressor test-induced dilations in coronary arteries of hypertensive patients. Circulation 1996, 94:3115–3122. This very elegant study demonstrates that acute administration of an ACE-inhibitor can restore endothelial function in the epicardial coronary arteries of essential hypertensive patients.PubMedGoogle Scholar
  33. 33.
    Mancini GBJ, Henry GC, Macaya C, et al.: 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 1996, 94:258–265. This study demonstrates that ACE-inhibitor treatment can improve the response to acetylcholine in patients with coronary artery disease.PubMedGoogle Scholar
  34. 34.
    Mimran A, Ribstein J, DuCailar G: Contrasting effect of antihypertensive treatment on the renal response to L-Arginine. Hypertension 1995, 26(pt 1):937–941.PubMedGoogle Scholar
  35. 35.
    Creager MA, Roddy MA: Effect of captopril and enalapril on endothelial function in hypertensive patients. Hypertension 1994, 24:499–505.PubMedGoogle Scholar
  36. 36.
    Kiowski W, Linder L, Nuesch R, Martina B: Effect of cilazapril on vascular structure and function in essential hypertension. Hypertension 1996, 27(pt 1):371–376.PubMedGoogle Scholar
  37. 37.
    Taddei S, Virdis A, Mattei P, et al.: Effect of lisinopril on endothelial function. J Hypertens 1998, 16:447–456.PubMedCrossRefGoogle Scholar
  38. 38.
    Taddei S, Ghiadoni L, Virdis A, et al.: Vasodilation to bradikinin is mediated by an ouabain-sensitive pathway as a compensatory mechanism for impaired nitric oxide availability in essential hypertension. Circulation 1999, 100:1400–1405. This study demonstrates the existence of bradykinin-activated NO-independent pathway in essential hypertensive patients. ACE-inhibitor treatment can potentiate this pathway.PubMedGoogle Scholar
  39. 39.
    Hahn AW, Resink TJ, Scott-Burden T, et al.: Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. Cell Regul 1990, 1:649–659.PubMedGoogle Scholar
  40. 40.
    Lin L, Mistry M, Stier CT Jr, Nasjletti A: Role of prostanoids in renin-dependent and renin-independent hypertension. Hypertension 1991, 17:517–525.PubMedGoogle Scholar
  41. 41.
    Harrison DG, Venema RC, Arnal JF, et al.: The endothelial cell nitric oxide synthase: is it really constitutively expressed? Agent Actions 1995, 45:107–117.Google Scholar
  42. 42.
    Griendling K, Ollerenshaw JD, Minieri CA, Alexander RW: Angiotensin II stimulates NADH and NADPH activity in cultured vascular smooth muscle cells. Circ Res 1994, 74:1141–1148.PubMedGoogle Scholar
  43. 43.
    Maeso R, Navarro-Cid J, Munoz-García R, et al.: Losartan reduces phenylephrine constrictor response in aortic rings from spontaneously hypertensive rats. Hypertension 1996, 28:967–972.PubMedGoogle Scholar
  44. 44.
    Wiemer G, Scholkens BA, Busse R, et al.: The functional role of angiotensin II subtype AT2-receptors in endothelial cells and isolated ischemic rat hearts. Pharm Pharmacol Lett 1993, 3:24–27.Google Scholar
  45. 45.
    Seyedi N, Xu X, Nasjletti A, Hintze TH: Coronary kinin generation mediated nitric oxide release after angiotensin receptor stimulation. Hypertension 1995, 26:164–170.PubMedGoogle Scholar
  46. 46.
    Park JB, Integan D, Schiffrin EL: AT1 angiotensin receptor antagonist treatment normalizes resistance artery structure and function in essential hypertension. Circulation 1999, 100:I-105 (Abs).Google Scholar
  47. 47.
    Ghiadoni L, Virdis A, Magagna A, et al.: Effect of the angiotensin II receptor blocker candesartan on endothelial function in patients with essential hypertension. Hypertension 1999. In press.Google Scholar
  48. 48.
    Taddei S, Virdis A, Ghiadoni L, et al.: Vasoconstriction to endogenous endothelin-1 is increased in the peripheral circulation of patients with essential hypertension. Circulation 1999, 100:1680–1683.PubMedGoogle Scholar

Copyright information

© Current Science Inc 2000

Authors and Affiliations

  • Stefano Taddei
    • 1
  • Agostino Virdis
    • 1
  • Lorenzo Ghiadoni
    • 1
  • Isabella Sudano
    • 1
  • Antonio Salvetti
    • 1
  1. 1.Department of Internal MedicineUniversity of Pisa, ItalyPisaItaly

Personalised recommendations