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References 1. M. Lunder, M. Janić, B. Jug and M. Šabovič, The effects of low-dose fluvastatin and valsartan combination on arterial function: A randomized clinical trial, Eur. J. Intern. Med. 23 (2012) 261-266; https://doi.org/10.1016/j.ejim.2011.11.011 2. V. Savić, B. Eržen, M. Janić, M. Lunder, M. Boncelj, K. Kanc, A. Janež and M. Šabovič, Improvement of arterial wall characteristics by the low-dose fluvastatin and valsartan combination in type 1 diabetes mellitus patients, Diab. Vasc. Dis. Res. 10 (2013) 420-425; https://doi.org/10.1177/1479164113485102 3. M

individual patients: ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet. 2000;355:1575-81. Cohn JN, Tognoni G. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-75. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759-66. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left

References [1] Andriamainty F, Čižmarik J, Holikova M. Study of local anaesthetics. Part 167. Micellization of local anaesthetic heptacainium chloride in aqueous electrolyte solution. Acta Fac. Pharm. Univ. Comen. 2004;51:38-44. [2] Antil P, Kaushik D, Jain G, Srinivas KS, Thakur I. UPLC Method for Simultaneous Determination of Valsartan & Hydrochlorothiazide in Drug Products. J. Chrom. Sep. Techn. 2013;4(5):1-5. [3] Bergstrom LM. Model calculations of the spontaneous curvature, mean and Gaussian bending constants for a thermodynamically open surfactant film. J

medicines for children, Int. J. Pharm. 379 (2009) 143-145; DOI: 10.1016/j.ijpharm.2009.06.033. 4. Atacand (Candesartan Cilexetil) Drug Information: Description, User Reviews, Drug Side Effects, Interactions - Prescribing Information at RxList; http://www.rxlist.com/atacand-drug.htm; access date October 28, 2014. 5. Atacand. Patient Information approved by the U.S. Food and Drug Administration, 2013; http:// www1.astrazeneca-us.com/pi/Atacand.pdf; access date October 28, 2014. 6. Diovan (Valsartan) Drug Information: Description, User Reviews, Drug Side Effects

D, Touyz RM. Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. Antioxid Redox Signal 2013; 19: 1110-1120 5. Nguyen Dinh Cat A, Touyz RM. Cell signaling of angiotensin II on vasculartone: novel mechanisms. Curr Hypertens Rep 2011; 13: 122-128 6. Kintscher U, Marx N, Martus P, Stoppelhaar M, Schimkus J, Schneider A et al. Effect ofhigh-dose valsartan on inflammatory and lipid parameters in patients with Type 2 diabetes and hypertension. Diabetes Res Clin Pract 2010; 89: 209-215 7. Ristic P, Srejovic I, Nikolic T, Stojic I, Ristic D, Zivkovic V

References H. Siragy, Angiotensin II receptor blockers: review of the binding characteristics, Am. J. Cardiol.   84 (1999) 3S-8S; DOI: 10.1016/2FS0002-9149/2899/2900727-4. E. Francotte, A. Davatz and P. Richert, Development and validation of chiral HPLC methods for the quantitation of valsartan and of the tosylate of valine benzyl ester, J. Chromatogr. B. Biomed. Appl.   686 (1996) 77-83; DOI: 10.1016/2FS0378-4347/2896/2900242-3. A. Sioufi, F. Morfil and J. Godbillon, Automated determination of an angiotensin II receptor antagonist in plasma by high

References N. Koseki, H. Kawashita, H. Hara, M. Niina, M. Tanaka, R. Kawai, Y. Nagae and N. Masuda, Development and validation of a method for quantitative determination of valsartan in human plasma by liquid chromatography-tandem mass spectrometry, J. Pharm. Biomed. Anal.   43 (2007) 1769-1774; DOI: 10.1016/j.jpba.2006.12.030. M. Doménech and A. Coca, Role of triple fixed combination valsartan, amlodipine and hydrochlorothiazide in controlling blood pressure, Patient Pref. Adh.   4 (2010) 105-113. The Merck Index (Ed. S. Budavari), 13th ed. Merck & Co. Inc

References El-Gizawy SM, Abdelmageed OH, Omar MA, Duryea SM, Abdel-Megied AM (2012) Development and validation of HPLC method for simultaneous determination of amlodipine, valsartan, hydrochlorothiazide in dosage form and spiked human plasma. Am. J. Analyt. Chem. 3: 422-430. Gupta KR, Wadodkar AR., Wadodkar SG (2010a) UVSpectrophotometric methods for estimation of valsartan in bulk and tablet dosage form. Int. J. Chemtech. Res. 2: 985-989. Gupta KR, Askarkar SS, Rathod PR, Wadodkar SG (2010b) Validated spectrophotometric determination of Fenofibrate in

References [1] Asmar R, Gosse P, Quere S, Achouba A. Efficacy of morning and evening dosing of amlodipine/valsartan combination in hypertensive patients uncontrolled by 5 mg of amlodipine. Blood Press Monit. 2011;16(2):80-86. [2] Braun MC, Herring SM, Gokul N et al. Hypertensive renal disease: susceptibility and resistance in inbred hypertensive rat lines. J Hypertens. 2013;31(10):2050-2059. [3] Cui H, Kohsaka A, Waki H, Bhuiyan ME, Gouraud SS, Maeda M. Metabolic cycles are linked to the cardiovascular diurnal rhythm in rats with essential hypertension. PLoS One

Abstract

Salt sensitive hypertension is known to be a contributing factor for the progression of kidney disease. This study was undertaken to investigate the role of excessive dietary salt on renal function and to evaluate the effect of valsartan and amlodipin given as a combination therapy on blood pressure and parameters specific to the renal function in salt loaded SHR rats. 48 male SHR rats at age of 20 weeks and body weight ranging between 270-350 g were used. SHR rats were divided into 3 groups: control group of rats -SHRC (n = 16) given tab water ad libitum and two salt treated groups in which tab water was replaced with a solution of NaCl (1%) from age of 8 weeks given ad libitum: SHRVAL+AMLO group (n = 16) where investigated drugs were administered at a dose of 10 mg/kg/ b.w. (valsartan) and 5 mg/kg/ b.w. (amlodipin) by gavage and SHR NaCl group (n = 16) that received saline in the same volume and the same time intervals as the SHRVAL+AMLO group. For a period of 12 weeks we have investigated the effect of the VAL+AMLO drug combination on systolic blood pressure (SBP), body weight and renal function tests. Salt loading with 1% solution in the SHR NaCl group has lead to significant increase of blood pressure, proteinuria and decrease in creatinine clearance. Combined treatment with АТ1-receptor blocker and calcium antagonist has managed to control blood pressure and ameliorated renal damage.