Effects of inhibition of the renin-angiotensin system on hypertension-induced target organ damage: clinical and experimental evidence

Submitted: August 13, 2020
Accepted: October 3, 2020
Published: February 10, 2021
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The dysregulation of renin-angiotensin-system (RAS) plays a pivotal role in hypertension and in the development of the related target organ damage (TOD). The main goal of treating hypertension is represented by the long-term reduction of cardiovascular (CV) risk. RAS inhibition either by angiotensin converting enzyme (ACE)-inhibitors or by type 1 Angiotensin II receptors blockers (ARBs), reduce the incidence of CV events in hypertensive patients. Actually, ACE-inhibitors and ARBs have been demonstrated to be effective to prevent, or delay TOD like left ventricular hypertrophy, chronic kidney disease, and atherosclerosis. The beneficial effects of RAS blockers on clinical outcome of hypertensive patients are due to the key role of angiotensin II in the pathogenesis of TOD. In particular, Angiotensin II through an inflammatory-mediated mechanism plays a role in the initiation, progression and vulnerability of atherosclerotic plaque. In addition, Angiotensin II can be considered the hormonal transductor of the pressure overload in cardiac myocytes, and through an autocrine-paracrine mechanism plays a role in the development of left ventricular hypertrophy. Angiotensin II by modulating the redox status and the immune system participates to the development of chronic kidney disease. The RAS blocker should be considered the first therapeutic option in patients with hypertension, even if ACE-inhibitors and ARBs have different impact on CV prevention. ARBs seem to have greater neuro-protective effects, while ACE-inhibitors have greater cardio-protective action.



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Volpe M, Gallo G, Battistoni A, Tocci G. Highlights of ESC/ESH 2018 Guidelines on the management of hypertension: What every doctor should know. High Blood Press Cardiovasc Prev 2019;26:1-8. doi: 10.1007/s40292-018-00297-y DOI: https://doi.org/10.1007/s40292-018-00297-y
Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003. doi: 10.1016/S0140-6736(02)08089-3 DOI: https://doi.org/10.1016/S0140-6736(02)08089-3
Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Sleight P, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53. [Corrections in N Engl J Med 2000;342:1376 and 2000;342:748]. doi: 10.1056/NEJM200001203420301
ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59. doi: 10.1056/NEJMoa0801317 DOI: https://doi.org/10.1056/NEJMoa0801317
Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, Yusuf S, Teo K, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008;372:1174-83. [Correction in Lancet 2008;372:1384]. doi: 10.1016/S0140-6736(08)61242-8 DOI: https://doi.org/10.1016/S0140-6736(08)61242-8
Carpinella G, Pagano G, Buono F, et al. Prognostic value of combined target-organ damage in patients with essential hypertension. Am J Hypertens 2015;28:127-34. doi: 10.1093/ajh/hpu098 DOI: https://doi.org/10.1093/ajh/hpu098
Buono F, Crispo S, Pagano G, et al. Determinants of left ventricular hypertrophy in patients with recent diagnosis of essential hypertension. J Hypertens 2014;32:166-73. doi: 10.1097/HJH.0b013e328365c87d DOI: https://doi.org/10.1097/HJH.0b013e328365c87d
Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA 1996;275:1507-13. DOI: https://doi.org/10.1001/jama.1996.03530430051039
Klingbeil AU, Schneider M, Martus P, et al. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med 2003;115:41-6. doi: 10.1016/s0002-9343(03)00158-x DOI: https://doi.org/10.1016/S0002-9343(03)00158-X
Fagard RH, Celis H, Thijs L, Wouters S. Regression of left ventricular mass by antihypertensive treatment: a meta-analysis of randomized comparative studies. Hypertension 2009;54:1084-91. doi: 10.1161/HYPERTENSIONAHA.109.136655 DOI: https://doi.org/10.1161/HYPERTENSIONAHA.109.136655
Ciulla MM, Paliotti R, Esposito A, et al. Different effects of antihypertensive therapies based on losartan or atenolol on ultrasound and biochemical markers of myocardial fibrosis: results of a randomized trial. Circulation 2004;110:552-7. doi: 10.1161/01.CIR.0000137118.47943.5C DOI: https://doi.org/10.1161/01.CIR.0000137118.47943.5C
Bruckschlegel G, Holmer SR, Jandeleit K, et al. Blockade of the renin-angiotensin system in cardiac pressure-overload hypertrophy in rats. Hypertension 1995;25:250-9. doi: 10.1161/01.hyp.25.2.250 DOI: https://doi.org/10.1161/01.HYP.25.2.250
Kojima M, Shiojima I, Yamazaki T, et al. Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and inhibits the intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro. Circulation 1994;89:2204-11. doi: 10.1161/01.cir.89.5.2204 DOI: https://doi.org/10.1161/01.CIR.89.5.2204
Weinberg EO, Schoen FJ, George D, et al. Angiotensin-converting enzyme inhibition prolongs survival and modifies the transition to heart failure in rats with pressure overload hypertrophy due to ascending aortic stenosis. Circulation 1994;90:1410-22. doi: 10.1161/01.cir.90.3.1410 DOI: https://doi.org/10.1161/01.CIR.90.3.1410
Yamazaki T, Komuro I, Kudoh S, et al. Angiotensin II partly mediates mechanical stress-induced cardiac hypertrophy. Circ Res 1995;77:258-65. doi: 10.1161/01.res.77.2.258 DOI: https://doi.org/10.1161/01.RES.77.2.258
Suzuki J, Matsubara H, Urakami M, Inada M. Rat angiotensin II (type 1A) receptor mRNA regulation and subtype expression in myocardial growth and hypertrophy. Circ Res 1993;73:439-47. doi: 10.1161/01.res.73.3.439 DOI: https://doi.org/10.1161/01.RES.73.3.439
Malhotra R, Sadoshima J, Brosius FC 3rd, Izumo S. Mechanical stretch and angiotensin II differentially upregulate the renin-angiotensin system in cardiac myocytes in vitro. Circ Res 1999;85:137-46. doi: 10.1161/01.res.85.2.137 DOI: https://doi.org/10.1161/01.RES.85.2.137
Shyu KG, Chen JJ, Shih NL, et al. Angiotensinogen gene expression is induced by cyclical mechanical stretch in cultured rat cardiomyocytes. Biochem Biophys Res Commun 1995;211:241-8. doi: 10.1006/bbrc.1995.1802 DOI: https://doi.org/10.1006/bbrc.1995.1802
Bendall JK, Cave AC, Heymes C, et al. Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 2002;105:293-6. doi: 10.1161/hc0302.103712 DOI: https://doi.org/10.1161/hc0302.103712
Bigazzi R, Bianchi S, Baldari D, Campese VM. Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension. J Hypertens 1998;16:1325-33. doi: 10.1097/00004872-199816090-00014 DOI: https://doi.org/10.1097/00004872-199816090-00014
Meccariello A, Buono F, Verrengia E, et al. Microalbuminuria predicts the recurrence of cardiovascular events in patients with essential hypertension. J Hypertens 2016;34:646-53. doi: 10.1097/HJH.0000000000000846 DOI: https://doi.org/10.1097/HJH.0000000000000846
Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int 2000;57:1803-17. doi: 10.1046/j.1523-1755.2000.00031.x DOI: https://doi.org/10.1046/j.1523-1755.2000.00031.x
[No authors listed]. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997;349:1857-63. DOI: https://doi.org/10.1016/S0140-6736(96)11445-8
Kshirsagar AV, Joy MS, Hogan SL, et al. Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: a systematic overview of randomized placebo-controlled trials. Am J Kidney Dis 2000;35:695-707. doi: 10.1016/s0272-6386(00)70018-7 DOI: https://doi.org/10.1016/S0272-6386(00)70018-7
Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data Ann Intern Med 2001;135:73-87. [Correction in Ann Intern Med 2002;137:299]. doi: 10.7326/0003-4819-135-2-200107170-00007 DOI: https://doi.org/10.7326/0003-4819-135-2-200107170-00007
Burnier M, Lin S, Ruilope L, et al. Effect of angiotensin receptor blockers on blood pressure and renal function in patients with concomitant hypertension and chronic kidney disease: a systematic review and meta-analysis. Blood Press 2019;28:358-74. doi: 10.1080/08037051.2019.1644155 DOI: https://doi.org/10.1080/08037051.2019.1644155
Yang LY, Ge X, Wang YL, et al. Angiotensin receptor blockers reduce left ventricular hypertrophy in dialysis patients: a meta-analysis. Am J Med Sci 2013;345:1-9. doi: 10.1097/MAJ.0b013e318249d387 DOI: https://doi.org/10.1097/MAJ.0b013e318249d387
Iino Y, Hayashi M, Kawamura T, et al. Renoprotective effect of losartan in comparison to amlodipine in patients with chronic kidney disease and hypertension--a report of the Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients (JLIGHT) study. Hypertens Res 2004;27:21-30. doi: 10.1291/hypres.27.21 DOI: https://doi.org/10.1291/hypres.27.21
Vogt L, Navis G, Köster J, et al. The angiotensin II receptor antagonist telmisartan reduces urinary albumin excretion in patients with isolated systolic hypertension: results of a randomized, double-blind, placebo-controlled trial. J Hypertens 2005;23:2055-61. doi: 10.1097/01.hjh.0000186829.56372.04 DOI: https://doi.org/10.1097/01.hjh.0000186829.56372.04
Catapano F, Chiodini P, De Nicola L, et al. Antiproteinuric response to dual blockade of the renin-angiotensin system in primary glomerulonephritis: meta-analysis and metaregression. Am J Kidney Dis 2008;52:475-85. doi: 10.1053/j.ajkd.2008.03.008 DOI: https://doi.org/10.1053/j.ajkd.2008.03.008
Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008;148:30-48. doi: 10.7326/0003-4819-148-1-200801010-00190 DOI: https://doi.org/10.7326/0003-4819-148-1-200801010-00190
Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin II and renal fibrosis. Hypertension 2001;38:635-8. doi: 10.1161/hy09t1.094234. DOI: https://doi.org/10.1161/hy09t1.094234
Ruiz-Ortega M, Lorenzo O, Suzuki Y, Rupérez M, Egido J. Proinflammatory actions of angiotensins. Curr Opin Nephrol Hypertens 2001;10:321-9. doi: 10.1097/00041552-200105000-00005 DOI: https://doi.org/10.1097/00041552-200105000-00005
Stenvinkel P, Ketteler M, Johnson RJ, et al. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly. Kidney Int 2005;67:1216-33. doi: 10.1111/j.1523-1755.2005.00200.x DOI: https://doi.org/10.1111/j.1523-1755.2005.00200.x
Andersson P, Cederholm T, Johansson AS, Palmblad J. Captopril-impaired production of tumor necrosis factor-alpha-induced interleukin-1beta in human monocytes is associated with altered intracellular distribution of nuclear factor-kappaB. J Lab Clin Med 2002;140:103-9. doi: 10.1067/mlc.2002.125905 DOI: https://doi.org/10.1067/mlc.2002.125905
Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Sleight P, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53 [corrections in 2000;342:1376 and N Engl J Med 2000;342:748]. doi: 10.1056/NEJM200001203420301 DOI: https://doi.org/10.1056/NEJM200001203420301
Lonn E, Yusuf S, Dzavik V, et al. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation 2001;103:919-25. doi: 10.1161/01.cir.103.7.919 DOI: https://doi.org/10.1161/01.CIR.103.7.919
Baguet JP, Asmar R, Valensi P, Nisse-Durgeat S, Mallion JM. Effects of candesartan cilexetil on carotid remodeling in hypertensive diabetic patients: the MITEC study. Vasc Health Risk Manag 2009;5:175-183. doi: 10.2147/vhrm.s3409 DOI: https://doi.org/10.2147/VHRM.S3409
Sonoda M, Aoyagi T, Takenaka K, Uno K, Nagai R. A one-year study of the antiatherosclerotic effect of the angiotensin-II receptor blocker losartan in hypertensive patients. A comparison with angiotensin-converting enzyme inhibitors. Int Heart J 2008;49:95-103. doi: 10.1536/ihj.49.95 DOI: https://doi.org/10.1536/ihj.49.95
Koh KK, Chung WJ, Ahn JY, et al. Angiotensin II type 1 receptor blockers reduce tissue factor activity and plasminogen activator inhibitor type-1 antigen in hypertensive patients: a randomized, double-blind, placebo-controlled study. Atherosclerosis 2004;177:155-60. doi: 10.1016/j.atherosclerosis.2004.07.008 DOI: https://doi.org/10.1016/j.atherosclerosis.2004.07.008
Rosei EA, Rizzoni D, Muiesan ML, et al. Effects of candesartan cilexetil and enalapril on inflammatory markers of atherosclerosis in hypertensive patients with non-insulin-dependent diabetes mellitus. J Hypertens 2005;23:435-44. doi: 10.1097/00004872-200502000-00027 DOI: https://doi.org/10.1097/00004872-200502000-00027
Hirohata A, Yamamoto K, Miyoshi T, et al. Impact of olmesartan on progression of coronary atherosclerosis a serial volumetric intravascular ultrasound analysis from the OLIVUS (impact of OLmesarten on progression of coronary atherosclerosis: evaluation by intravascular ultrasound) trial. J Am Coll Cardiol 2010;55:976-82. doi: 10.1016/j.jacc.2009.09.062 DOI: https://doi.org/10.1016/j.jacc.2009.09.062
Turnbull F, Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527-35. doi: 10.1016/s0140-6736(03)14739-3 DOI: https://doi.org/10.1016/S0140-6736(03)14739-3
Reboldi G, Angeli F, Cavallini C, et al. Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis. J Hypertens 2008;26:1282-9. doi: 10.1097/HJH.0b013e328306ebe2 DOI: https://doi.org/10.1097/HJH.0b013e328306ebe2
Lu GC, Cheng JW, Zhu KM, et al. A systematic review of angiotensin receptor blockers in preventing stroke. Stroke 2009;40:3876-8. doi: 10.1161/STROKEAHA.109.559989 DOI: https://doi.org/10.1161/STROKEAHA.109.559989
Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:2022-31. doi: 10.1016/S0140-6736(04)16451-9 DOI: https://doi.org/10.1016/S0140-6736(04)16451-9
Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ 2004;329:1248-9. doi: 10.1136/bmj.329.7477.1248 DOI: https://doi.org/10.1136/bmj.329.7477.1248
Bangalore S, Kumar S, Wetterslev J, Messerli FH. Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147 020 patients from randomised trials. BMJ 2011;342:d2234. doi: 10.1136/bmj.d2234 DOI: https://doi.org/10.1136/bmj.d2234
Strauss MH, Hall AS. Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation 2006;114:838-4. [Correction in Circulation 2006;114:e576]. doi: 10.1161/CIRCULATIONAHA.105.594986 DOI: https://doi.org/10.1161/CIRCULATIONAHA.105.594986
Strauss MH, Hall AS. Angiotensin receptor blockers do not reduce risk of myocardial infarction, cardiovascular death, or total mortality: Further evidence for the ARB-MI paradox. Circulation 2017;135:2088-90. doi: 10.1161/CIRCULATIONAHA.117.026112 DOI: https://doi.org/10.1161/CIRCULATIONAHA.117.026112
Salvador GL, Marmentini VM, Cosmo WR, Junior EL. Angiotensin-converting enzyme inhibitors reduce mortality compared to angiotensin receptor blockers: Systematic review and meta-analysis. Eur J Prev Cardiol 2017;24:1914-24. doi: 10.1177/2047487317728766 DOI: https://doi.org/10.1177/2047487317728766
Fiordelisi A, Iaccarino G, Morisco C, Coscioni E, Sorriento D. NFkappaB is a Key Player in the Crosstalk between Inflammation and Cardiovascular Diseases. Int J Mol Sci 2019;20:1599. doi: 10.3390/ijms20071599 DOI: https://doi.org/10.3390/ijms20071599
Celi A, Cianchetti S, Dell'Omo G, Pedrinelli R. Angiotensin II, tissue factor and the thrombotic paradox of hypertension. Expert Rev Cardiovasc Ther 2010;8:1723-9. doi: 10.1586/erc.10.161 DOI: https://doi.org/10.1586/erc.10.161
Gigante B, Bellis A, Visconti R, et al. Retrospective analysis of coagulation factor II receptor (F2R) sequence variation and coronary heart disease in hypertensive patients. Arterioscler Thromb Vasc Biol 2007;27:1213-9. doi: 10.1161/ATVBAHA.107.140541 DOI: https://doi.org/10.1161/ATVBAHA.107.140541
Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angiotensin system and cardiovascular risk. Lancet 2007;369:1208-19. doi: 10.1016/S0140-6736(07)60242-6 DOI: https://doi.org/10.1016/S0140-6736(07)60242-6
Chobanian AV, Haudenschild CC, Nickerson C, Hope S. Trandolapril inhibits atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Hypertension 1992;20:473-7. doi: 10.1161/01.hyp.20.4.473 DOI: https://doi.org/10.1161/01.HYP.20.4.473
Linz W, Jessen T, Becker RH, Schölkens BA, Wiemer G. Long-term ACE inhibition doubles lifespan of hypertensive rats. Circulation 1997;96:3164-72. doi: 10.1161/01.cir.96.9.3164 DOI: https://doi.org/10.1161/01.CIR.96.9.3164
Thoene-Reineke C, Rumschüssel K, Schmerbach K, et al. Prevention and intervention studies with telmisartan, ramipril and their combination in different rat stroke models. PLoS One 2011;6:e23646. doi: 10.1371/journal.pone.0023646 DOI: https://doi.org/10.1371/journal.pone.0023646
Krikov M, Thone-Reineke C, Müller S, Villringer A, Unger T. Candesartan but not ramipril pretreatment improves outcome after stroke and stimulates neurotrophin BNDF/TrkB system in rats. J Hypertens 2008;26:544-52. doi: 10.1097/HJH.0b013e3282f2dac9 DOI: https://doi.org/10.1097/HJH.0b013e3282f2dac9
Bellis A, Sorriento D, Fiordelisi A, et al. autocrine bradykinin release promotes ischemic preconditioning-induced cytoprotection in bovine aortic endothelial cells. Int J Mol Sci 2020;21:2965. doi: 10.3390/ijms21082965 DOI: https://doi.org/10.3390/ijms21082965
Kim MP, Zhou M, Wahl LM. Angiotensin II increases human monocyte matrix metalloproteinase-1 through the AT2 receptor and prostaglandin E2: implications for atherosclerotic plaque rupture. J Leukoc Biol 2005;78:195-201. doi: 10.1189/jlb.1204715 DOI: https://doi.org/10.1189/jlb.1204715

How to Cite

De Luca, Maria Rosaria, Daniela Sorriento, Domenico Massa, Valeria Valente, Federica De Luise, Emanuele Barbato, and Carmine Morisco. 2021. “Effects of Inhibition of the Renin-Angiotensin System on Hypertension-Induced Target Organ Damage: Clinical and Experimental Evidence”. Monaldi Archives for Chest Disease 91 (1). https://doi.org/10.4081/monaldi.2021.1570.