Protective Effect Of Losartan Research Articles

P-1 Potential neuroprotective effects of losartan and donepezil on oxaliplatin-induced peripheral neuropathy in rats

Oxaliplatin (OXL) is a platinum-based antineoplastic drug widely used for treating colorectal cancer which induces peripheral neuropathy as dose-limiting toxicity. We assess the neuroprotective effects of losartan (LOS) and donepezil (DPZ) on OXL-induced peripheral neuropathy in rats. Forty Sprague-Dawley rats were divided into four groups; control (vehicle-treated), OXL (2.4 mg/kg/d; intraperitoneal), OXL+LOS (100 mg/kg/d; oral), and OXL+DPZ (1 mg/kg/d; oral). All were given 5 times/week for 2 weeks. Behavioral assessment of pain, sensory, and motor disturbances was done on days 7 and 14 using a paintbrush, acetone, tail-flick latency, and grip strength tests. The levels of interleukin (IL)-1β, and tumor necrosis factor (TNF)-α were measured in L4-L6 samples. Histopathological examination of the sciatic nerve was done to assess nerve degeneration. OXL induced significant mechanical dynamic allodynia, cold allodynia, and thermal hyperalgesia compared to the control group. LOS significantly ameliorated mechanical and cold allodynia, while DPZ improved mechanical allodynia and thermal hyperalgesia. OXL significantly increased IL-1β, and TNF-α compared to the control group. Only LOS significantly attenuated these markers. In the OXL group, the axons were swollen, and nerve fiber degeneration with neuron gaps occurred. Both treatments improved these histopathological changes. LOS and DPZ attenuate the neurotoxic effect of oxaliplatin by attenuating behavioral and histopathological alterations and the protective effect of LOS may involve in the inhibition of spinal pro inflammatory cytokines. Therefore, LOS and DPZ are promising agents to prevent OXA-induced peripheral neuropathy.

Protective effects of losartan on bladder dysfunction in spontaneously hypertensive rats

Protective effects of losartan on bladder dysfunction in spontaneously hypertensive rats

The protective effect of losartan against sorafenib induced cardiotoxicity: Ex-vivo isolated heart and metabolites profiling studies in rat

Sorafenib, a tyrosine kinase inhibitor that is used in the treatment of hepatocellular and renal cell carcinoma, was reported to induce cardiotoxicity. This study aimed to investigate the potential cardioprotective effect of losartan against sorafenib-induced cardiotoxicity in rat. Sorafenib significantly reduced the left ventricular pressure, heart rate dp/dt max & dp/dt min (indexes of myocardial contractility and relaxation; respectively), and prolonged both the systolic and diastolic periods. Coadminstration of losartan significantly reversed the effects of sorafenib on heart rate, dp/dt max and dp/dt min. In addition, there was a tendency for losartan to reverse sorafenib reduction in left ventricular pressure and perfusion pressure but it did not reach statistical significance. A GC-MS non-targeted based metabolites profiling of rat plasma revealed elevated metaboites, including urea and fatty acids levels, associated with sorafenib induced cardiotoxicity. However, only glycine and lactic acid were statistically significant. Interestingly, losartan co-administration with sorafenib restored these changes, and resulted in a significantly reduced glycine, urea and some fatty acids levels namely; Cis-vaccenic acid, oleic acid, stearic acid and undecanoic acid. In addition, based on histology results, losartan coadminitration almost obviated sorafenib-induced changes in cardiac tissues. The study suggests that losartan has the potential to exert a protective effect against sorafenib-induced cardiotoxicity.

Protective effects of losartan on some type 2 diabetes mellitus-induced complications in Wistar and spontaneously hypertensive rats.

Diabetes mellitus type 2 (T2DM) is characterized by resistance of insulin receptors and/or inadequate insulin secretion resulting in metabolic and structural complications including vascular diseases, arterial hypertension and different behavioral alterations. We aimed to study the effects of the antihypertensive angiotensin AT1 receptor antagonist losartan on the T2DM-induced changes of exploratory behavior, anxiety, nociception and short term memory in normotensive Wistar and spontaneously hypertensive rats (SHRs). The experimental model of T2DM induced by a combination of high fat diet and streptozotocin, decreased exploratory activity and increased the level of carbonylated proteins in selected brain structures in both strains; as well it increased corticosterone level, pain threshold, anxiety-like behavior, and decline short term memory only in SHRs. Losartan treatment alleviated some of the T2DM- induced metabolic complications, abolished the T2DM-induced hypo activity, and normalized the corticosterone level, carbonylated proteins in brain, nociception and memory. Losartan did not exert effect on the anxiety behavior in both strains. We showed that T2DM exerted more pronounced negative effects on the rats with comorbid hypertension as compared to normotensive rats. Overall effects on the studied behavioral parameters are related to decreased exploration of the new environment, increased anxiety-like behavior, and decline in short-term memory. The systemic sub-chronic treatment with an angiotensin AT1 receptor antagonist losartan ameliorated most of these complications.

Abstract 115: AT2 Receptor Regulates Ascending Aortic Dilation during AT1 Receptor Blockade in Transverse Aortic Constriction Mouse Model

Introduction: The angiotensin II (Ang II) type 1 receptor (AT1R) antagonist losartan can slow aortic enlargement in mouse models and patients with Marfan syndrome. We have previously shown that losartan attenuates aortic enlargement and remodeling induced by thoracic aortic constriction (TAC). Objective: We investigated the role of the Ang II type 2 receptor (AT2R) in an acute hypertensive remodeling of the ascending aorta induced by TAC. Methods: 160 male C57BL/6J mice were subjected to TAC surgeries with 27-gauge needle or sham surgery. Echocardiography measurements were performed 2 weeks post-operation using the Vevo 3100 imaging system. Blood pressure was measured in the ascending aorta using a Millar catheter introduced through the right common carotid artery. Results: TAC induced significant enlargement in aortic root and ascending aorta two weeks after surgery. The angiotensin converting enzyme inhibitor, captopril, decreased intraluminal systolic blood pressure (SBP) to the same degree as losartan, but did not prevent the increased aortic dilation, adventitial inflammation, medial elastin breakage, or Mmp9 expression compared with TAC mice. Captopril plus an AT2R agonist, compound 21 (C21) attenuated TAC-indcued aortic dilation, elastin break numbers and Mmp9 expression similar to losartan, despite an increase in SBP compared with captopril-treated TAC mice. Consistent with these results, treatment with losartan and an AT2R antagonist, PD123319, reversed the protective effects of losartan on TAC-induced aortic enlargement and remodeling. Note that treating with captopril and a Mas receptor agonist AVE0991 did not prevent TAC-induced aortic enlargement. Importantly, treating with C21 alone did not prevent TAC-induced aortic dilation, elastin breakage or Mmp9 expression despite significantly decreased SBP. Conclusions: These data indicate signaling through both AT1R and AT2R are key modulators in aortic dilation and remodeling with acute increases in biomechanical forces induced by TAC and these protective effects are independent of alterations in blood pressure.

Protective effect of losartan and ramipril against stress induced insulin resistance and related complications: Anti-inflammatory mechanisms

Chronic restraint stress (CRS) is known to cause various behavioural and biochemical alterations, leading to several negative health outcomes. The present study was designed to explore the impact of inhibiting Renin angiotensin aldosterone system (RAAS) and inflammatory pathways in stress pathophysiology. In the present study, male LACA mice were subjected to restraint stress daily for 30 days. Losartan, nimesulide, ramipril, minocycline and their combinations were administered 45min prior to restraint stress daily and their effects were observed. Restraint stressed mice depicted depression like behavior along with increased oxidative stress markers in their brains. CRS induced insulin resistance depicted by hyperglycemia, hyperinsulinemia, hypercholesteremia, increased glycosylated hemoglobin and HOMA-IR. Besides, treatment with losartan, nimesulide, ramipril and minocycline significantly restored the behavioural and biochemical alterations and improved insulin sensitivity in stressed mice. Combination treatments synergistically reversed depression like behavior and decreased plasma glucose levels. Moreover they restored insulin levels, glycosylated hemoglobin levels and HOMA-IR values to the normal. This study signifies the synergistic effect of simultaneously blocking RAS and inflammatory pathways in stress pathophysiology.

Losartan attenuates aortic endothelial apoptosis induced by chronic intermittent hypoxia partly via the phospholipase C pathway.

Endoplasmic reticulum (ER) stress is known to play key roles in the development of endothelial cell apoptosis induced by chronic intermittent hypoxia (CIH), and the angiotensin II-phospholipase C-inositol-1,4,5-triphosphate (AngII-PLC-IP3) pathway has been demonstrated to induce ER stress. To explore whether the AngII-PLC-IP3 pathway is involved in the vascular damage induced by CIH, we examined whether the AngII-PLC-IP3 pathway is involved in ER stress induced by CIH and whether losartan, a selective angiotensin II type 1 receptor (AT1R) blocker, could suppress endothelial cell apoptosis induced by CIH. Adult male Sprague Dawley rats were subjected to 8h/day of intermittent hypoxia/normoxia, with or without losartan, a selective AT1R blocker, and/or U73122, a selective PLC inhibitor, for 8weeks. Endothelial cell apoptosis, ER stress markers, and levels of PLC-γ1 and IP3R expression were determined. Losartan prevented increases in PLC-γ1 and IP3R protein levels and inhibited ER stress markers induced by CIH. Addition of U73122 reproduced all the protective effects of losartan. Losartan administration before CIH significantly ameliorated CIH-induced endothelial cell apoptosis. This study showed that the AngII-PLC-IP3 pathway is involved in ER stress induced by CIH and that pre-losartan administration ameliorates endothelial cell apoptosis following CIH partly via inhibition of the AngII-PLC-IP3 pathway and ER stress.

The protective effect of losartan on diabetic neuropathy in a diabetic rat model.

Involvement of the peripheral and autonomic nervous systems is possibly the most frequent complication of diabetes. Important risk factors included hyperglycemia, dyslipidemia, hypertension, and smoking. Angiotensin-converting-enzyme inhibitor (ACE) inhibitors should be beneficial in all vascular beds, including neuropathy and retinopathy. In this study we aimed to evaluate the effect of the angiotensin receptor blocker losartan on diabetic neuropathy in a diabetic rat model. 24 male, Sprague Dawley albino mature rats were divided into 3 groups; (1) control group: No drug was administered to the remainder of rats which blood glucose levels were under 120 mg/dl, (2) diabetic control: rats were given no medication, but 4 ml per day of tap water was given by oral gavage, (3) losartan groups: rats were given 10 mg/kg/day oral of losartan for 4 weeks. Electromyography (EMG) was applied to anesthetized rats at the end of 4(th) weekend. Then, the animals were euthanized and sciatic nerve was performed for histopathological examination. Compound Muscle Action Potential (CMAP) amplitude of diabetic rats receiving the Saline in the EMG was significantly reduced when compared to the control group. Distal latency value and CMAP duration of diabetic rats receiving the saline were meaningfully increased when compared to the control group. CMAP amplitude and CMAP duration of diabetic rats receiving the Losartan treatment in the EMG were meaningfully reduced when compared to diabetic rats receiving the Saline.Perineural thickness in the rats receiving the Losartan treatment was found to be significantly reduced when compared to the group receiving the Saline. As a result, it has been shown in this study that perineural thickness of the Losartan treatment was significantly reduced when compared to saline receiving group, significantly increased the immunoexpression of NGF, and also provided a significantly recovery in EMG when compared to Saline receiving group.

Coronary Arteries Injury in a Model of Pulmonary Fat Embolism Syndrome (PES)

Lung inflammation, vasculitis, and fibrosis occur in FES following bone fractures, surgical procedures, and liposuction. We reported the onset of myocardial damage in a rat model of FES with pulmonary fibrosis. This study continues our earlier work with attention to the evolution of the inflammatory process of the coronaries.Of 28 male SD rats, 14 received 0.2 mL IV triolein (FES model) and 14 received IV saline. Six weeks later, Losartan (0.3 mg/kg) was given IP to half of each group up to ten weeks. At necropsy, the tissues were stained for H&E, SMA‐1, and Trichrome for collagen. Six photos at 400x were made of each heart. The coronary vasculitis was assessed by measurement of the medial thickening and lumen patency.In addition to the lung fibrosis, the heart of the triolein treated rats showed intense SMA‐1 staining of the coronary media, intima, and adventitia. Lumen patency was reduced versus saline controls (p < 0.05). Losartan and saline treated rats did not differ from controls. Losartan protected the triolein treated rats from the heart damage with mild medial staining and wider lumen patency (p = 0.05). A small rim of collagen (trichrome) was seen in the adventitia of all the rats with more intensity in the triolein treated groups. Losartan reduced its presence.SMA‐1 staining by evidencing the transformation of fibroblasts and myofibroblasts shows the beginnings of collagen‐induced fibrosis. Would a longer treatment result in a more severe coronaropathy? The protective effect of Losartan was again confirmed underlining the role of the Renin‐Angiotensin system in this disease. Information from this model may help treating patients with FES.

Losartan treating podocyte injury induced by Ang II via downregulation of TRPC6 in podocytes.

In this study, we investigated the molecule mechanisms of podocyte injury and proteinuria and the protective effects of losartan. This study set up three groups: a control group; an Ang II group (Ang II 10(-6) mol/l, Sigma); and a losartan group (losartan 10(-6) mol/l, Sigma). We used RT-PCR assay to detect TRPC6 mRNA expression, and Western blot to detect TRPC6 protein expression. TRPC6 overexpression was the basic change of podocyte injury and proteinuria occurrence. Losartan can treat podocyte injury and proteinuria induced by Ang II via downregulation of TRPC6 in podocytes. These findings maybe provide an ideal drug target for the diagnosis and treatment of acquired glomerular diseases.

Involvement of the HIF-1α and Wnt/β-catenin pathways in the protective effects of losartan on fatty liver graft with ischaemia/reperfusion injury

Besides cardioprotective effects, the AT1R (angiotensin-II type 1 receptor) antagonist losartan protects the liver from IRI [IR (ischaemia/reperfusion) injury], but the mechanism has not been fully determined. The HIF (hypoxia inducible factor)-1α and Wnt/β-catenin signalling pathways have been reported to be involved in the mechanism of liver IRI. Therefore the aim of the present study was to determine whether the Wnt/HIF axis is part of the mechanism of the positive effect of AngII inhibition by losartan in liver IRI in rats. Various measurements were made in MCD/HF-NASH (methionine- and choline-deficient-diet/high-fat-diet-induced non-alcoholic steatohepatitis) rats with liver IRI. Acute losartan pre-administration markedly reversed the IR-suppressed levels of the hepatic-protective factors IL (interleukin)-6, IFN (interferon)-γ, Wnt3a, β-catenin and HIF-1α, and decreased hepatic blood flow and IR-elevated serum ALT (alanine aminotransferase), hepatic TNF (tumour necrosis factor)-α, IL-1α, hepatic congestion, vacuolization and necrosis, hepatic Suzuki IRI scores, necrotic index and levels of TBARS (thiobarbituric acid-reacting substances) in MCD/HF-NASH rats. Furthermore, acute Wnt3a pre-treatment significantly inhibited IR-elevated serum ALT, hepatic Suzuki IRI scores and TBARS, and restored the IR-depleted β-catenin/HIF-1α activity in MCD/HF-NASH rats. Simultaneous acute sFRP2 (secreted frizzled-related protein 2; a Wnt3a inhibitor) pre-treatment eliminated the losartan-related beneficial effects in MCD/HF-NASH rats with liver IRI, which was accompanied by a decrease in hepatic HIF-1α/β-catenin activity. Losartan-induced up-regulation of HIF-1α and Wnt/β-catenin signalling was associated with the recovery of IR-inhibited hepatic Bcl-2, Mn-SOD (manganese superoxide), Cu/Zn-SOD (copper/zinc superoxide) and GSH levels, and the suppression of IR-increased hepatic catalase and caspase 3/caspase 8 levels in MCD/HF-NASH rats. In conclusion, up-regulation of the HIF-1α and Wnt/β-catenin signalling pathways are part of the mechanism of the positive effects of losartan-related AngII inhibition in MCD/HF-NASH rats with liver IRI. Our study highlights the potential of the dual-organ protective agent losartan in NASH patients with steatotic livers and cardiovascular risk.

Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the phospholipase C pathway

As shown in a large clinical prospective trial, inhibition of the renin-angiotensin system (RAS) can delay the onset of type 2 diabetes in high-risk individuals. We evaluated the beneficial effects of RAS inhibition on β-cell function under glucotoxic conditions. Human islets from 13 donors were cultured in 5.5 mM (controls) or 16.7 mM glucose [high glucose (HG)] for 4 d with or without losartan (5 μM), a selective AT1R blocker, and/or U73122 (2 μM), a selective PLC inhibitor, during the last 2 d. HG induced RAS activation with overexpression of AT1R (P<0.05) and angiotensinogen (P<0.001) mRNAs. HG increased endoplasmic reticulum (ER) stress markers (P<0.001) such as GRP78, sXBP1, and ATF4 mRNAs and Grp78 protein levels (P<0.01). HG also decreased reticular calcium concentration (P<0.0001) and modified protein expressions of ER calcium pumps with reduction of SERCA2b (P<0.01) and increase of IP3R2 (P<0.05). Losartan prevented these deleterious effects and was associated with improved insulin secretion despite HG exposure. AT1R activation triggers the PLC-IP3-calcium pathway. Losartan prevented the increase of PLC β1 and γ1 protein levels induced by HG (P<0.05). U73122 reproduced all the protective effects of losartan. AT1R blockade protects human islets from the deleterious effects of glucose through inhibition of the PLC-IP3-calcium pathway.

A modified rat model of exercise-induced renal injury and the protective effects of losartan and Yishen Huanji decoction

We modified a rat model of exercise-induced renal injury by forcing 4-week-old male Sprague-Dawley (SD) rats (the MOD group) running on a treadmill for 8 weeks under conditions of high temperature, high humidity, bearing weight with some additional stimulations. Compared with the control (CON) group, the traditional running group (TRA), the losartan potassium intervention running group (LOS) and the traditional Chinese medicine “Yishen Huanji Decoction” intervention running group (CHI), the urinary, biochemistry indicators, the concentrations of angiotensin II (Ang II) were significantly higher in the MOD group than in the TRA group. After 3--4 weeks and 8-week training program, the 24-h urine protein and NAG levels in the LOS group and CHI group were lower than in the MOD group respectively. The BUN and SCr levels in the CHI group were lower than in the MOD group and higher than in the LOS group. AngII concentrations in the LOS group were higher than the MOD group. The modified rat renal injury model induced greater lesions than the traditional model. High temperatures, humidity and weight bearing were critical factors to induce Ang II activation, which can aggravate renal injury. Losartan potassium and the “Yishen Huanji Decoction” can protect against renal injury.

Histological and biochemical study on the protective effect of losartan on rat renal cortex in experimentally induced liver failure

Introduction Hepatic ischemia/reperfusion (I/R) injury is an unavoidable problem during liver surgery that often results in acute liver failure, with its complications. Losartan may be beneficial in such conditions. Objectives This study was designed to investigate the histological and biochemical alterations that could occur in the renal cortex in case of liver cell failure and to assess the possible protective role of losartan. Materials and methods Thirty male albino rats were equally divided into three groups: group I (control) was equally subdivided into sham operated-untreated (Ca) and sham-operated, losartan-treated (Cb) subgroups. In group II (operated), rats were subjected to experimentally induced I/R. In group III (losartan treated), rats were subjected to a surgical procedure and treated with losartan (5 mg/kg body weight). At the end of the experiment, blood samples were obtained for the biochemical assay. The liver was processed for assessment of antioxidant markers and for light microscope examination. Both kidneys were processed for light and electron microscope examinations. The results were morphometrically and statistically analyzed. Results Light microscope examination of the operated group indicated shrunken glomeruli with wide Bowman’s space. Some tubules were distorted with cytoplasmic vacuoles and cellular casts, whereas others were dilated. The interstitium contained an acidophilic material, increased collagen fibers, cellular infiltration, and congested blood vessels. Ultrastructurally, podocytes had small electron-dense nuclei and fused foot processes. Some renal tubules had small heterochromatic nuclei, mitochondria with disrupted cristae, and small electron-dense bodies. The biochemical results of the same group showed the occurrence of oxidative stress and deterioration in liver and kidney functions. The treated group showed preserved structure of the renal corpuscles and tubules. Conclusion Liver I/R adversely affected the renal cortex histologically and biochemically. Losartan could be promising as an adjuvant therapy before hepatic surgery for rescuing the kidney from hepatic I/R injury.

Protective effects of losartan in mice with chronic viral myocarditis induced by coxsackievirus B3

AimTo investigate whether losartan has protective effects in mice with chronic viral myocarditis induced by coxsackievirus B3 (CVB3). Main methodsThirty two male Balb/c mice were intraperitoneally injected with CVB3 (10×TCID50) to induce chronic viral myocarditis (CVM). Losartan at 12.5mg/kg (n=16) or normal saline (n=16) were orally administered daily for 28days to these mice. Uninfected mice (n=6) were used as controls. On day 29, all mice underwent anesthesia and echocardiography prior to sacrifice. Serum IL-17, IL-4, IFN-γ and TNF-α levels were measured by enzyme-linked immunosorbent assay, and cardiac tissues were histologically examined after hematoxylin & eosin staining. In addition, the effect of losartan on the virus titers in primary cultured neonatal rat cardiomyocytes infected with CVB3 was measured on Hep-2 cells at 72h post infection. Key findingsMice infected with CBV3 had significantly increased mortality, heart/body weight ratios, necrosis and inflammatory scores and decreased cardiac ejection fractions, compared with the controls (all P<0.05). Losartan significantly decreased mortality from 40.0% to 12.5%, heart/body weight ratios from 7.08±2.17 to 4.15±0.99, and necrosis and inflammatory scores from 3.33±0.50 to 2.50±0.65 (all P<0.05), and increased ejection fractions from 55.80±9.25 to 72.31±12.15 (P<0.05). Losartan significantly enhanced IL-4, and decreased IFN-γ, TNF-α and IL-17 (all P<0.05). In the in vitro experiment, losartan had no influence on virus titers. SignificanceLosartan protects mice against CVB3-induced CVM, most likely through upregulating Th2 responses, and down-regulating Th1 and Th17 responses.

Abstract 24: Normalization of Blood Pressure and the Inhibition of Local Angiotensin II Prevent Aneurysm Rupture in Mice

Background and Purpose Hypertension is generally considered as a major risk factor for aneurysmal subarachnoid hemorrhage. The renin-angiotensin system plays a crucial role in the regulation of blood pressure. Angiotensin II type 2 receptor (AT2R) counters most effects of angiotensin II type 1 receptor (AT1R). In our recently established mouse model of intracranial aneurysms, aneurysmal rupture occurs at a high incidence and results in neurological symptoms. We hypothesized that either normalization of blood pressure or inhibition of local renin angiotensin system alone can prevent aneurysmal subarachnoid hemorrhage. Furthermore, we tested relative contributions of AT1R and AT2R. Methods Intracranial aneurysms were induced in male mice using a combination of a single injection of elastase into the cerebrospinal fluid and deoxycorticosterone acetate (DOCA) salt hypertension. Six days after aneurysm induction, we started treatments with vehicle control (VC; n=87), hydralazine (direct vasodilator, 250mg/L in drinking water; n=15), angiotensin-converting enzyme inhibitor (captopril; 6mg/kg/day; n=17), an AT1R antagonist (losartan 30mg/kg/day; n=37), the same AT1R antagonist and an AT2R antagonist (PD123319; 10mg/kg/day; n=16), and an AT2R agonist ( CGP42112 ; 1ug/kg/min; n=16), and continued for 15 days. Mice were sacrificed when the mice developed neurological symptoms, or at day 21 if mice did not develop any symptoms. Symptom-free survival curves were analyzed using Kaplan-Meier analysis. Results Normalization of blood pressure by hydralazine significantly reduced the rate of symptomatic ruptured aneurysms (mice with symptomatic ruptured aneurysms / mice with any aneurysms), and improved symptom free survival curve compared to the vehicle control group (P &lt; 0.05). As expected, losartan or captopril did not affect DOCA salt induced hypertension. However, these treatments reduced the rate of symptomatic ruptured aneurysms (P &lt; 0.05). Whereas the AT2R antagonist abolished the protective effect of losartan ( Figure ), the AT2R agonist alone reduced the rate of aneurysmal rupture (P &lt; 0.05). Conclusions Either normalization of blood pressure or inhibition of local renin-angiotensin system was protective against aneurysmal rupture. Moreover, our data suggested potentially protective effects of AT2R activation against aneurysmal rupture. These data may be useful in choosing anti-hypertensive agents for patients with unruptured aneurysms.

The protective effect of losartan in the nephropathy of the diabetic rat includes the control of monoamine oxidase type A activity

Monoamine oxidase activity (MAO-A and B) levels, as intracellular source of reactive oxygen species, might increase in diabetic nephropathy (DN) contributing to reduce dopamine levels and to unbalance kidney redox state. We explored the hypothesis that beneficial effects of losartan, an angiotensin-II type 1 receptor (AT1) blocker, in DN included the control of MAO activity levels.In kidneys of normoglycemic and diabetic, streptozotocin-injected (55mg/kg) rats, treated or untreated with losartan, an AT1 antagonist (20mg/kg/day in the drinking water), we investigated MAO activity radiochemically and antioxidant enzymes including catalase, aldehyde dehydrogenase and superoxide dysmuthase spectrophotometrically. In addition, we also evaluated malondialdehyde and carbonylated protein levels spectrophotometrically as indexes of oxidative attack to lipids and proteins.Diabetic rats showed signs of nephropathy, including renal hypertrophy, proteinuria, high acethylglucosaminidase and γ-glutamyltranspeptidase urinary levels. In diabetic kidneys, MAO-A and catalase activities as well as malondialdehyde levels, were found significantly higher than in normoglycemic ones. Interestingly, in diabetic kidneys, MAO-A activity correlated not only with catalase but also with γ-glutamyltranspeptidase urinary levels.Our results indicate that the control of MAO-A activity is to be included amongst the mechanisms of protection afforded by losartan in DN. In fact, the prevention of MAO-A raise might increase dopamine availability and, as suggested by the correlation with γ-GGT, reduce oxidative attack to tubular cells.

Involvement of prolylcarboxypeptidase in the protective effect of losartan on the kidney of renovascular hypertensive rats

we set up a blank control group with WKY rats (n=6 in each group). All animals were treated for 4 weeks. The expression of mRNA and the protein level of TRPC3 and TPRC6 in aorta were determined by RTPCR, immunohistochemistry and Western blot analysis respectively. Result: Compared with black control group, the systolic blood pressure was increased in experimental control group, Pb0.05 before treatment. With 4 weeks treatment, the blood pressure in the three medication groups was decreased than it was before the medication (Pb0.05), the expression of mRNA and the protein level of TRPC3 were also decreased (Pb0.05). The expression of mRNA and the protein level of TRPC3 and TRPC6 had no obvious changes among the three medication groups. Conclusion: Ramipril, valsartan and amlodipine could reduce the blood pressure and meanwhile, reduce the expression of mRNA and the protein level of TRPC3 in SHR, which implied that TRPC3 might be involved in the regulation of blood pressure in SHR.

Effects of antihypertensive drugs on activities of ion pumps and autocrine of angiotensin II in spontaneously hypertensive rats

increased, however, the expressions of PRCP, plasma kallikrein and tissue kallikrein were significantly decreased in the hypertensive rats, which were significantly reversed by treatment of losartan for 4 weeks. Conclusions: The mechanism of protective effect of losartan on the kidney is related to decrease the expression of TGF-β1 and increase the expression of PRCP, thereby activate the kallikrein-kinin system.

The Possible Protective Effect of Losartan on Bleomycin-Induced Pulmonary Fibrosis in Albino Rats: A Histological And Immunohistochemical Study

The possible protective effect of Losartan, an angiotensin II receptor 1 antagonist, on bleomycininduced rat lung fibrosis was evaluated using histological and immunohistochemical techniques. Twenty adult male albino rats were divided into 4 groups each of five rats: Group I (control) given saline both I.V and orally, Group II given bleomycin 10mg/Kg/day I.V., Group III given losartan 10 mg/Kg/day orally and Group IV given both bleomycin and losartan. Lung sections were taken at the 28th day of the experiment, stained with H&E, Masson’s trichrome, Orcein and immunohistochemical stain for α-SMA. This was followed by morphometric measurements and statistical analysis. The present study showed that bleomycin induced fibrotic changes in the lung in the form of thickened interalveolar septa filled with proliferated type II pneumocytes, fibroblasts and inflammatory cells with significant increase in collagen and elastic fibres deposition and in α-SMA immunoreactivity. It was found that concomitant treatment with losartan (Group IV) showed significant reduction in these fibrotic changes. The changes in α-SMA immunoreactivity in different groups showed the same pattern as those of collagen and elastic fibres. Thus, it could be concluded that myofibroblasts might play a pivotal role in induction of lung fibrosis and they could be a target of future therapeutic strategies