Renal and cardio-protective effects of direct renin inhibition: A systematic literature review

Journal of Hypertension

Volumn 27, Issue 12, 2009, Pages 2321-2331

  Lambers Heerspink, Hiddo J ^a,b   Perkovic, Vlado ^b   De Zeeuw, Dick ^a  

^a UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

^b UNIVERSITY OF SYDNEY   (Australia)

Author keywords

Cardiovascular diseases; Direct renin inhibitors; Nephropathy; Renin

Indexed keywords

ALISKIREN; BRAIN NATRIURETIC PEPTIDE; ENALKIREN; PLACEBO; REMIKIREN; ZANKIREN;

ALBUMINURIA; ARTERIAL PRESSURE; BLOOD PRESSURE REGULATION; CLINICAL TRIAL; CONGESTIVE HEART FAILURE; CONSTIPATION; DIARRHEA; DIZZINESS; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FATIGUE; HEART FAILURE; HEART LEFT VENTRICLE HYPERTROPHY; HEART PROTECTION; HUMAN; HYPERTENSION; KIDNEY PLASMA FLOW; MOUSE; NONHUMAN; PERIPHERAL EDEMA; PRIORITY JOURNAL; PROTEINURIA; RENAL PROTECTION; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; RHINOPHARYNGITIS; SYSTEMATIC REVIEW; UPPER RESPIRATORY TRACT INFECTION; VASCULAR RESISTANCE;

EID: 73649089010     PISSN: 02636352     EISSN: None     Source Type: Journal    
DOI: 10.1097/HJH.0b013e3283310f92     Document Type: Review

References (112)

1. Brewster UC, Setaro JF, Perazella MA. The renin-angiotensin-aldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states. Am J Med Sci 2003; 326:15-24.
2. Dzau V. The cardiovascular continuum and renin-angiotensln-aldosterone system blockade. J Hypertens 2006; 23:S9-S17.
3. Skeggs LT Jr, Kahn JR, Lentz K, Shumway NP. The preparation, purification, and amino acid sequence of a polypeptide renin substrate. J Exp Wed 1957; 106:439-453.
4. Cumin F, Evin G, Fehrentz JA, Seyer R, Castro B, Menard J, Corvol P. Inhibition of human renin by synthetic peptides derived from its prosegment. J Biol Chem 1985; 260:9154-9157.
5. Maibaum J. Renin inhibitors as novel treatments for cardiovascular disease. Expert Opinion Ther Patients 2003; 13:589-603.
6. Wood JM, Criscione L, de Gasparo M, Buhlmayer P, Rueger H, Stanton JL, et al. CGP 38 560: orally active, low-molecular-weight renin inhibitor with high potency and specificity. J Cardiovasc Pharmacol 1989; 14:221-226.
7. Wood JM, Cumin F, Maibaum J. Pharmacology of renin inhibitors and their application to the treatment of hypertension. Pharmacol Ther 1994; 61:325-344. (Pubitemid 24207703)
8. Rongen GA, Lenders JW, Smits P, Thien T. Clinical pharmacokinetics and efficacy of renin inhibitors. Clin Pharmaeokinet 1995; 29:6-14.
9. KleinbloesemCH,WeberC,FahrnerE,DellenbachM,WelkerH,SchraterV,BelzGG. Hemodynamics,biochemicaleffects, andpharmacokineticsoftherenininhibitorremikireninhealthyhumansubjects. ClinPharmacolTher1993;53:585-592.(Pubitemid23161207)
10. Menard J, Boger RS, Moyse DM, Guyene TT, Glassman HN, Kleinen HD. Dose-dependent effects of the renin inhibitor zankiren HCl after a single oral dose in mildly sodium-depleted normotensive subjects. Circulation 1995; 91: 330-338.
11. Wood JM, Maibaum J, Rahuel J, Grutter MG, Cohen NC, Rasetti V, et al. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res Commun 2003; 308:698-705.
12. Frampton JE, Curran MP. Aliskiren: a review of its use in the management of hypertension. Drugs 2007; 67:1767-1792.
13. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25:1105-1187.
14. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42:1206-1252.
15. Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet 2006; 368:1449-1456.
16. AziziM,GuyeneTT,ChatellierG,MenardJ. Bloodpressureeffectsofacuteintravenousreninororalangiotensinconvertingenzymeinh ibitioninessentialhypertension.JHypertens1994;12:419-427.(Pubitemid24145395)
17. Himmelmann A, Bergbrant A, Svensson A, Hansson L, Aurell M. Remikiren (Ro 42-5892): an orally active renin inhibitor in essential hypertension. Effects on blood pressure and the renin-angiotensin-aldosterone system. Am J Hypertens 1996; 9:517-522. (Pubitemid 26228072)
18. Kiowski W, Beermann J, Rickenbacher P, Haemmerli R, Thomas M, Burkart F, Meinertz T. Angiotensinergic versus nonangiotensinergic hemodynamic effects of converting enzyme inhibition in patients with chronic heart failure. Assessment by acute renin and converting enzyme inhibition. Circulation 1994; 90:2748-2756.
19. RongenGA,LendersJW,KleinbloesemCH,WeberC,WelkerH,FahrnerE,etal. EfficacyandtolerabilityoftherenininhibitorRo42-5892inpatientswithhypertension. ClinPharmacolTher1993;54:567-577.(Pubitemid23349094)
20. Camenzind E, Nussberger J, Juillerat L, Munafo A, Fischli W, Coassolo P, et al. Effect of the renin response during renin inhibition: oral Ro 42-5892 in normal humans. J Cardiovasc Pharmacol 1991; 18:299-307.
21. MacFadyen RJ, Jones CR, Doig JK, Birnbock H, Reid JL Responses to an orally active renin inhibitor, remikiren (Ro 42-5892), after controlled salt depletion in humans. J Cardiovasc Pharmacol 1995; 25:347-353.
22. van den Meiracker AH, Admiraal PJ, Derkx FH, Kleinbloesem C, Man in 't Veld AJ, van Brummelen P, et al. Comparison of blood pressure and angiotensin responses to the renin inhibitor Ro 42-5892 and the angiotensin converting enzyme inhibitor enalapril in essential hypertension. J Hypertens 1993; 11:831-838.
23. FisherND,AllanD,KlforI,GabouryCL,WilliamsGH,MooreTJ,HollenbergNK. Responses-convertingenzymeandrenininhibition.RoleofangiotensinIIinhumans. Hypertension1994;23:44-51.(Pubitemid24022043)
24. DelabaysA,NussbergerJ,PorohetM,WaeberB,HoyosP,BogerR,etal. Hemodynamicandhumoraleffectsofthenewrenininhibitorenalkireninnormalhumans. Hypertension1989;13:941-947.(Pubitemid19157994)
25. Boger RS, Glassman HN, Cavanaugh JH, Schmitz PJ, Lamm J, Moyse D, et al. Prolonged duration of blood pressure response to enalkiren, the novel dipeptide renin inhibitor, in essential hypertension. Hypertension 1990; 15:835-840.
26. Fisher ND, Hollenberg N. Renal vascular responses to renin inhibition with zankiren in men. Clin Pharmacol Ther 1995; 57:342-348.
27. Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension 2002; 39:E1-E8.
28. Azizi M, Menard J, Bissery A, Guyene TT, Bura-Riviere A. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol 2004; 15:3126-3133.
29. Azizi M, Menard J, Bissery A, Guyene TT, Bura-Riviere A. Hormonal and hemodynamic effects of aliskiren and valsartan and their combination in sodium-replete normotensive individuals. Clin J Am Soc Nephrol 2007; 2:947-955.
30. Zhao C, Vaidyanathan S, Yeh C-M, Maboudian M, Dieterich H-A. Aliskiren exhibits similar pharmacokinetics in healthy volunteers and patients with diabetes. Clin Pharmacokinet 2006; 45:1125-1134. (Pubitemid 44631391)
31. Oparil S, Yaraws SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet 2007; 370:221-229. (Pubitemid 47069535)
32. Gradman AH, Traub DM. Clinical experience with aliskiren. in Zipes, Libby, Bonow, Braunwald, editors. Braunwald's heart disease. 2006 (online edition).
33. Nussberger J, Gradman AH, Schmieder RE, Lins RL, Chiang Y, Prescott MF. Plasma renin and the antihypertensive effect of the orally active renin inhibitor aliskiren in clinical hypertension. Int J Clin Pract 2007;61:1461-1468. (Pubitemid 47228610)
34. Hong Y, Dingemanse J, Mager D. Pharmacokinetic/pharmacodynamic modeling of renin blomarkers in subjects treated with the renin inhibitor aliskiren. Clin Pharmacol Ther 2008; 84:136-143. (Pubitemid 351861495)
35. van Paassen P, Navis GJ, De Jong PE, De Zeeuw D. Pretreatment renal vascular tone predicts the effect of specific renin inhibition on natriuresis in essential hypertension. Eur J Clin Invest 1999; 29:1019-1026.
36. van Paassen P, de Zeeuw D, de Jong PE, Navis G. Renin inhibition improves pressure natriuresis in essential hypertension. J Am Soc Nephrol 2000; 11:1813-1818.
37. Frandsen E, Boomsma F, Persson F, Yeh C-M, Dieterich H-A, Sandford L, et al. Aliskiren reduces renin system activity in patients with hypertension, type 2 diabetes and albuminuria. J Clin Hypertens 2008; 10 (Suppl A): A21; P-36.
38. Frandsen E, Persson F, Boomsma F, Prescott MF, Dieterich H-A, Dole WP, et al. The effect of direct renin inhibition alone and in combination with angiotensin II receptor blockade on markers of the renin-angiotensin-aldosterone system. Diabetologia 2008; 61:S491 -S492; (abstract 1217).
39. Villamil A, Chrysant SG, Calhoun D, Schober B, Hsu H, MatriscianoDimichino L, Zhang J, et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens 2007; 25:217-226. (Pubitemid 44885684)
40. Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 109:1417-1427.
41. Saris JJ, t Hoen PA, Garrelds IM, Dekkers DH, den Dunnen JT, Lamers JM, Jan Danser AH. Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II. Hypertension 2006; 48:564-571.
42. Feldt S, Batenburg WW, Mazak I, Maschke U, Wellner M, Kvakan H, et al. Prorenin and renin-induced ERK 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide. Hypertension 2007; 51:682-688.
43. Schefe JH, Neumann C, Goebel M, Danser J, Kirsch S, Gust R, et al. Prorenin engages the (pro)renin receptor like renin and both ligand activities are unopposed by aliskiren. J Hypertens 2008; 26:1787-1794.
44. Schefe JH, Unger T, Funke-Kaiser H. PLZF and the (pro)renin receptor. J Mol Med 2008; 86:623-627.
45. Batenburg WW, de Bruin RJ, van Gool JM, Muller DN, Bader M, Nguyen G, Danser AH. Alisklren-binding increases the half life of renin and prorenin in rat aortic vascular smooth muscle cells. Arterioscler Thromb Vase Biol 2008; 28:1151-1157.
46. KobrinI,ViskoperRJ,LasztA,BockJ,WeberC,CharlonV. Effectsofanorallyactiverenininhibitor,Ro42-5892, inpatientswithessentialhypertension.AmJHypertens1993;6:349-366. (Pubitemid23161685)
47. van Paassen P, de Zeeuw D, de Jong PE. Renal and systemic effects of the renin inhibitor remikiren in patients with essential hypertension. J Cardiovasc Pharmacol 1995; 26:39-45.
48. van Paassen P, de Zeeuw D, Navis G, de Jong PE. Renal and systemic effects of continued treatment with renin inhibitor remikiren in hypertensive patients with normal and impaired renal function. Nephrol Dial Transplant 2000; 15:637-643.
49. ViskoperRJ,CharlonV,LasztA,YosefyC,BockJ,LandauM,KobrinI. TimedependencyoftheantihypertensiveefficacyofthenewrenininhibitorRo42-5892. JHumHypertens1994;8:133-136.(Pubitemid24065901)
50. Fischli W, Clozel JP, el Amrani K, Wostl W, Neidhart W, Stadler H, Branca Q. Ro 42-5892 is a potent orally active renin inhibitor in primates. Hypertension 1991; 18:22-31.
51. WeberMA,NeutelJM,EssingerI,GlassmanHN,BogerRS,LutherR. Assessmentofrenindependencyofhypertensionwithadipeptiderenininhibitor. Circulation1990;81:1768-1774.(Pubitemid20183825)
52. Neutel JM, Luther RR, Boger RS, Weber MA. Immediate blood pressure effects of the renin inhibitor enalkiren and the angiotensin-converting enzyme inhibitor enalaprilat. Am Heart J 1991; 122:1094-1100.
53. Kushiro T, Itakura H, Abo Y, Gotou H, Terao S, Keefe DL Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension. Hypertens Res 2006; 29:997-1005. (Pubitemid 46206586)
54. Oh BH, Mitchell J, Herron JR, Chung J, Khan M, Keefe DL Aliskiren, an Oral renin inhibitor, provides dose-dependent efficacy and sustained 24-h blood pressure control in patients with hypertension. J Am Coll Cardiol 2007; 49:1157-1163. (Pubitemid 46400330)
55. Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005; 111:1012-1018.
56. Stanton A, Jensen C, Nussberger J, O'Brien E. Blood pressure lowering in essential hypertension with an Oral renin inhibitor, aliskiren. Hypertension 2003; 42:1137-1143. (Pubitemid 37549068)
57. Andersen K, Weinberger MH, Constance CM, Baek IY, Keefe DL, Prescott MF. Aliskiren-based therapy provides long-term antiproteinuric effects in patients with hypertension and proteinuria: subgroup analysis of a 6-month, randomized, double-blind trial. J Am Soc Nephrol 2008; 19:616A; (abstract SA-P02246).
58. Chrysant SG, Murray AV, Hoppe UC, Dattani D, Patel S, Hsu H, Zhang J. Long-term safety, tolerability and efficacy of aliskiren in combination with valsartan in patients with hypertension: a 6-month interim analysis. Curr Med Res Opin 2008; 24:1039-1047.
59. Sica D, Andersen K, Oh BH, Arara V, Bush C, Keefe DL Effects of aliskiren on blood pressure and plasma renin activity persist after stopping treatment in patients with hypertension. J Clin Hypertens 2008; 10 (Suppl A):A34-A35 P-69.
60. Gradman AH, Kolloch R, Meyers M, Cai J, Zhang J. Aliskiren in combination with hydrochlorothiazide is effective and well tolerated during long-term treatment of hypertension. J Clin Hypertens 2007; 9 (Suppl A):A160; P-384.
61. Schmieder RE, Philipp T, Guerediaga J, Gorostidi M, Smith B, Weissbach N. Long-term antihypertensive efficacy and safety of the oral direct renin inhibitor aliskiren: a 12-month randomized, double-blind comparator trial with hydrochlorothiazide. Circulation 2009; 119:417-425.
62. Andersen K, Weinberger MH, Egan B, Constance CM, Ali MA, Jin J, Keefe DL. Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial. J Hypertens 2008; 26:589-599.
63. Pool JL, Schmieder RE, Azizi M, Aldigier JC, Januszewicz A, Zidek W, et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens 2007; 20:11-20. (Pubitemid 46014059)
64. Uresin Y, Taylor AA, Kilo C, Tschope D, Santonastaso M, Ibram G, et al. Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. J Renin Angiotensin Aldosterone Syst 2007; 8:190-198. (Pubitemid 351166266)
65. Jordan J, Engell S, Boye SW, Le Breton S, Keefe DL. Direct renin inhibition with aliskiren in obese patients with arterial hypertension. Hypertension 2007; 49:1047-1055.
66. Duprez DA, Davis P, Botha J. The AGELESS study: the effect of aliskiren vs ramipril alone or in combination with hydrochlorothiazide and amlodipine in patients >65 years of age with systolic hypertension. Circulation 2008; 18:S886-S887; (abstract 4423).
67. Verburg KM, Kleinert HD, Chekal MA, Kadam JR, Young GA. Renal hemodynamic and excretory responses to renin inhibition induced by A-64662. J Pharmacol Exp Ther 1990; 252:449-455.
68. el Amrani Al, Menard J, Gonzales MF, Michel JB. Effects of blocking the angiotensin II receptor, converting enzyme, and renin activity on the renal hemodynamics of normotensive guinea pigs. J Cardiovasc Pharmacol 1993; 22:231-239.
69. Neisius D, Wood JM, Hofbauer KG. Renal vasodilatation after inhibition of renin or converting enzyme in marmoset. Am J Physiol 1986; 251 :H897-H902.
70. Major TC, Olszewski B, Rosebury W, Okerberg C, Carlson T, Ostroski R, et al. A nonpeptide, piperidine renin inhibitor provides renal and cardiac protection in double-transgenic mice expressing human renin and angiotensinogen genes. Cardiovasc Drugs Ther 2008; 22:469-478.
71. Kang JJ, Toma I, McCulloch F, Peti-Peterdi J. In vivo imaging of the effects of aliskiren in the diabetic kidney. J Am Soc Nephrol 2006; 17:399A; (abstract F-PO290).
72. Pomposiello S, Laurent D, Jin L, Casadas V, Sari-Sarraf F, Feldman D. Aliskiren (ALI) improves endothelial function and restores renal function in double transgenic rats (dTGR). J Hypertens 2008; 26:S201 ; PS12/MON/63.
73. Pilz B, Shagdarsuren E, Wellner M, Fiebeler A, Dechend R, Gratze P, et al. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension 2005; 46:569-576. (Pubitemid 41376839)
74. Kelly DJ, Zhang Y, Moe G, Naik G, Gilbert RE. Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats. Diabetologia 2007; 50:2398-2404.
75. Feldman DL, Jin L, Xuan H, Contrepas A, Zhou Y, Webb RL, et al. Effects of aliskiren on blood pressure, albuminuria, and (pra)renin receptor expression in diabetic TG(mREN-2)27 rats. Hypertension 2008; 52:130-136.
76. Dechend R, Shagdarsuren E, Gratze P, Fiebeler A, Pilz B, Meiners S, et al. Low-dose renin inhibitor and low-dose AT(1)-receptor blocker therapy ameliorate target-organ damage in rats harbouring human renin and angiotensinogen genes. J Renin Angiotensin Aldosterone Syst 2007; 8:81-84. (Pubitemid 47272471)
77. Jin L, Miserindino-Moltini R, Xuan H, Müller DN, Luft FC, Feldman DL. Effect of human renin inhibitor aliskiren on renal damage in double transgenic rats (DTGR). J Am Soc Nephrol 2005; 16:214A; (abstract TH-PO440).
78. SegererS,NelsonPJ,SchlondorffD.Chemokines,chemokinereceptors, andrenaldisease:frombasicscience-pathophysiologicandtherapeuticstudies. JAmSocNephrol2000;11:152-176.(Pubitemid30020438)
79. Feldman DL, Jin L, Xuan H, Miserindino-Molteni R. Effect of the direct renin inhibitor (DRI) aliskiren on renal gene expression of pro-fibrotic molecules in experimental hypertensive diabetic nephropathy. J Am Soc Nephrol 2007; 18:168A; (abstract F-P0296).
80. Krop M, Garrelds IM, de Bruin RJ, van Gool JM, Fisher ND, Hollenberg NK, Jan Danser AH. Aliskiren accumulates in renin secretory granules and binds plasma prorenin. Hypertension 2008; 52:1076-1083.
81. Fisher ND, Jan Danser AH, Nussberger J, Dole WP, Hollenberg NK. Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans. Circulation 2008; 117:3199-3205.
82. Persson F, Rossing P, Reinhard H, Juhl T, Stehouwer CD, Schalkwijk C, et al. Renoprotective effects of direct renin inhibition compared to and in combination with irbesartan in patients with type 2 diabetes, hypertension and albuminuria. Diabetologia 2008; 51:S492; (abstract 1218).
83. Persson F, Rossing P, Schjoedt KJ, Juhl T, Tarnow L, Stehouwer CD, et al. Time course of the antiprotelnuric and antihypertensive effects of direct renin inhibition in type 2 diabetes. Kidney lnt 2008; 73:1419-1425.
84. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. Aliskiren combined with Iosartan in type 2 diabetes and nephropathy. N Engl J Med 2008; 368:2433-2446.
85. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. Aliskiren trial in type 2 diabetes using cardio-renal endpolnts (ALTITUDE): rationale and study design. Nephrol Dial Transplant 2009; 24:1663-1671.
86. Sweet CS, Ludden CT, Frederick CM, Bush LR, Ribeiro LG. Comparative hemodynamic effects of MK-422, a converting enzyme inhibitor, and a renin inhibitor in dogs with acute left ventricular failure. J Cardiovasc Pharmacol 1984; 6:1067-1075.
87. Mento PF, Malta ME, Murphy WR, Holt WF, Wilkes BM. Comparison of angiotensin converting enzyme and renin inhibition in rats following myocardial infarction. J Cardiovasc Pharmacol 1993; 21:791-796.
88. Fitzpatrick MA, Rademaker MT, Charles CJ, Yandle TG, Espiner EA, Ikram H, Nussberger J. Comparison of the effect of renin inhibition and angiotensin-converting enzyme inhibition in ovine heart failure. J Cardiovasc Pharmacol 1992; 19:169-175.
89. ZhangQ,KoharaK,QuiHY,HiwadaK.Comparativeeffectsofthreesitesofrenin- angiotensinblockadeontheregressionofleftventricularhypertrophyinspontaneouslyh ypertensiverats.AmJTher1997;4:199-202.(Pubitemid27263925)
90. Singh VP, Le R, Khode R, Baker KM, Kumar R. Intracellular angiotensin II production in diabetic rats is involved in cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Diabetes 2008; 57:3297-3306.
91. Fischer R, Dechend R, Qadri F, Markovic M, Feldt S, Herse F, et al. Dietary n-3 polyunsaturated fatty acids and direct renin inhibition improve electric remodeling in a model of high human renin hypertension. Hypertension 2008; 51:540-546.
92. Whaley-Connell A, Habibi J, Cooper SA, Demarco VG, Hayden MR, Stump CS, et al. Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat. Am J Physiol Endocrinol Metab 2008; 295:E103-E109.
93. Neuberg GW, Kukin ML, Penn J, Medina N, Yushak M, Packer M. Hemodynamic effects of renin inhibition by enalkiren in chronic congestive heart failure. Am J Cardiol 1991 ; 67:63-66.
94. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, 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. (Pubitemid 34286536)
95. de Simone G, Gottdiener JS, Chinali M, Maurer MS. Left ventricular mass predicts heart failure not related to previous myocardial infarction: the Cardiovascular Health Study. Eur Heart J 2008; 29:741-747.
96. Solomon SD, Appelbaum E, Manning WJ, Verma A, Berglund T, Lukashevich V, et al. Effect of the direct renin inhibitor aliskiren, the angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy. Circulation 2009; 119:530-537.
97. Okin PM, Devereux RB, Gerdts E, Snapinn SM, Harris KE, Jern S, et al. Impact of diabetes mellitus on regression of electrocardiographic left ventricular hypertrophy and the prediction of outcome during antihypertensive therapy: the Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study. Circulation 2006; 113:1588-1596.
98. LevyD,GarrisonRJ,SavageDD,KannelWB,CastelliWP. Prognosticimplicationsofechocardiographicallydeterminedleftventricularmassinthe FraminghamHeartStudy.WEnglJMed1990;322:1561-1566.(Pubitemid20176696)
99. Okura H, Takada Y, Kubo T, Asawa K, Taguchi H, Toda I, et al. Functional mitral regurgitation predicts prognosis independent of left ventricular systolic and diastolic indices in patients with ischemic heart disease. J Am Soc Echocardiogr 2008; 21:355-360.
100. Bruoh C, Klem I, Breithardt G, Wichter T, Gradaus R. Diagnostic usefulness and prognostic implications of the mitral E/E' ratio in patients with heart failure and severe secondary mitral regurgitation. Am J Cardiol 2007; 100:860-865. (Pubitemid 47268279)
101. McMurray J, Pitt B, Latini R, Maggionl A, Solomon SD, Keefe DL ,et al. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Failure 2008; 1:17-24.
102. Seed A, Gardner R, McMurray J, Hillier C, Murdoch DR, McFadyen R, et al. Neurohumoral effects of the new orally active renin inhibitor, aliskiren, in chronic heart failure. Eur J Heart Fail 2007; 9:1120-1127. (Pubitemid 47633316)
103. Novartis. Efficacy and safety of aliskiren and valsartan versus placebo in patients stabilized following an acute coronary syndrome. http://www.olinicaltrials.gov/ct2/show/NCT00409578. [Accessed on 2 August 2009]
104. Rashid H. Direct renin inhibition: an evaluation of the safety and tolerability of aliskiren. Curr Med Res Opin 2008; 24:2627-2637.
105. Strasser RH, Puig JG, Farsang C, Croket M, Li J, van Ingen H. A comparison of the tolerability of the direct renin inhibitor aliskiren and Iisinopril in patients with severe hypertension. J Hum Hypertens 2007; 21:780-787. (Pubitemid 47450003)
106. 106GradmanAH,TraubD.Theefficacyofaliskiren,adirectrenininhibitor, inthetreatmentofhypertension.RevCardiovascMed2007;8(Suppl2):S22-S30. (Pubitemid46427751)
107. Sica D, Gradman AH, Lederballe O, Meyers M, Cai J, Keefe DL Aliskiren, a novel renin inhibitor, is well tolerated and has sustained BP-lowering effects alone or in combination with HCTZ during long-term (52 weeks) treatment of hypertension. Eur Heart J 2006; 27 (Suppl):121 ; P-797.
108. Verdecchia P, Calvo C, Mockel V, Keeling L, Satlin A. Safety and efficacy of the oral direct renin inhibitor aliskiren in elderly patients with hypertension. Stood Press 2007; 16:381-391. (Pubitemid 350237079)
109. Vaidyanathan S, Bigler H, Yeh C, Bizot MN, Dieterich HA, Howard D, Dole WP. Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment. Clin Pharmacokinet 2007;46:661-675. (Pubitemid 47204852)
110. Vaidyanathan S, Warren V, Yeh C, Bizot MN, Dieterich H-A, Dole WP. Pharmacokinetics, safety, and tolerability of the oral renin inhibitor aliskiren in patients with hepatic impairment. J Clin Pharmacol 2007; 47:192-200. (Pubitemid 46146485)
111. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramlpril, or both in patients at high risk for vascular events. N Engl J Med 2008; 368:1547-1559.
112. Weir MR, Bush C, Anderson DR, Zhang J, Keefe DL, Satlin A. Antihypertensive efficacy, safety and tolerability of the oral direct renin inhibitor aliskiren in patients with hypertension: a pooled analysis. J Am Soc Hypertens 2007; 1:264-277. (Pubitemid 47091546)