Protective Effects Of Valsartan Research Articles

Protective effect of valsartan alone and in combination with neprilysin inhibitor (valsartan + sacubitril) against hepatic ischemia-reperfusion injury: targeting angiotensin II receptor-neprilysin and modulating SMAD-4/NF-κβ/JNK pathways in rats.

Ischemia-reperfusion injury (IRI) is a common pathogenic situation that arises throughout all liver surgeries, including liver transplants. We aimed to compare the preventive effects of valsartan (VST) against valsartan + sacubitril (LCZ696) on hepatic injury caused by IRI. A total of thirty-six male Westar albino rats were split into six groups randomly: sham, IRI, VST + IRI, LCZ696 + IRI, VST, and LCZ696. The medicines were given orally for 10days in a row. Hepatic tissues and blood were examined through histopathological imaging and immunohistochemical detection of hepatic SMAD-4 protein expression plus serum aminotransferase (ALT, AST) and gamma-glutamyl transferase (GGT) levels. Angiotensin II, aldosterone, and plasma renin activity were evaluated in rat serum. Liver tissue homogenate was utilized to assess reduced glutathione (GSH), myeloperoxidase (MPO), malondialdehyde (MDA), and total nitric oxide (NOx) levels. Pro-inflammatory indicators, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β), moreover with apoptosis indicators, BCL2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), and galactine-9 (GAL9) proteins plus caspase-3, were measured in hepatic tissue homogenate. Hepatic endothelin-1 and neprilysin activity were evaluated. Western blot was done for c-Jun N-terminal kinase (JNK-7) plus nuclear factor-kappa B (NF-κβ) expressions. The study revealed that VST and LCZ696 pretreatment showed significant restoration of liver injury, correction of oxidative profile, and inhibition in the angiotensin II receptor-neprilysin pathway. Inflammatory mediators and apoptosis were significantly inhibited. The expression of SMAD-4, JNK-7, and NF-κβ proteins was notably diminished. The improvement in hepatic architecture supports these histopathological results. In conclusion, LCZ696 possesses a potentially significant protective effect against liver IRI superior to VST alone.

Protective Effects of Valsartan on Gentamicin Induced Tubular Injury through Down Regulation of Urinary N-Acetyl-?-D-Glucosaminidase in Rats

Urinary N-acetyl-β-D-glucosaminidase is a marker of early tubular damage. Therefore, the current study was to investigate effects and its underling mechanisms of valsartan on gentamicin induced renal tubular injury through urinary N-acetyl-β-D-glucosaminidase parameter variety in rats. Animals were divided into four groups consisting of 12 rats each. The study lasted for 10 d. Rats were treated in two batches on the 6th and 11th d of the experiment, with 6 rats in each group. Control group rats were administered with distilled water (10 ml/kg) daily via an intragastric gavage; gentamicin group rats were given gentamicin 100 mg/kg/d intraperitoneally; valsartan (10 mg/kg/d, intragastric gavage) +gentamicin group; valsartan (20 mg/kg/d, intragastric gavage) +gentamicin group. Rats treated with gentamicin showed significant elevation in the activity and expression of urinary N-acetyl-β-D-glucosaminidase as compared with the control group; the activities of superoxide dismutase, glutathione peroxidase and catalase were lower while malondialdehyde was higher in kidney tissues; urinary protein content was not changed; serum creatinine and blood urea nitrogen were increased. Moreover, pathological damage of the renal tubules was serious in gentamicin treated rats. Valsartan significantly inhibited activity and expression of urinary N-acetyl-β-D-glucosaminidase in a dose dependent manner; dramatically increased superoxide dismutase, glutathione peroxidase and catalase activities and markedly decreased malondialdehyde levels in kidney tissues; renal tubular structural damages were also effectively ameliorated by valsartan. These results show that changes of urinary N-acetyl-β-Dglucosaminidase levels can reflect the extent of renal tubular injury, that valsartan has protective role on gentamicin-induced renal tubular injury by down-regulation urinary N-acetyl-β-D-glucosaminidase, and its down-regulation urinary N-acetyl-β-D-glucosaminidase effect may be due to its antioxidant properties in kidney tissues.

Antioxidative and anti-inflammatory impact of valsartan against renal ischemia-reperfusion injury; role of nitric oxide signaling pathway

Introduction: Renal ischemia reperfusion injury is one of the main causes of acute renal failure, which is associated with high mortality. Tissue damage caused by ischemia-reperfusion occurs due to the release of oxygen free radicals. Type I angiotensin receptor antagonists such as valsartan can be useful in the treatment of chronic kidney disease and hypertension. Objectives: We aimed to evaluate the protective effect of valsartan against renal ischemia reperfusion via antioxidant property and nitric oxide (NO) signaling pathway. Materials and Methods: Fifty male Wistar rats (220±10 g) were randomly divided into five groups as follows: Group 1; healthy rats without ischemia-reperfusion (control group). Group 2; rats with ischemia reperfusion (IR) (IR control group). Group 3; rats with IR which received 30 mg/kg valsartan orally. Group 4; rats with IR which received 30 mg/kg valsartan together with 40 mg/kg L-NAME. Group 5; rats with IR which received 30 mg/kg valsartan together with 40 mg/kg L-arginine. To induce ischemia-reperfusion, rats were anesthetized with thiopental and underwent surgery. Then, we induced ischemia with blocking blood vessels for 45 minutes by clamping. Biochemical parameters including urea and creatinine were measured using commercial kits. Oxidative stress and inflammatory parameters were measured by ELISA method. Renal tissues were stained with hematoxylin and eosin. Finally, the Kolmogorov-Smirnov test was used to determine the normal distribution of data. Results: The findings of this study indicated that treatment with valsartan and valsartan plus L-arginine leads to significant decrease in the serum levels of creatinine, urea, and albumin/creatinine, malondialdehyde (MDA), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in contrast to IR control group which has increased level of these parameters. On the other hand, treatment with valsartan and valsartan plus L-arginine lead to increase in the serum levels of glutathione peroxidase (GPX), in contrast to ischemia reperfusion control group. Conclusion: Our data revealed that valsartan as a type I angiotensin receptor antagonist could decrease oxidative stress and inflammation due to renal ischemia reperfusion injury. Hence, valsartan could propose as a therapeutic agent for kidney diseases such as renal ischemia-reperfusion injury regarded to these renoprotective effects.

Valsartan prevents glycerol-induced acute kidney injury in male albino rats by downregulating TLR4 and NF-κB expression

In this study, the protective effect of valsartan against glycerol-induced acute kidney injury (AKI) in male albino rats was investigated. Valsartan is used to treat high blood pressure and congestive heart failure and can prolong lifespan following a heart attack. The rats were divided into control, AKI, AKI + valsartan 100 mg/kg bw, and AKI + valsartan 200 mg/kg bw groups. Superoxide dismutase, glutathione peroxidase, catalase, lipid peroxidation, and reduced glutathione were assessed, and histopathological, immunohistochemical and western blot analyses were performed. Valsartan supplementation in AKI rats substantially increased superoxide dismutase, catalase, glutathione peroxidase, and glutathione levels but reduced the level of lipid peroxidation. Valsartan significantly reduced the severity of the renal tubular injury, renal lesions, and necrosis. Valsartan decreased NF-κB and TLR4 mRNA expression by >50% and their protein levels by >40%. Therefore, valsartan supplementation inhibited glycerol-induced functional and pathological damage to the kidney in a concentration-dependent manner. We propose that valsartan protects rat kidney tissue by downregulating NF-κB and TLR4 expression.

Protective Effect of Valsartan on Podocyte Injury in Rats with Diabetic Nephropathy

To investigate the mechanism of valsartan protecting podocytes and inhibiting renal injury in diabetic rats. The rat model of diabetic nephropathy was induced by combination of valsartan and high-sugar and high-fat diet. The urinary protein content, renal index, inflammatory and antioxidant indexes in the kidney, renal pathological changes and podocyte holes were investigated. Membrane WT1 and P-Cadherin protein expression levels. Compared with the model group, the 24h urine protein content of valsartan was significantly decreased (P<0.05). Valsartan significantly inhibited the body weight of the model group (P<0.01), and significantly inhibited The increase of renal index (P<0.05); the high and middle doses of valsartan could significantly reduce the levels of IL-β, TNF-α and IL-6 in rat kidney (P<0.05-0.01). The valsartan high and middle dose groups significantly reduced MDA content in rat kidney (P<0.05), and significantly increased SOD activity (P<0.05). HE and PAS staining showed that valsartan was used in model group rats. The pathological changes were alleviated, and the glomerular morphology returned to normal. The protein expression of WT1 and P-Cadherin in the kidney of DN rats by Western blot showed that P- in the kidney tissue of valsartan rats. The expression levels of Cadherin and WT1 protein were significantly increased (P<0.05). Valsartan can regulate the expression of podocyte membrane proteins WT1 and P-Cadherin to protect podocytes, and then repair renal function and anti-diabetic nephropathy.

Protective Effect of Valsartan on Beleomycine-Induced Fibrosis

Background: Pulmonary fibrosis (PF) is among the world’s most prevalent and common respiratory system diseases. Several previous studies have revealed the contribution of angiotensin in the pathogenesis of PF; subsequently, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARDs) have been proposed for the treatment of pulmonary fibrosis using therapeutic approaches. Objectives: This study aimed to investigate the anti-fibrotic effect of valsartan as an angiotensin receptor blocker. Methods: Rats were given a single intratracheal administration of bleomycin (7.5 IU/kg); valsartan (20, 40, 80 mg/kg/day) was administrated to the rats orally, starting seven days before the induction of lung fibrosis and continuing until the end of the study. The control group received a vehicle. Results: The rats that received valsartan exhibited decreased hydroxyprolin content and pulmonary index values. Pathological examination showed that valsartan could prevent inflammation and fibrotic scarring induced by bleomycin. Conclusions: Valsartan displayed an anti-fibrotic and protective effect against bleomycin-induced lung fibrosis in an animal model.

Protective Effect of Valsartan on Beleomycine-Induced Fibrosis

Background: Pulmonary fibrosis (PF) is among the world’s most prevalent and common respiratory system diseases. Several previous studies have revealed the contribution of angiotensin in the pathogenesis of PF; subsequently, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARDs) have been proposed for the treatment of pulmonary fibrosis using therapeutic approaches. Objectives: This study aimed to investigate the anti-fibrotic effect of valsartan as an angiotensin receptor blocker. Methods: Rats were given a single intratracheal administration of bleomycin (7.5 IU/kg); valsartan (20, 40, 80 mg/kg/day) was administrated to the rats orally, starting seven days before the induction of lung fibrosis and continuing until the end of the study. The control group received a vehicle. Results: The rats that received valsartan exhibited decreased hydroxyprolin content and pulmonary index values. Pathological examination showed that valsartan could prevent inflammation and fibrotic scarring induced by bleomycin. Conclusions: Valsartan displayed an anti-fibrotic and protective effect against bleomycin-induced lung fibrosis in an animal model.

Pre-treatment with LCZ696, an orally active angiotensin receptor neprilysin inhibitor, prevents ischemic brain damage

Angiotensin II receptor blockers (ARBs) are known to prevent ischemic brain damage after stroke. Natriuretic peptides, which are increased by a neprilysin inhibitor, are also reported to protect against brain damage. Therefore, we investigated the possible protective effect of valsartan (VAL) compared with LCZ696 (VAL+ neprilysin inhibitor; 1:1) after middle cerebral artery (MCA) occlusion. Eight-week-old male C57BL/6J mice were treated with VAL (3mg/kg per day) or LCZ696 (6mg/kg per day) for 2 weeks before MCA occlusion. Blood pressure and heart rate were measured by telemetry. Cerebral blood flow (CBF) was determined by laser-Doppler flowmetry. Ischemic area was evaluated by triphenytetrasodium chloride staining, and oxidative stress was determined by dihydroethidium staining. Blood pressure and heart rate were not significantly different before and after treatment. Pre-treatment with LCZ696 or VAL reduced the ischemic area, and this effect of LCZ696 was more marked than that of VAL pre-treatment. The decrease in CBF in the peripheral region of the ischemic area was significantly attenuated by pre-treatment with LCZ696 or VAL, without any significant effect on CBF in the core region. VAL or LCZ696 pre-treatment significantly decreased the increase of superoxide anion production in the cortex on the ischemic side. However, no significant difference in CBF and superoxide anion production was observed between VAL and LCZ696 pre-treatment. The preventive effect of LCZ696 on ischemic brain damage after stroke was more marked than that of VAL. LCZ696 could be used as a new approach to prevent brain damage after stroke. (246 words)

Abstract 225: Treatment with LCZ696, an Orally Active Angiotensin Receptor Neprilysin Inhibitor Prevents Ischemic Brain Damage

Objective: Recent accumulating evidence suggests that an orally active angiotensin II receptor-neprilysin inhibitor, LCZ696, was supposed to be superior compared to angiotensin II receptor blocker (ARB), valsartan alone in treating cardiovascular disease. We previously reported that ARBs prevent ischemic brain damage using middle cerebral artery occlusion (MCAO) mouse model. Moreover, natriuretic peptides such as atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) increased by neprilysin inhibitor are also reported to protect brain damage. Therefore, we investigate the possible protective effects of valsartan (VAL) compared with LCZ696 (LCZ) (VAL+ neprilysin inhibitor; 1:1) on the prevention of ischemic damage after stroke. Methods: Focal brain ischemia was induced by MCAO with the intraluminal filament technique in 10-week male C57BL/6J mice. Mice were treated with VAL (3 mg/kg) or LCZ (6 mg/kg) orally as powder in gelatin mini-capsules daily for 2 weeks before MCAO. Ischemic area was evaluated by triphenyl tetrazolium chloride staining, cerebral blood flow (CBF) by laser-Doppler flowmetry, oxidative stress by dihydroethidium staining. Results: Telemetry method showed that systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) did not change before and after treatments. Protective effect of LCZ treatment on ischemic brain damage in each brain section seemed to be more marked than that of VAL treatment. The average ischemic area ratio showed a significant reduction in VAL and LCZ groups compared with CON group. CBF in the peripheral region around ischemic core was significantly improved after treatments. Moreover, VAL and LCZ treatments significantly decreased the increase of superoxide anion production in the cortex of ischemic side. However, significant differences of CBF and superoxide anion production were not observed in VAL and LCZ. Conclusions: Both valsartan and LCZ696 treatments exerted preventive effects on ischemic stroke. The preventive effect of LCZ696 seemed more prominent than VAL. LCZ696 could be a novel powerful approach to protect brain after stroke. Further investigation has been performed to clarify the protective effect of LCZ696 on ischemic brain damage.

Protective effect of valsartan for stroke in Japanese subjects

Protective effect of valsartan for stroke in Japanese subjects

Cardio‐cerebrovascular protective effects of valsartan in high-risk hypertensive patients with overweight/obesity: A post-hoc analysis of the KYOTO HEART Study

PurposeThe objective was to examine whether baseline overweight/obesity influences the ARB, valsartan add-on effects on the cardio‐cerebrovascular (CV) morbidity and mortality in the high-risk hypertensive patients who participated in the KYOTO HEART Study. Methods and resultsThe primary endpoint was the same as in the main study: a composite of defined CV events. Median follow-up period was 3.27years. According to the presence of overweight/obesity (body mass index≥25) at baseline, the study population was divided into two groups (with overweight/obesity; n=1177 and without overweight/obesity; n=1854), in which prevalence of primary endpoint events were similar in patients with overweight/obesity and patients without overweight/obesity (7.6% vs. 8.0%; HR 0.96, 95% CI 0.74–1.23). Valsartan add-on significantly decreased the occurrence of primary endpoint events in both overweight/obesity-positive patients (4.0% vs. 11.3%; HR 0.36, 95% CI 0.23–0.56) and overweight/obesity-negative patients (6.4% vs. 9.6%; HR 0.67, 95% CI 0.49–0.92) compared with non-ARB treatment. In the presence of overweight/obesity, the patients with valsartan add-on treatment had significantly smaller prevalence of new occurrence or exacerbation of angina pectoris, stroke, and heart failure than those with non-ARB treatment, while valsartan add-on effects on angina, stroke, and heart failure were not significant in the absence of overweight/obesity. Changes in blood pressure during the follow-up period did not differ significantly among the study subgroups. ConclusionsHigh-risk hypertensive patients with overweight/obesity might obtain more CV benefits from valsartan add-on treatment, compared with patients without overweight/obesity.

Protective Effects of Valsartan Combined with Ulinastatin on Hepatic Ischemia-reperfusion Injury

Objective To study the protective effects of valsartan combined with/without ulinastatin on primary hepatic carcinoma with liver cirrhosis and portal hypertension in patients with hepatic ischemia-reperfusion injury.Methods Thirty patients with hepatic carcinoma scheduled for hepatectomy were divided into three groups randomly: control group,ulinastatin group,valsartan and ulinastatin combined group.Ulinastatin group by 10 000 u / kg after induction of anesthesia before skin incision add 5% glucose intravenous drip of saline 100 ml.Combined group was given valsartan orally 80 mg once daily for a week,intraoperative with ulinastatin group.Control group,5% glucose intravenous infusion of saline 100ml.Venous blood samples were used to measure the concentration of TXB2 and 6-keto-PGF1α,before,end and opening 60 min of the hilar blocking separately in three groups.Preoperative,postoperative 1 day,3 days and 5 days venous blood samples for alanine aminotransferase,aspartate aminotransferase and total bilirubin measurement.Results All 30 cases had been resected successfully,three groups of patients with TXB2,6-keto-PGF1α,alanine aminotransferase,aspartate aminotransferase and total bilirubin in plasma increased(P0.05),ulinastatin group and combined group rate of increase were lower than the control group(P0.05),but the protective effect of combined group and alone ulinastatin group had no significant difference(P0.05).Conclusion Ulinastatin group had obvious protective effect on the patients of hilar primary hepatic carcinoma with liver cirrhosis and portal hypertension,but the effect of Ulinastatin combining with valsartan,needs to be explored further.

Chronopharmacology of Angiotensin II–receptor Blockers in Stroke-Prone Spontaneously Hypertensive Rats

Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time–dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time–dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time–dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time–dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time–dependent event.

Protective Effects of Valsartan and Benazeprilat in Salt-Loaded Stroke-Prone Spontaneously Hypertensive Rats

These experiments examined the effectiveness of chronic blockade of the renin angiotensin system with either valsartan or benazeprilat on survival, blood pressure and end-organ damage in salt-loaded stroke-prone SHR. Valsartan or benazeprilat given continuously by subcutaneous osmotic minipump beginning at 10.5 weeks of age lowered blood pressure, as determined by radiotelemetry, prevented proteinuria, prolonged survival and decreased the severity of histopathological changes in the heart and kidney. These results indicate that angiotensin receptor blockade affords a similar degree of protection as inhibition of angiotensin converting enzyme in salt-loaded stroke-prone SHR. Furthermore, our results are consistent with a primary contribution of angiotensin I1 to the maintenance of blood pressure and support a principal role for angiotensin II-dependent mechanisms in the development of end-organ damage in the salt-loaded strokeprone SHR.