Background: Diabetic nephropaty (DN) occurs in approximately 40% of patients with diabetes mellitus, and is the most common cause of end-stage renal disease. The combination of ACE inhibitors with ARB could lead to a more effective inhibition of rennin angiotensin aldosterone system (RAAS).
Aim: The present study was undertaken to evaluate the effects of dual RAAS blockade with ARB (candesartan) and ACE inhibitor (perindopril) in streptozotocin induced diabetic nephropathy versus ACE-inhibitor or ARB alone.
Materials and Methods: Wistar rats (n=125), were used in this investigation. Diabetes was induced by streptozotocin (STZ) 60 mg/kg. The diabetic rats (n=100) were randomly assigned to receive vehicle, ARB-Candesartan (5 mg/kg/per d), ACE inhibitor-Perindopril (6 mg/kg/per d), or a combination of low dose Can+Per (2.5 mg/kg/per d and 3 mg/kg/per d) respectively, from weeks 4-12.
Results: Treatment with candesartan or perindopril as monotherapy, although significantly, only partially prevented the symptoms and signs of DN. Candesartan and perindopril were equally effective in treatment of DN. Combination therapy was more effective than monotherapy with either drug.
Conclusion: The results from this study demonstrate that combination treatment with both ACE and ARB in low doses may offer synergistic blockade of the RAAS, not obtainable with either drug alone.
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1. Choudhury D Tuncel M Levi M. Diabetic nephropathy-a multifaceted target of new therapies. Discov Med. 2010; 10(54):406-15
2. Kaul K Hodgkinson A Tarr JM Kohner EM Chibber R. Is inflammation a common retinal-renal-nerve pathogenic link in diabetes? Curr Diabetes Rev. 2010; 6(5):294-303.
3. Wu AY Kong NC De Leon FA Pan CY Tai TY Yeung VT Yoo SJ Rouillon A Weir MR. An alarmingly high prevalence of diabetic nephropathy in Asian type 2 diabetic patients: the MicroAlbuminuria Prevalence (MAP) Study. Diabetologia. 2005; 48(1):17-26.
4. di Mario U Morano S Cancelli A Bacci S Frontoni S Pietravalle P et al. New parameters to monitor the progression of diabetic nephropathy. Am J Kidney Dis. 1989;13(1):45-48.
5. Kverneland A Feldt-Rasmussen B Vidal P Welinder B Bent- Hansen L Soegaard U et al. Evidence of changes in renal charge selectivity in patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1986; 29(9):634-639.
6. 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. 2000; 32:387-392.
7. Nussberger J Brunner DB Waeber B Brunner HR. Plasma angiotensins under sustained converting enzyme inhibition with enalapril in normal humans. J Hypertens. 1985; Suppl 3: S269 -S270.
8. Cao Z Kelly DJ Cox AJ Casley D Forbes J Martinello P Dean R Gilbert R Cooper M. The angiotensin type 2 receptor is expressed in adult rat kidney and promotes cellular proliferation and apoptosis. Kidney Int. 2000; 58:2437 -2451.
9. Esteban V Lorenzo O Ruiperez M Suzuki Y Mezzano S Blanco J Kretzles M Sugaya T Egido J Ruiz Ortega M. Angiotensin II via AT1 and AT2 receptors and NF-kappaB pathway regulates the inflammatory response in unilateral ureteral obstruction. J Am Soc Nephrol. 2004; 15:1514-1529.
10. Azizi M Ménard J. Combined blockade of the reninangiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation. 2004; 109:2492-2499.
11. Ennezat PV Berlowitz M Sonnenblick EH Le Jemtel TH. Therapeutic implications of escape from angiontensinconverting enzyme inhibition in patients with chronic heart failure. Curr Cardiol Rep. 2000; 2:258-262
12. Earle K Viberti GC. Familial hemodynamic and metabolic factors in the predisposition to diabetic kidney disease. Kidney Int. 1994; 45: 434.
13. Ritz E Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med. 1999; 341:1127.
14. Chavers BM Bilous RW Ellis EN et al. Glomerular lesions and urinary albumin excretion in type I diabetes without overt proteinuria. N Engl J Med. 1989; 320:966.
15. Cooper ME. Pathogenesis prevention and treatment of diabetic nephropathy. Lancet. 1998; 352:213.
16. Ismail N Becker B Strzelczyk P Ritz E. Renal disease and hypertension in non-insulin-dependent diabetes mellitus. Kidney Int. 1999; 55:1.
17. Gross JL de Azevedo MJ Silveiro SP et al. Diabetic nephropathy: diagnosis prevention and treatment. Diabetes Care. 2005; 28:164.
18. Lasaridis AN Sarefidis PA. Diabetic nephropathy and antihypertensive treatment: what are the lessons from clinical trials? Am J Hypertens. 2003; 16:689-97.
19. Christensen EI Carone FA Rennke HG. Effect of molecular charge on endocytic uptake of ferritin in renal proximal tubule cells. Lab Invest. 1981; 44(4):351-358.
20. Hollenberg NK Fisher NDL Price DA. Pathways for angiotensin II generation in intact human tissue. Evidence from comparative pharmacological interruption of the renin system. Hypertension. 1998; 32:387-392.
21. Brenner BM Cooper ME de Zeeuw D Keane WF Mitch WE Parving HH 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.
22. Jacobsen P Andersen S Jensen BR Parving HH. Additive effect of ACE inhibition and Angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. J Am Soc Nephrol. 2003; 14(4):992-9.
23. Bakris GL Copley JB Vicknair N Sadler R Leurgans S. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int. 1996; 50:1641-1650.
24. Nielsen FS Rossing P Gall M-A Skøtt P Smidt UM Parving HH. Long-term effect of lisinopril and atenolol on kidney function in hypertensive non-insulin-dependent diabetic subjects with diabetic nephropathy. Diabetes. 1997; 46:1182-1188.
25. Vanhoutte PM: Endothelium and control of vascular function. State of the Art lecture. Hypertension. 1989; 13:658-667.
26. 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; 32:387-392.
27. Nussberger J Brunner DB Waeber B Brunner HR. Plasma angiotensins under sustained converting enzyme inhibition with enalapril in normal humans. J Hypertension. 1985; Suppl 3: S269-S270.
28. Wolf G Ziyadeh FN Thaiss F Tomaszewski J Caron RJ Wenzel U Zahner G Helmchen U Stahl RA. Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. J Clin Invest. 1997; 100:1047-1058.
29. Cao Z Kelly DJ Cox A Casley D Forbes JM Martinello P Dean R Gilbert RE Cooper ME. Angiotensin type 2 receptor is expressed in the adult rat kidney and promotes cellular proliferation and apoptosis. Kidney Int. 2000; 58:2437-2451.
30. Cao Z Bonnet F Candido R Nesteroff SP Burns WC Kawachi H Shimizu F Carey RM De Gasparo M Cooper ME. Angiotensin type 2 receptor antagonism confers renal protection in a rat model of progressive renal injury. J Am Soc Nephrol. 2002; 13: 1773-1787.
31. Komine N Khang S Wead LM Blantz RC Gabbai FB. Effect of combining an ACE inhibitor and an angiotensin II receptor blocker on plasma and kidney tissue angiotensin II levels. Am J Kidney Dis. 2002; 39(1):159-164.
32. Navar LG Harrison-Bernard LM Imig JD Wang CT Cervenka L Mitchell KD. Intrarenal angiotensin II generation and renal effects of AT1 receptor blockade. J Am Soc Nephrol. 1999;10(Suppl. 12):S266-S272.