Advances in Therapy

, Volume 18, Issue 2, pp 57–66 | Cite as

Valsartan and the kidney: Review of preclinical and clinical data

  • Luis M. Ruilope


In both diabetic and nondiabetic renal disease, reducing blood pressure with antihypertensive therapy has beneficial effects on renal function. The key role of the renin-angiotensin system in blood pressure and volume homeostasis has long been established, but its importance for the overall normal functioning of the kidney itself is also increasingly being recognized. Angiotensin-converting enzyme (ACE) inhibitors, widely and successfully used in the treatment of hypertension, may also provide renal protection independent of blood pressure reduction; however, their relatively nonspecific mode of action in blocking an early metabolic step entails major clinical disadvantages, such as accumulation of bradykinin and substance P, that may cause the characteristic ACE-inhibitor side effects of persistent dry cough and, more rarely, angioneurotic edema. Angiotensin II antagonists or receptor blockers, a new class of antihypertensive agent, selectively antagonize the AT1 receptor subtype and, because of greater specificity, do not give rise to the side effects associated with ACE inhibitors. More important, these new drugs may have mechanistic advantages over other antihypertensives, including ACE inhibitors.


ACE inhibitors angiotensin hypertension renal function renin-angiotensin system 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Parving HH, Hommel E. Prognosis in diabetic nephropathy.BMJ. 1989; 299:230–233.PubMedGoogle Scholar
  2. 2.
    Christiansen CK, Modensen CE. Effect of antihypertensive treatment on progression of incipient diabetic nephropathy.Hypertension. 1985;7:109–113.Google Scholar
  3. 3.
    Sealey JE, Laragh JH. The renin-angiotensin-aldosterone system for normal regulation of blood pressure and sodium and potassium homeostasis. In: Brenner BM, Laragh JH, eds.Hypertension. New York, NY: Raven Press; 1990:1287–1319.Google Scholar
  4. 4.
    Johnston C, Fabris B, Jandeleit K. Intrarenal renin-angiotensin system in renal physiology and pathophysiology.Kidney Int. 1993;44:59–63.Google Scholar
  5. 5.
    MacGregor GA. Blood pressure, angiotensin converting enzyme (ACE) inhibitors and the kidney.Am J Med. 1992;92:20S-27S.PubMedCrossRefGoogle Scholar
  6. 6.
    Weidmann P, Boehlen LM, de Courten M, Ferrari P. Antihypertensive therapy in diabetic patients.J Hum Hypertens. 1992;6:S23-S36.PubMedGoogle Scholar
  7. 7.
    Bohlen L, de Courten M, Weidmann P. Comparative study of the effect of ACE-inhibitors and other antihypertensive agents on proteinuria in diabetic patients.Am J Hypertens. 1994;7:84S-92S.PubMedGoogle Scholar
  8. 8.
    Mimran A. Renal effects of antihypertensive agents in parenchymal renal disease and renovascular hypertension.J Cardiovasc Pharmacol. 1992;19:S45-S50.PubMedCrossRefGoogle Scholar
  9. 9.
    Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.N Engl J Med. 1996;334:939–945.PubMedCrossRefGoogle Scholar
  10. 10.
    Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology.Ann Intern Med. 1992;117:234–242.PubMedGoogle Scholar
  11. 11.
    Morice AH, Brown MJ, Higenbottam T. Cough associated with angiotensin converting enzyme inhibition.J Cardiovasc Pharmacol. 1989;13:S59-S62.PubMedCrossRefGoogle Scholar
  12. 12.
    Clauser E, Curnow KM, Davies E, et al. Angiotensin II receptors: protein and gene structures, expression and potential pathological involvements.Eur J Endocrinol. 1996;134:403–411.PubMedGoogle Scholar
  13. 13.
    Inagami T, Guo DF, Kitami Y. Molecular biology of angiotensin II receptors: an overview.J Hypertens Suppl. 1994;12:S83-S94.PubMedGoogle Scholar
  14. 14.
    de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International Union of Pharmacology, XXIII: the angiotensin II receptors.Pharmacol Rev. 2000;52:415–472.PubMedGoogle Scholar
  15. 15.
    Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists.N Engl J Med. 1996;334:1649–1654.PubMedCrossRefGoogle Scholar
  16. 16.
    Zitnay C, Siragy HM. Action of angiotensin receptor subtypes on the renal tubules and vasculature: implications for volume homeostasis and atherosclerosis.Miner Electrolyte Metab. 1998;24:362–370.PubMedCrossRefGoogle Scholar
  17. 17.
    de Gasparo M, Levens NR. Pharmacology of angiotensin II receptors in the kidney.Kidney Int. 1994;46:1486–1491.PubMedCrossRefGoogle Scholar
  18. 18.
    Goldfarb DA, Diz DI, Tubbs RR, Ferrario CM, Novick AC. Angiotensin II receptor subtypes in the human renal cortex and renal cell carcinoma.J Urol. 1994;151:208–213.PubMedGoogle Scholar
  19. 19.
    Ozono R, Wang ZQ, Moore AF, Inagami T, Siragy HM, Carey RM. Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney.Hypertension. 1997;30:1238–1246.PubMedGoogle Scholar
  20. 20.
    Lo M, Liu KL, Lantelme P, Sassard J. Subtype 2 of angiotensin II receptors controls pressurenatriuresis in rats.J Clin Invest. 1995;95:1394–1397.PubMedCrossRefGoogle Scholar
  21. 21.
    Siragy HM, Inagami T, Ichiki T, Carey RM. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor.Proc Natl Acad Sci USA. 1999;96:6506–6510.PubMedCrossRefGoogle Scholar
  22. 22.
    Criscione L, Bradley WA, Bühlmayer P, et al. Valsartan: preclinical and clinical profile of an antihypertensive angiotensin II antagonist.Cardiovasc Drug Rev. 1995;13:230–250.CrossRefGoogle Scholar
  23. 23.
    Weber MA. Clinical experience with the angiotensin II receptor antagonist losartan. A preliminary report.Am J Hypertens. 1992;5:247S-251S.PubMedGoogle Scholar
  24. 24.
    Li XC, Widdop RE. Regional haemodynamic effects of the AT1 receptor antagonist, valsartan, in conscious spontaneously hypertensive rats.J Hypertens. 1996;14:S93.Google Scholar
  25. 25.
    Endlich K, Steinhausen M. Role of kinins and angiotensin II in the vasodilating action of angiotensin converting enzyme inhibition in rat renal vessels.J Hypertens. 1997;15:633–641.PubMedCrossRefGoogle Scholar
  26. 26.
    Hayashi N, Yamamoto S, Kometani M, Nakao K. Pharmacological profile of valsartan, a nonpeptide angiotensin II type 1 receptor antagonist. Third communication: hemodynamic effects of valsartan in rats and dogs.Arzneimittelforschung. 1997;47:620–625.PubMedGoogle Scholar
  27. 27.
    Arima S, Endo Y, Yaoita H, et al. Possible role of P-450 metabolite of arachidonic acid in vasodilator mechanism of angiotensin II type 2 receptor in the isolated microperfused rabbit afferent arteriole.J Clin Invest. 1997;100:2816–2823.PubMedCrossRefGoogle Scholar
  28. 28.
    Ajikobi DO, Novak P, Salevsky FC, Cupples WA. Pharmacological modulation of spontaneous renal blood flow dynamics.Can J Physiol Pharmacol. 1996;74:964–972.PubMedCrossRefGoogle Scholar
  29. 29.
    Jaiswal N, Diz DI, Chappell MC, Khosla MC, Ferrario CM. Stimulation of endothelial cell prostaglandin production by angiotensin peptides. Characterization of receptors.Hypertension. 1992;19:II49-II55.PubMedGoogle Scholar
  30. 30.
    Siragy HM, Carey RM. The subtype 2 (AT1) angiotensin receptor mediates renal production of nitric oxide in conscious rats.J Clin Invest. 1997;100:264–269.PubMedCrossRefGoogle Scholar
  31. 31.
    Siragy HM, Carey RM. The subtype 2 angiotensin receptor regulates renal prostaglandin F2 alpha formation in conscious rats.Am J Physiol. 1997;273:R1103-R1107.PubMedGoogle Scholar
  32. 32.
    Siragy HM, Senbonmatsu T, Ichiki T, Inagami T, Carey RM. Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor.J Clin Invest. 1999;104:181–188.PubMedCrossRefGoogle Scholar
  33. 33.
    Lafayette RA, Mayer G, Park SK, Meyer TW. Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass.J Clin Invest. 1992;90:766–771.PubMedCrossRefGoogle Scholar
  34. 34.
    Remuzzi G, Ruggenenti P. Slowing the progression of diabetic nephropathy.N Engl J Med. 1993; 329:1496–1497.PubMedCrossRefGoogle Scholar
  35. 35.
    Kim S, Ohta K, Hamaguchi A, et al. Role of angiotensin II in renal injury of deoxycorticosterone acetate-salt hypertensive rats.Hypertension. 1994;24:195–204.PubMedGoogle Scholar
  36. 36.
    Gansevoort RT, de Zeeuw D, de Jong PE. Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system?Kidney Int. 1994;45:861–867.PubMedCrossRefGoogle Scholar
  37. 37.
    de Gasparo M, Levens N. Does blockade of angiotensin II receptors offer clinical benefits over inhibition of angiotensin-converting enzyme?Pharmacol Toxicol. 1998;82:257–271.PubMedGoogle Scholar
  38. 38.
    Munoz-Garcia R, Maeso R, Rodrigo E, et al. Acute renal excretory actions of losartan in spontaneously hypertensive rats: role of AT2 receptors, prostaglandins, kinins and nitric oxide.J Hypertens. 1995;13:1779–1784.PubMedCrossRefGoogle Scholar
  39. 39.
    Siragy HM, Carey RM. The subtype-2 (AT2) angiotensin receptor regulates renal cyclic guanosine 3′, 5′-monophosphate and AT1 receptor-mediated prostaglandin E2 production in conscious rats.J Clin Invest. 1996;97:1978–1982.PubMedCrossRefGoogle Scholar
  40. 40.
    Wu L, Iwai M, Nakagami H, Chen R. AT1 receptor blocker improves pressure-overload induced cardiac remodeling via AT1 receptor inhibition and AT2 receptor stimulation: study using AT2 receptor null mice.Circulation. 2000;102:II-72.Google Scholar
  41. 41.
    Remuzzi A, Malanchini B, Battaglia C, Bertani T, Remuzzi G. Comparison of the effects of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade on the evolution of spontaneous glomerular injury in male MWF/Ztm rats.Exp Nephrol. 1996;4:19–25.PubMedGoogle Scholar
  42. 42.
    Baylis C, Engels K, Samsell L, Harton P. Renal effects of acute endothelial-derived relaxing factor blockade are not mediated by angiotensin II.Am J Physiol. 1993;264:F74-F78.PubMedGoogle Scholar
  43. 43.
    Xie MH, Liu FY, Wong PC, Timmermans PB, Cogan MG. Proximal nephron and renal effects of DuP 753, a nonpeptide angiotensin II receptor antagonist.Kidney Int. 1990;38:473–479.PubMedCrossRefGoogle Scholar
  44. 44.
    Burnier M, Pechere-Bertschi A, Nussberger J, Waeber B, Brunner HR. Studies of the renal effects of angiotensin II receptor blockade: the confounding factor of acute water loading on the action of vasoactive systems.Am J Kidney Dis. 1995;26:108–115.PubMedGoogle Scholar
  45. 45.
    Kometani M, Hayashi N, Yamamoto S, Nakao K, Inukai T. Pharmacological profile of valsartan, a non-peptide angiotensin II type 1 receptor antagonist. Second communication: valsartan prevents end-organ damage in spontaneously hypertensive stroke-prone rats during 1-year treatment.Arzneimittelforschung. 1997;47:613–619.PubMedGoogle Scholar
  46. 46.
    Webb RL, Barclay BW, Navarrete AE, Wosu NJ, Sahota P. Protective effects of valsartan and benazeprilat in salt-loaded stroke-prone spontaneously hypertensive rats.Clin Exp Hypertens. 1998;20:775–793.PubMedGoogle Scholar
  47. 47.
    Wu LL, Cox A, Roe CJ, Dziadek M, Cooper ME, Gilbert RE. Transforming growth factor beta 1 and renal injury following subtotal nephrectomy in the rat: role of the renin-angiotensin system.Kidney Int. 1997;51:1553–1567.PubMedCrossRefGoogle Scholar
  48. 48.
    Allen TJ, Cao Z, Youssef S, Hulthen UL, Cooper ME. Role of angiotensin II and bradykinin in experimental diabetic nephropathy. Functional and structural studies.Diabetes. 1997;46:1612–1618.PubMedCrossRefGoogle Scholar
  49. 49.
    Remuzzi A, Fassi A, Sangalli F, et al. Prevention of renal injury in diabetic MWF rats by angiotensin II antagonism.Exp Nephrol. 1998;6:28–38.PubMedCrossRefGoogle Scholar
  50. 50.
    Amuchastegui SC, Azzollini N, Mister M, Pezzotta A, Perico N, Remuzzi G. Chronic allograft nephropathy in the rat is improved by angiotensin II receptor blockade but not by calcium channel antagonism.J Am Soc Nephrol. 1998;9:1948–1955.PubMedGoogle Scholar
  51. 51.
    Fricker AF, Nussberger J, Meilenbrock S, Brunner HR, Burnier M. Effect of indomethacin on the renal response to angiotensin II receptor blockade in healthy subjects.Kidney Int. 1998;54:2089–2097.PubMedCrossRefGoogle Scholar
  52. 52.
    Burnier M, Rutschmann B, Nussberger J, et al. Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.Hypertension. 1993;22:339–347.PubMedGoogle Scholar
  53. 53.
    Plum J, Bunten B, Nemeth R, Grabensee B. Effects of the angiotensin II antagonist valsartan on blood pressure, proteinuria, and renal hemodynamics in patients with chronic renal failure and hypertension.J Am Soc Nephrol. 1998;9:2223–2234.PubMedGoogle Scholar
  54. 54.
    Prasad P, Mangat S, Choi L, et al. Effect of renal function on the pharmacokinetics of valsartan.Clin Pharmacokinet. 1997;13:207–214.Google Scholar
  55. 55.
    Kaplan NM.Clinical Hypertension. Baltimore, Md: Williams & Wilkins; 1994.Google Scholar
  56. 56.
    Perico N, Spormann D, Peruzzi E, Bodin F, Sioufi A, Bertocchi F. Efficacy and tolerability of valsartan compared with lisinopril in patients with hypertension and renal insufficiency.Clin Drug Invest. 1997;14:252–259.CrossRefGoogle Scholar
  57. 57.
    Brookman LJ, Rolan PE, Benjamin IS, et al. Pharmacokinetics of valsartan in patients with liver disease.Clin Pharmacol Ther. 1997;62:272–278.PubMedCrossRefGoogle Scholar
  58. 58.
    Faulhaber HD, Mann JF, Stein G, et al. Effect of valsartan on renal function in hypertensive patients with stable renal insufficiency.Curr Ther. 1999;60:170–183.CrossRefGoogle Scholar
  59. 59.
    Pickering TG. Renovascular hypertension. Medical evaluation and non-surgical treatment. In: Laragh JH, Brenner BM, eds.Hypertension: Pathophysiology, Diagnosis and Management. New York, NY: Raven Press; 1990:1539–1560.Google Scholar
  60. 60.
    Arzilli F, Favilla S, Motolese M, Peruzzi E, Oddou-Stock P, Salvetti A. Tolerability and effects on renal function in patients with renovascular arterial hypertension.High Blood Press Cardiovasc Prevent. 1997;6:153–158.Google Scholar
  61. 61.
    Viberti G, Mogensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria.JAMA. 1994;271:275–279.PubMedCrossRefGoogle Scholar
  62. 62.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.N Engl J Med. 1993;329:1456–1462.PubMedCrossRefGoogle Scholar
  63. 63.
    Lukman LF, Berk LS, Tan LG, Tan SA. Losartan regresses left ventricular hypertrophy, improves ejection fraction, and decreases proteinuria in hypertensive diabetics.J Invest Med. 1996;44:337A.Google Scholar
  64. 64.
    Muirhead N, Feagan BF, Mahon J. The effects of valsartan and captopril on reducing microalbuminuria in patients with type 2 diabetes mellitus: a placebo-controlled trial.Curr Ther Res. 2000;60:650–660.CrossRefGoogle Scholar
  65. 65.
    Wheeldon VM, on behalf of the MARVAL Investigators. Microalbuminuria reduction with valsartan. Presented at: ASH 2001; May 15–19, 2001; San Francisco, Clif, USA.Google Scholar
  66. 66.
    Bakris GL, Siomos M, Kasprowicz S, et al. Differential effects of valsartan and lisinopril on potassium homeostasis in hypertensive patients with nephropathy.Am J Hypertens. 1999;12:36A.CrossRefGoogle Scholar
  67. 67.
    Fumeron S, Schmitt F, Brillet G, Francillon A, Lacour B, Grünfeld JP. Renal effects of valsartan and benazepril in healthy volunteers.Am J Hypertens. 1998;11:179A.CrossRefGoogle Scholar
  68. 68.
    Ruilope LM, Aldigier JC, Ponticelli C, Oddou-Stock P, Botteri F, Mann JF. Safety of the combination of valsartan and benazepril in patients with chronic renal disease.J Hypertens. 2000;18:89–95.PubMedGoogle Scholar

Copyright information

© Health Communications Inc 2001

Authors and Affiliations

  • Luis M. Ruilope
    • 1
  1. 1.Nephrology ServiceHospital 12 de OctubreMadridSpain

Personalised recommendations