Is there a future for direct renin inhibitors?

Expert Opinion on Investigational Drugs

Volumn 19, Issue 5, 2010, Pages 653-661

  Chaudhary, Kunal ^a,b   Nistala, Ravi ^a   Whaley Connell, Adam ^a,b  

^a VETERANS AFFAIRS MEDICAL CENTER   (United States)

^b University of Missouri   (United States)

Author keywords

Direct renin inhibition; Hypertension; Renin angiotensin aldosterone system

Indexed keywords

ALBUMIN; ALDOSTERONE; ALISKIREN; AMLODIPINE; ANGIOTENSIN I; ANGIOTENSIN II; ANGIOTENSINOGEN; BRAIN NATRIURETIC PEPTIDE; CAPTOPRIL; CJP 38560A; COLLAGEN TYPE 1; CONNECTIVE TISSUE GROWTH FACTOR; CONNEXIN 43; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENALAPRILAT; ENALKIREN; HYDRALAZINE; HYDROCHLOROTHIAZIDE; IRBESARTAN; LOSARTAN; MITOGEN ACTIVATED PROTEIN KINASE; PLACEBO; PRORENIN; RAMIPRIL; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; RENIN; RENIN INHIBITOR; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; VALSARTAN;

ALBUMINURIA; ALDOSTERONE URINE LEVEL; ANTIHYPERTENSIVE ACTIVITY; AREA UNDER THE CURVE; ARRHYTHMOGENESIS; BILIARY EXCRETION; BLOOD PRESSURE; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CHRONIC KIDNEY DISEASE; CLINICAL ASSESSMENT; CLINICAL TRIAL; CONGESTIVE HEART FAILURE; DIABETIC NEPHROPATHY; DIASTOLIC BLOOD PRESSURE; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG TOLERABILITY; ENZYME ACTIVITY; FEEDBACK SYSTEM; GLOMERULOSCLEROSIS; GLUCOSE INTOLERANCE; HEART LEFT VENTRICLE HYPERTROPHY; HEART LEFT VENTRICLE MASS; HEART MUSCLE FIBROSIS; HEART STROKE VOLUME; HUMAN; HYPERKALEMIA; HYPERTENSION; KIDNEY FIBROSIS; KIDNEY PLASMA FLOW; MAXIMUM PLASMA CONCENTRATION; MICROALBUMINURIA; MITRAL VALVE REGURGITATION; MONOTHERAPY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; ORGAN INJURY; PANCREAS ISLET; PERIPHERAL EDEMA; PLASMA RENIN ACTIVITY; POST HOC ANALYSIS; POTASSIUM BLOOD LEVEL; PROTEINURIA; QRS COMPLEX; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; SALT INTAKE; SIDE EFFECT; SINGLE DRUG DOSE; SODIUM RESTRICTION; STEADY STATE; STOICHIOMETRY; SURVIVAL; SYSTOLIC HYPERTENSION; TRANSGENIC RAT; TRANSMISSION ELECTRON MICROSCOPY; TREATMENT DURATION;

AMIDES; ANIMALS; ANTIHYPERTENSIVE AGENTS; BLOOD PRESSURE; CARDIOVASCULAR DISEASES; DRUG DESIGN; DRUG THERAPY, COMBINATION; FUMARATES; HUMANS; HYPERTENSION; KIDNEY DISEASES; RENIN; RENIN-ANGIOTENSIN SYSTEM;

EID: 77951457508     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543781003781906     Document Type: Review

References (78)

1. Mancia G, De Backer G, Dominiczak A, 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;19(6):1105-1187 (Pubitemid 46924065)
2. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003; 42(6):1206-1252
3. Reudelhuber TL, Ramla D, Chiu L, et al. Proteolytic processing of human prorenin in renal and non-renal tissues. Kidney Int 1994;46(6):1522-1524
4. Gaddam KK, Oparil S. Renin inhibition: should it supplant ACE inhibitors and ARBS in high risk patients? Curr Opin Nephrol Hypertens 2008;17(5):484-490
5. Danser AH, Derkx FH, Schalekamp MA, et al. Determinants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans. J Hypertens 1998;16(6):853-862
6. 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(1):15-24
7. Dzau V. The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. J Hypertens Suppl 2005;23(1):S9-17
8. Pimenta E, Oparil S. Renin inhibitors: novel agents for renoprotection or a better angiotensin receptor blocker for blood pressure lowering? Cardiol Clin 2008;26(4):527-535
9. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362(9395):1527-1535
10. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345(12):861-869
11. 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(1):30-48
12. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329(20):1456-1462
13. Jorde UP. Suppression of the renin-angiotensin-aldosterone system in chronic heart failure: choice of agents and clinical impact. Cardiol Rev 2006;14(2):81-87
14. Azizi M, Menard J, Bissery A, et al. 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(12):3126-3133
15. Belova LA. Angiotensin II-generating enzymes. Biochemistry (Mosc) 2000;65(12):1337-1345
16. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet 2000;355(9204):637-645
17. Mooser V, Nussberger J, Juillerat L, et al. Reactive hyperreninemia is a major determinant of plasma angiotensin II during ACE inhibition. J Cardiovasc Pharmacol 1990;15(2):276-282
18. Weber MA, Giles TD. Inhibiting the renin-angiotensin system to prevent cardiovascular diseases: do we need a more comprehensive strategy? Rev Cardiovasc Med 2006;7(2):45-54
19. Skeggs LT Jr, Kahn JR, Lentz K, Shumway NP. The preparation, purification, and amino acid sequence of a polypeptide renin substrate. J Exp Med 1957;106(3):439-453
20. Oparil S, Yarows SA, Patel S, et al. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet 2007;370(9583):221-229
21. Pool JL, Schmieder RE, Azizi M, et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens 2007;20(1):11-20
22. Parving HH, Persson F, Lewis JB, et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008;358(23):2433-2446
23. Ingelfinger JR. Aliskiren and dual therapy in type 2 diabetes mellitus. N Engl J Med 2008;358(23):2503-2505
24. Van Tassell BW, Munger MA. Aliskiren for renin inhibition: a new class of antihypertensives. Ann Pharmacother 2007;41(3):456-464
25. Jensen C, Herold P, Brunner HR. Aliskiren: the first renin inhibitor for clinical treatment. Nat Rev Drug Discov 2008;7(5):399-410
26. Gradman AH, Kad R. Renin inhibition in hypertension. J Am Coll Cardiol 2008;51(5):519-528
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(1):E1-8
28. Zhao C, Vaidyanathan S, Yeh CM, et al. Aliskiren exhibits similar pharmacokinetics in healthy volunteers and patients with type 2 diabetes mellitus. Clin Pharmacokinet 2006;45(11):1125-1134
29. Fisher ND, Hollenberg NK. Renin inhibition: what are the therapeutic opportunities? J Am Soc Nephrol 2005;16(3):592-599
30. Danser AH, Charney A, Feldman DL, et al. The renin rise with aliskiren: it's simply stoichiometry. Hypertension 2008;51(4):e27-28, e29
31. Sealey JE, Laragh JH. It is the plasma renin activity level that counts, not stoichiometry. Hypertension 2008;52(2):e20, e21
32. Hollenberg NK. A brief response to Sealey and Laragh. J Renin Angiotensin Aldosterone Syst 2007;8(2):53
33. Wei Y, Sowers JR, Nistala R, et al. Angiotensin II-induced NADPH oxidase activation impairs insulin signaling in skeletal muscle cells. J Biol Chem 2006;281(46):35137-35146
34. Whaley-Connell AT, Chowdhury NA, Hayden MR, et al. Oxidative stress and glomerular filtration barrier injury: role of the renin-angiotensin system in the Ren2 transgenic rat. Am J Physiol Renal Physiol 2006;291(6):F1308-14
35. Feldman DL, Jin L, Xuan H, et al. Effects of aliskiren on blood pressure, albuminuria, and (pro) renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension 2008;52(1):130-136
36. Danser AH. (Pro) renin receptors: are they biologically relevant? Curr Opin Nephrol Hypertens 2009;18(1):74-78
37. Ichihara A, Hayashi M, Kaneshiro Y, et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the 'handle' region for nonproteolytic activation of prorenin. J Clin Invest 2004;114(8):1128-1135
38. Feldt S, Batenburg WW, Mazak I, et al. Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide. Hypertension 2008;51(3):682-688
39. Imanishi T, Tsujioka H, Ikejima H, et al. Renin inhibitor aliskiren improves impaired nitric oxide bioavailability and protects against atherosclerotic changes. Hypertension 2008;52(3):563-572
40. Verma S, Gupta MK. Aliskiren improves nitric oxide bioavailability and limits atherosclerosis. Hypertension 2008;52(3):467-469
41. Carey RM. Antihypertensive and renoprotective mechanisms of Renin inhibition in diabetic rats. Hypertension 2008;52(1):63-64
42. Serebruany VL, Malinin A, Barsness G, et al. Effects of aliskiren, a renin inhibitor, on biomarkers of platelet activity, coagulation and fibrinolysis in subjects with multiple risk factors for vascular disease. J Hum Hypertens 2008;22(5):303-310
43. Lastra G, Habibi J, Whaley-Connell AT, et al. Direct renin inhibition improves systemic insulin resistance and skeletal muscle glucose transport in a transgenic rodent model of tissue renin overexpression. Endocrinology 2009;150(6):2561-2568
44. Whaley-Connell AT, Nistala R, Habibi J, et al. Comparative Effect of Direct Renin Inhibition and AT1R Blockade on Glomerular Filtration Barrier Injury in the Transgenic Ren2 Rat. Am J Physiol Renal Physiol 2010;298(3):F655-61
45. Habibi J, Whaley-Connell A, Hayden MR, et al. Renin inhibition attenuates insulin resistance, oxidative stress, and pancreatic remodeling in the transgenic Ren2 rat. Endocrinology 2008;149(11):5643-5653
46. Bedair HS, Karthikeyan T, Quintero A, et al. Angiotensin II receptor blockade administered after injury improves muscle regeneration and decreases fibrosis in normal skeletal muscle. Am J Sports Med 2008;36(8):1548-1554
47. Zaman AK, Fujii S, Goto D, et al. Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity. J Mol Cell Cardiol 2004;37(2):525-535
48. Segerer S, Nelson PJ, Schlondorff D. Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. J Am Soc Nephrol 2000;11(1):152-176
49. Pilz B, Shagdarsuren E, Wellner M, et al. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension 2005;46(3):569-576 (Pubitemid 41376839)
50. Nguyen G, Delarue F, Burckle C, et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002;109(11):1417-1427 (Pubitemid 34596167)
51. Schefe JH, Unger T, Funke-Kaiser H. PLZF and the (pro)renin receptor. J Mol Med 2008;86(6):623-627
52. Batenburg WW, de Bruin RJ, van Gool JM, et al. Aliskiren-binding increases the half life of renin and prorenin in rat aortic vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2008;28(6):1151-1157
53. Jeunemaitre X, Menard J, Nussberger J, et al. Plasma angiotensins, renin, and blood pressure during acute renin inhibition by CGP 38 560A in hypertensive patients. Am J Hypertens 1989;2(11 Pt 1):819-827 (Pubitemid 19267646)
54. 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(4 Pt 1):1094-1100
55. Uresin Y, Taylor AA, Kilo C, 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(4):190-198 (Pubitemid 351166266)
56. Sealey JE, Laragh JH. Aliskiren fails to lower blood pressure in patients who have either low PRA levels or whose PRA falls insufficiently or reactively rises. Am J Hypertens 2009;22(1):112-121
57. Nussberger J, Gradman AH, Schmieder RE, et al. Plasma renin and the antihypertensive effect of the orally active renin inhibitor aliskiren in clinical hypertension. Int J Clin Pract 2007;61(9):1461-1468 (Pubitemid 47228610)
58. Stanton A, Jensen C, Nussberger J, O'Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension 2003;42(6):1137-1143 (Pubitemid 37549068)
59. O'Brien E, Barton J, Nussberger J, et al. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. Hypertension 2007;49(2):276-284 (Pubitemid 46143002)
60. Duprez DA, Davis P, Botha J. Abstract 4423: 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;118:S886-7
61. Dechend R, Shagdarsuren E, Gratze P, 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(2):81-84 (Pubitemid 47272471)
62. Fisher ND, Jan Danser AH, Nussberger J, et al. Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans. Circulation 2008;117(25):3199-3205
63. Hollenberg NK, Fisher ND, Price DA. Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system. Hypertension 1998;32(3):387-392
64. Parving HH, Brenner BM, McMurray JJ et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant 2009;24(5):1663-1671
65. Major TC, Olszewski B, Rosebury W, 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(6):469-478
66. Zhang Q, Kohara K, Qui HY, Hiwada K. Comparative effects of three sites of renin-angiotensin blockade on the regression of left ventricular hypertrophy in spontaneously hypertensive rats. Am J Ther 1997;4(5-6):199-202 (Pubitemid 27263925)
67. Whaley-Connell A, Habibi J, Cooper SA, et al. Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat. Am J Physiol Endocrinol Metab 2008;295(1):E103-109
68. Fischer R, Dechend R, Qadri F, et al. Dietary n-3 polyunsaturated fatty acids and direct renin inhibition improve electrical remodeling in a model of high human renin hypertension. Hypertension 2008;51(2):540-546 (Pubitemid 351156445)
69. Neuberg GW, Kukin ML, Penn J, et al. Hemodynamic effects of renin inhibition by enalkiren in chronic congestive heart failure. Am J Cardiol 1991;67(1):63-66
70. Solomon SD, Appelbaum E, Manning WJ, 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(4):530-537
71. McMurray JJ, Pitt B, Latini R, et al. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail 2008;1(1):17-24
72. Gratze P, Boschmann M, Dechend R, et al.: Energy metabolism in human renin-gene transgenic rats: does renin contribute to obesity? Hypertension 2009;53(3):516-523
73. Stucchi P, Cano V, Ruiz-Gayo M, Fernandez-Alfonso MS. Aliskiren reduces body-weight gain, adiposity and plasma leptin during diet-induced obesity. Br J Pharmacol 2009;158(3):771-778
74. Dong YF, Liu L, Kataoka K, et al. Aliskiren prevents cardiovascular complications and pancreatic injury in a mouse model of obesity and type 2 diabetes. Diabetologia 2010;53(1):180-191
75. Jordan J, Engeli S, Boye SW, et al. Direct Renin inhibition with aliskiren in obese patients with arterial hypertension. Hypertension 2007;49(5):1047-1055
76. Schmieder RE, Philipp T, Guerediaga J, et al. Aliskiren-based therapy lowers blood pressure more effectively than hydrochlorothiazide-based therapy in obese patients with hypertension: sub-analysis of a 52-week, randomized, double-blind trial. J Hypertens 2009;27(7):1493-1501
77. Lambers Heerspink HJ, Perkovic V, de Zeeuw D. Renal and cardio-protective effects of direct renin inhibition: a systematic literature review. J Hypertens 2009;27(12):2321-2331
78. Rashid H. Direct renin inhibition: an evaluation of the safety and tolerability of aliskiren. Curr Med Res Opin 2008;24(9):2627-2637