Macedonian Journal of Medical Sciences. 2013 Sep 1 ; 6(3):219-226. 5 http://dx.doi.org/10.3889/MJMS.1857-5773.2013.0301 Basic Science Effects of Dual RAAS Blockade with Candesartan and Perindopril on Functional Renal Tests in Streptozotocin Induced Diabetic Nephropathy Jasmina Trojacanec 1* , Dimce Zafirov 1 , Krume Jakjovski 1 , Kalina Gjorgjievska 1 , Plamen Trojacanec 2 , Nikola Labacevski 1 1 Department of Preclinical and Clinical Pharmacology with Toxicology, Medical Faculty, Skopje, Republic of Macedonia; 2 Department of Veterinary Surgery, Faculty for Veterinary Medicine, Skopje, Republic of Macedonia Citation: Trojacanec J, Zafirov D, Jakjovski K, Gjorgjievska K, Trojacanec P, Labacevski N. Effects of Dual RAAS Blockade with Candesartan and Perindopril on Functional Renal Tests in Streptozotocin Induced Diabetic Nephropathy. Maced J Med Sci. 2013 Sep 15; 6(3):219-226. http://dx.doi.org/10.3889/MJMS.1857- 5773.2013.0301. Key words: Streptozocin; RAAS; candesartan; perindopril; diabetic nephropathy; rats. * Correspondence: Jasmina Trojacanec. Department of Preclinical and Clinical Pharmacology with Toxicology, Medical Faculty, Ss Cyril and Methodius University, 1000 Skopje, Republic of Macedonia. Tel. +389 23111828; +389 71 551166. e-mail: jasmina.trojacanec@yahoo.com Received: 17-Jun-2013; Revised: 20-Jun- 2013; Accepted: 01-Jul-2013; Online first: 22-Aug-2013 Copyright: © 2013 Trojacanec J. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Competing Interests: The authors have declared that no competing interests exist. Abstract 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. Introduction Diabetic nephropathy (DN) remains the most common cause for end stage renal disease (ESRD) as the burden of diabetes increases worldwide [1- 3]. The mechanisms of DN are not very clear, but the extensive investigation has documented the key role of the rennin angiotensin aldosterone system (RAAS) in the pathogenesis and pathophysiology of DN [4]. Accordingly, blockade of the RAAS is first-line therapy in the treatment of diabetic nephropathy [5]. Blockade of the RAAS has been shown to reduce proteinuria and the rate of decline of glomerular filtration rate (GFR) in proteinuric nephropathies, including diabetic nephropathy. However not all patients who are treated with angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARB) show a clear antiproteinuric response. An insufficient response to ACE inhibition might be explained by incomplete blockade: At least 40% of angiotensin II (AngII) is produced via other non-ACE pathways, such as chymase [6]. This incomplete blockade possibly explains the observation that plasma AngII levels return to normal after chronic ACEI treatment, a phenomenon that is known as ACE escape [7]. Theoretically, treatment with ARB may result in more complete blockade of the unfavorable actions of AngII mediated through AT1 receptors. Until _______________________________________________________________________________________________________________________________ Maced J Med Sci. 2013 Sep 15; 6(3):219-226. 219