Pleiotropic Properties of Valsartan: Do They Result from the Antiglycooxidant Activity? Literature Review and In Vitro Study

Table 7

The pleiotropic properties of valsartan in experimental and clinical studies.

Valsartan properties	Study design	Measured parameters	Results	References
Valsartan presenting antioxidant properties in myocardial ischemia and myocardial infarction model in rats	Seven male albino rats pretreated intraperitoneally (i.p.) with valsartan (10 mg/kg) before left anterior descending artery (LAD) ligation vs. rats which undergo the same intervention, but with no pretreatment or saline i.p. injection	Cardiac troponin T (cTnT) in heart blood plasma	↓cTnT concentration in valsartan-pretreated group vs. control ()	Hadi et al. 2015 [79]
		Malondialdehyde (MDA) and reduced glutathione (GSH) in heart blood serum	↓MDA concentration in valsartan-pretreated group vs. control ()
		Tumor necrosis factor (TNF), interleukin 6 (IL-6), interleukin 10 (IL-10), caspase 3, and BAX protein in cardiac tissue	↓TNF, ↓IL-6, ↓IL-10 ↓caspase 3, ↓BAX concentrations in valsartan-pretreated group vs. control ()
		Histopathological study of cardiac tissue	Histopathological injure improvement in valsartan-pretreated rats vs. control (14.3% of the group had no signs of injury; )
	16 male Sprague-Dawley rats treated with p.o. valsartan (10 mg/kg/d, 2 weeks) after ligation of LAD vs. 16 not pretreated rats that undergone the same procedure	Plasma MDA, superoxide dismutase (SOD) activity, and TNF-α	↓MDA, ↑SOD after 4 h of reperfusion vs. ischemia-reperfusion control group ()	Wu et al. 2013 [80]
		Myocardial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and nuclear factor–kappa B (NF-κB)	↓TNF-α in 60 min, 120 min, and 240 min after reperfusion vs. ischemia-reperfusion control ()
			↓NADPH oxidase activity, ↓NF-κB expression vs. ischemia-reperfusion control ()
	2 groups of 6 male Wistar rats premedicated with valsartan 50 mg/kg or 100 mg/kg for 14 days and then treated with isoproterenol (ISO) to induce MI	Total antioxidant activity (TAC) and nitric oxide (NO) in serum	↓1.6x/2.03x TAC (VAL 50/100, /) vs. MI-control	Imran et al. 2019 [81]
		Catalase, SOD, glutathione peroxidase (GPX), glutathione reductase (GR), glutathione S-transferase (GST), thiobarbituric acid-reactive substances (TBARS) in cardiac tissue	↓1.58x NO (VAL 100, )
			↑ CAT (VAL 100, )
			↑ SOD (VAL 100,
			↑2.7x/3.45x GPX
			(VAL 50/100, /)
		Histopathological study of cardiac tissue	↑2.26x/2.42x GR (VAL 50/100, )
			↑1.86x/2.11x GST (VAL 50/100, /)
			1.86x/2.29x ↓TBARS (VAL 50/100, /)
			A few inflammatory cells and vacuolization in VAL 50 myocardium
			Muscle fibers with no significant changes except for larger nucleus in VAL 100
Valsartan ameliorates cardiac hypertrophy resulting from cardiac pressure overload in rats	4 groups of Sprague-Dawley rats (sham (), vehicle (), valsartan (), sacubitril/valsartan ()) undergoing aortic banding to induce cardiac pressure overload	Left ventricular weight	No significant change of left ventricular weight in VAL group vs. vehicle ()	Nordén et al. 2021 [91]
		Mean arterial pressure (MAP)	↓16% MAP in VAL group vs. sham
		Atrial and brain natriuretic peptide (ANP, BNP)	↑ANP, BNP in VAL group vs. sham ()
		Histopathological study of cardiac tissue	↑Expression of collagen 1, 3, and metalloproteinase-2 of cardiac tissue in VAL group
Reduction of oxidative damage of kidneys with valsartan in streptozotocin-induced diabetes in rats	8 male Wistar rats with streptozotocin-induced diabetes treated with p.o. valsartan (100 mg/kg/d, 1 month) vs. 8 diabetic, nontreated rats	MDA, SOD, GPX, renal TNF-α-mRNA, renal TGF-β-mRNA, renal IL-6, NAD/NADH ratio in renal tissue homogenate	↓TNF-α-mRNA, ↓IL-6, ↓urine IL-6, ↓TGF-β-mRNA, ↑NAD/NADH ratio vs. diabetic rats control group ()	Sanajou et al. 2019 [82]
		IL-6 in urine	↓Renal MDA, ↑renal GPX, ↑renal SOD vs. diabetic rats control group ()
		Histopathological study of renal tissue	Significant reduction of collagen deposition in the tubulointerstitial area
Antiatherogenic effect of valsartan in cholesterol-fed rabbits	Male rabbits fed with normal (), cholesterol (), or cholesterol + valsartan () diet (1 mg/kg, subcutaneously)	Systolic and diastolic blood pressure (SBP, DBP)	No significant change of SBP or DBP in VAL group vs. cholesterol-fed	Li et al. 2004 [92]
		Total cholesterol and triglycerides (TC, TG)	No significant change of TC in VAL group vs. cholesterol-fed
		Serum ACE activity	↓TG in VAL group vs. cholesterol-fed; ()
		Morphology and histopathological studies of aorta	↓Of atherosclerotic lesion area in VAL group, but not statistically significant
Inflammation and vascular remodeling attenuation in valsartan-treated diabetic and hyperlipidemic swine	24 diabetic and hyperlipidemic swine divided into three groups (early and late); placebo (), valsartan 320 mg daily (), valsartan + simvastatin 320 mg/40 mg ()	Progression of atherosclerotic lesions	Slower progression of atherosclerotic plaques vs. placebo	Chatzizisis et al. 2009 [93]
		Histopathological studies	↓area of inflammation in plaques in VAL group vs. placebo ()
		Expression of extracellular matrix metalloproteinases (MMP-2, MMP-9)	↓MMP-9 ratio in plaques with expansive remodeling in VAL group ()
		Expression of tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2)	↓MMP/TIMP ratio in plaques with expansive remodeling in VAL group ()
Antioxidant action of valsartan in high-glucose-cultured rat mesangial cells	HBZY-1 rat mesangial cells cultured with high glucose (30 mmol/lLconcentration and valsartan (10 μmol/L) vs. cells cultured in high-glucose only vs. osmotic pressure control group (25 mmol/L of mannitol, 5 mmol/L of glucose)	SOD activity, nitric oxide (NO), and malondialdehyde (MDA) contents in supernatant	↑SOD activity and ↑NO, ↓MDA contents in valsartan + high-glucose group vs. high-glucose only group (after 24 hrs of incubation)	Liu et al. 2016 [83]
Oxidative stress parameters in type 2 diabetic and hypertensive patients treated with valsartan	33 patients with type 2 diabetes and hypertension treated with valsartan (80 mg/d) for 24 weeks (no other antihypertensive drugs 2 weeks before the screening date)	Nitrotyrosine in blood	↓Nitrotyrosine after 24 weeks of treatment (/L vs. , )	Kim et al. 2017 [84]
	26 patients with hypertension (>140/90 mmHg) and mild diabetes () treated with 40 or 80 mg/kg valsartan for 3 months, all previously taken drugs were continued	Blood inflammatory markers (hs-CRP, IL-6, IL-18, VCAM-1, L-selectin)	↓hs-CRP (0.231 vs. 0.134, )	Kuboki et al. 2007 [85]
			↓VCAM-1 (471.1 vs. 403.2, )
			↑IL-6, IL-18, L-selectin (but statistically insignificant)
		8-Isoprostane and 8-OHdG in urine	↓8-OHdG after treatment (12.12 vs. 8.07, )
			↑8-Isoprostane after treatment (283.5 vs. 302.0, but statistically insignificant)
	15 patients with type 2 diabetes treated with 40 mg/d valsartan (in 6 patients dose increased to 80 mg/d after 6 months) for 1 year	AGE in blood	↓AGE ( vs. , )	Komiya et al. 2008 [86]
		Urine 8-isoprostane	↓8-Isoprostane ( vs. , )
Valsartan ameliorated oxidative stress in patients with hypertension	25 patients with hypertension (>140/90 mmHg) treated with 80 or 160 mg/d valsartan depending on basal arterial pressure	Urine 8-isoprostane and 8-hydroxy-2-deoxyguanosine (8-OHG)	55% ↓urine 8-isoprostane and 30% ↓8-OHdG after 12 months of treatment ()	Hirooka et al. 2008 [29]
	17 patients with hypertension (>140/90 mmHg) treated with 40 or 80 mg/d valsartan if BP did not decrease below 140/90 mmHg	Serum levels of lipoperoxidation (LPO)	↓LPO after 6 months, when pretreatment LPO levels were ≥1.5 pg/mL ( vs. , )	Miyajima et al. 2008 [87]
	8 patients with hypertension and hyperlipidemia treated with 80 mg/d valsartan for 2 months	Plasma TBARS	↓TBARS after the treatment ( vs. , )	Hussein et al. 2002 [88]
		Lag time required for the initiation of LDL oxidation	↑Lag time after the treatment ( vs. , )
Valsartan improved an atherosclerotic lesion in mice by oxidative stress improvement	Male apoE-deficient mice on standard or high-cholesterol diet (HCD) treated with 0.5 mg/kg valsartan i.p. in osmotic minipump	Expression of NADPH oxidase subunit p47^phox	58% ↓p47^phox in HCD + valsartan group vs. HCD-only ()	Suzuki et al. 2006 [89]
		The area of the atherosclerotic lesion in the aorta	2% of area in HCD + valsartan group vs. 5% in HCD group ()
Effect of valsartan on redox balance in hemodialysed patients with end-stage renal disease	19 patients with end-stage renal disease treated with 320 mg/d valsartan for 6 weeks	Protein carbonyls (PC), 8-OHdG, 13-hydroxyoctadecadienoic acid (13-HODE), hs-CRP in plasma	No change in PC ( before and after, but statistically insignificant)	Aslam et al. 2006 [90]
		Glutathione disulfide: reduced glutathione ratio (GSSG:GSH) in whole blood	19.5% ↓ 8-OHdG ( vs. , )
			14.4% ↓13-HODE ( vs. , but statistically insignificant)
			↑hs-CRP ( vs. , but statistically insignificant)
			79% ↓GSSG: GSH ( vs. )