Beneficial Effects Of Losartan Research Articles

LOSARTAN, ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKER, REDUCED AORTIC STIFFNESS AND IMPROVED COGNITIVE FUNCTION IN DAHL SALT SENSITIVE RAT MODEL OF AGE-ASSOCIATED VASCULAR DEMENTIA

Objective: Cardiovascular diseases are the major contributors to the pathogenesis of vascular dementia. The Dahl salt sensitive (Dahl-S) rat model is characterized by the development of central arterial stiffness (CAS), hypertension and cognitive decline with age on a normal salt diet. We hypothesized that treatment with losartan (LOS), angiotensin II type 1 receptor (AT1R) blocker, via reduction of blood pressure (BP) and CAS, will improve cognitive function in aged Dahl-S rats. Design and method: Male Dahl-S rats (n = 30) were kept on a normal salt diet (0.5% NaCl) for the duration of the study. Baseline measurements were taken at 3- and/or 6-mo of age following by the treatment with LOS in drinking water (30 mg/kg/day, n = 14) or control treatment (n = 16) for 6-mo. Measurements were taken every 3 months and included systolic and diastolic BP (SBP, DBP), pulse wave velocity (PWV), a measure of CAS, left ventricular posterior wall thickness in diastole (LVPWd), fractional shortening (FS) and LV mass (by echocardiography). At 12-mo of age the rats were tested in operant chambers using a simple reaction task to assess attention and impulsivity, and in elevated plus maze (EPM) to assess anxiety-like behavior. Statistical analyses were performed using 2-way ANOVA and t-test. Data are presented as mean ± SEM. Results: Prior to the treatment, LOS and control groups did not display differences in any parameter analyzed. Following the treatment, LOS rats had lower SBP, DBP, PWV, thinner LVPWd, higher FS and smaller LV mass at 9- and 12-mo of age vs. control group (Fig.1A-F). In the reaction task, LOS rats demonstrated more correct responses and fewer premature responses. The LOS rats exhibited lower anxiety level, because they spent more time in the open arm of EPM vs. control rats (Fig.1G,H). Conclusions: Beneficial effect of LOS on cognitive function in aged male Dahl-S rats was associated with the improvement of cardiovascular function and remodeling. The CAS stabilizing and BP reduction by LOS treatment was associated with improved attentional performance, lower impulsivity and lower anxiety. The mechanistic basis of these effects of LOS on cognition via cerebrovascular and brain changes will be further investigated.

Effect of Losartan on Patellar Cartilage Volume Among Patients With Knee Osteoarthritis

Purpose Losartan previously in murine Osteoarthritis (OA) model displaying the heterozygous chondroplasia gene (cho/+), a col11a1 mutation shown reduced cartilage loss in temporomandibular joint (TMJ) condylar and knee joint articular cartilage (Osteoarthritis and Cartilage, 2019, 27; 676-686). Losartan is an angiotensin receptor blocker and an inhibitor of TGF-beta. This cross sectional study explores the effect of losartan on patellar cartilage volume in patients with knee osteoarthritis using publicly available database. Methods Using data from Osteoarthritis Initiative (OAI), we compared patellar cartilage volume in patients with and without losartan. A total of 4796 men and women aged 45-79 years were enrolled into the study primarily consisting of those with knee OA and those at high risk for developing knee OA. Our study focused on the progression sub cohort, which consisted of 1390 subjects with knee OA. This study used three measurement periods; baseline, 12 months and 24 months. Patients with missing data for entire series or part missing data and patients who were taking other angiotensin receptor blocker drugs excluded from analysis. Patients data then divided into losartan group and control group (patients without losartan). Specific data sets for the analysis included of demographics such age, sex, race (Clinical_FNOH, Enrollees), patient drug usage (MIF00), Magnetic Resonance Imaging (MRI) data sets on cartilage volume were used from KMRI_FNIH_Qcart_Biomediq00 (baseline), KMRI_FNIH_Qcart_Biomediq01 (12 months), and KMRI_FNIH_Qcart_Biomediq03 (24 months). The patellar cartilage volume variables were V00PatellarCartilage (baseline), V01PatellarCartilage (12 months) and V03PatellarCartilage (24 months). Additional protocol details are published and available on the internet (https://oai.epi-ucsf.org/datarelease/docs/StudyDesignProtocol.pdf). Results Our analysis of the progression sub cohort included a total of 85 (44 %) were men and 108 (56 %) women with symptomatic knee OA (Total n=193). Average age of the participants was 59.6 years (SD, 8.7 years; range, 45–78 years). The majority of the participants were Caucasian (n=142; 73.6 %) and African American (n=42; 21.8 %) (Table 1). Of the 193 patients included in analysis, 30 patients were taking losartan and remaining 163 patients were placed into control group. Mean cartilage volume for losartan and control groups at baseline, 12 months and 24 months are shown in figure 1. Over the period of two years, there was a progressive decline in cartilage volume in both groups. Our analysis show that there was no significant loss of cartilage volume with patients on losartan over baseline at 12 months (5 %) and 24 months (8 %) post enrollment. Patients without losartan showed significantly higher cartilage loss at 24 months post enrollment over baseline (~15 %, p≤ 0.05, Student's t-test assuming unequal variances). Conclusion This study suggests that losartan reduces loss of patellar cartilage in patients with knee osteoarthritis. Further analysis is needed to ascertain association of losartan and reduced loss of cartilage volume and beneficial effects of losartan in osteoarthritis.

445Effects of losartan and beta-blockers on aortic root dilatation in patients with Marfan Syndrome - results of the extended COMPARE trial

Abstract Introduction Despite several randomized trials, beneficial effects of Losartan and β-blockers in adults with Marfan syndrome (MFS) are not entirely clear. The COMPARE trial previously showed a small but significant beneficial effect of Losartan on top of β-blocker use on aortic root dilatation rate. Yet, this effect was not reproduced by other trials, although in general a favourable effect of Losartan could be demonstrated. All trials in adults with MFS showed lower than expected aortic root dilatation rates, suggesting mildly affected study populations. Therefore we extended the follow-up period of the COMPARE trial up to 10 years and aimed to assess the clinical outcomes of the study cohort, as well as the effect of medication regimes on aortic root dilatation rates in the subgroup of patients with a native aortic root at initial randomization. Methods Patients previously enrolled in the COMPARE trial were retrospectively analyzed. Cardiovascular events (aortic dissections, ruptures and operations) and all-cause mortality were assessed. Individual aortic root dilatation rates were estimated in patients with a native aortic root at time of randomization on the basis of linear regression analysis of multiple transthoracic echocardiogram (TTE) results. Correlations between aortic root dilatation rates and cumulative Losartan or β-blocker treatment days were assessed with Spearman's rho (ρ). Results During a median follow-up of 8.0 years, two dissections and three deaths occurred in the 151 patients with a native aortic root at time of randomization. The 122 patients that were eligible for aortic root dilatation analysis, underwent a median of 6 TTEs. The median aortic root dilatation rate in these patients was 0.28 (interquartile range 0.09 - 0.59) mm/y. These patients were further classified as either patients with a stable aortic root (n=102) or with aortic root growth (n=20), based on the threshold of 0.9 mm per year. Patients with aortic root growth had significantly more aortic root replacements during follow-up (17/20 vs 18/102, P=0.001). Furthermore, aortic root dilatation rate was negatively correlated with the number of Losartan treatment days (ρ=−0.272, P=0.003), β-blocker treatment days (ρ=−0.217, P=0.017) and with the duration of follow-up (ρ=−0.437, P<0.001). Conclusions Our results support previous findings that Losartan and β-blockers appear to be equally effective on aortic root dilatation rate in Marfan Syndrome patients. The low event rate in the long term follow-up of this subgroup of the COMPARE trial represent a relatively mildly affected study population and an aggressive prophylactic surgical regime.

Beneficial effects of losartan or telmisartan on the local hepatic renin-angiotensin system to counter obesity in an experimental model

BACKGROUNDObesity has been associated with hepatic overexpression of the renin-angiotensin system (RAS).AIMTo evaluate the action of two angiotensin II (ANGII) receptor blockers (losartan or telmisartan) on the modulation of local hepatic RAS and the resulting metabolic effects in a diet-induced obesity murine model.METHODSTwenty C57BL/6 mice were randomly divided into two nutritional groups for 10 wk: control group (C, n = 5, 10% of energy as fat) or high-fat group (HF, n = 15, 50% of energy as fat). After treatment started, the HF group was randomly divided into three groups: untreated HF group (n = 5), HF treated with losartan (HFL, n = 5) and HF treated with telmisartan (HFT, n = 5). The treatments lasted for 5 wk, and the dose was 10 mg/kg body mass.RESULTSHF diet induced body mass gain (+28%, P < 0.0001), insulin resistance (+69%, P = 0.0079), high hepatic triacylglycerol (+127%, P = 0.0004), and overexpression of intrahepatic angiotensin-converting enzyme (ACE) 1/ ANGII type 1 receptor (AT1r) (+569.02% and +141.40%, respectively, P < 0.0001). The HFL and HFT groups showed higher ACE2/rMAS gene expression compared to the HF group (ACE2: +465.57%, P = 0.0002 for HFL and +345.17%, P = 0.0049 for HFT; rMAS: +711.39%, P < 0.0001 for HFL and +539.75%, P < 0.0001 for HFT), followed by reduced insulin/glucose ratio (-30% for HFL and -33% for HFT, P = 0.0181), hepatic triacylglycerol levels (-28%, P = 0.0381 for HFL; and -45%, P = 0.0010 for HFT, and Plin2 expression.CONCLUSIONModulation of the intrahepatic RAS, with favored involvement of the ACE2/rMAS axis over the ACE1/AT1r axis after losartan or telmisartan treatments, caused hepatic and metabolic beneficial effects as demonstrated by reduced hepatic triacylglycerol levels coupled with reduced PLIN 2 expression and improved glycemic control.

OS 32-09 THE BENEFICIAL EFFECT OF LOSARTAN ON PLATELET AGGREGATION RESULTS FROM THE REDUCTION OF ENDOGENOUS ASYMMETRIC DIMETHYL ARGININE IN SPONTANEOUSLY HYPERTENSIVE RATS

Objective: Previous studies show that platelet aggregation and asymmetric dimethyl arginine (ADMA) are increased in hypertensive patients and animals. However, the relationship between endogenous ADMA and platelet aggregation in spontaneous hypertensive rats (SHR) remains unclear. Since Losartan can increase the nitric oxide (NO) release and ameliorate the state of thrombosis, we aimed to test whether the beneficial effect of losartan on platelet aggregation results from the reduction of ADMA generation. Design and Method: With male Wistar Kyoto rats (WKY) as normal control, we randomly divided male SHR into three groups: SHR control group, L-arginine-treated (1.0 g/kg) and losartan-treated (30 mg/kg) group. For each group, we measured systolic blood pressure (SBP), platelet aggregation rate (pt-Ag), NO level, NOS activity and ADMA content in both plasma and platelets. Results: Compared with WKY rats, the ADMA level in both plasma and in platelets and platelet aggregation rate in SHR were higher, while the NO level and NOS activity were lower. L-arginine (1.0 g/kg) and losartan (30 mg/kg) treatment decreased platelet aggregation rate concomitantly with the decreased level of ADMA and the increased level of NO and the activity of NOS. Incubating platelets from SD rats with thoracic aortic rings for 5 min, the platelet aggregation rate in SHR was higher than that of WKY rats. L-arginine (1.0 g/kg) and losartan (30 mg/kg) significantly reduced the platelet aggregation rate. Conclusions: Our results suggest that endogenous ADMA plays a key role in platelet aggregation, and the beneficial effect of losartan is related to the reduced ADMA level.

Abstract 127: Agonistic Autoantibodies to Angiotensin II Type I Receptor Contributes Partly to Placental Ischemia-induced Cerebrovascular Abnormalities

Placental ischemia, a characteristic feature of preeclampsia, leads to impaired cerebral blood flow (CBF) autoregulation, cerebral edema, and increased blood-brain barrier (BBB) permeability; however, the placental factors that contribute to these cerebral abnormalities are not clear. Agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) are increased in preeclamptic patients as well as in a rat model of preeclampsia induced by placental ischemia. In this study, we tested the hypothesis that AT1-AA mediates placental ischemia-induced cerebrovascular abnormalities. To determine whether the AT1-AA contributes to impaired CBF autoregulation, we infused purified rat AT1-AA into normal pregnant rats from gestational day (GD) 12 to 19 via mini-osmotic pumps and measured CBF using laser Doppler flowmetry on GD 19. Autoregulatory index increased from 0.7 to 1.0±0.2 in the AT1-AA infused group over the range of 120 to 160 mmHg compared to pregnant controls (0.3 to 0.5±0.1 over the same range of pressures, p&lt;0.05) suggesting impaired CBF autoregulation. However, AT1-AA infusion did not affect brain water content at baseline blood pressures (104±2 mmHg in normal pregnant rats vs. 113±2 mmHg in AT1-AA infused rats, p&lt;0.01). To determine the role of endogenous AT1-AA in mediating placental ischemia-induced cerebrovascular abnormalities, losartan (5 mg/kg/day), an AT1 receptor antagonist, was administered in the drinking water from GD 14 to 19. Losartan reduced anterior brain water content from 79.6±0.2% in placental ischemic rats to 79.2±0.1% (compared to 79.1±0.1% in normal pregnant untreated rats) and BBB permeability from 0.06±0.01 in placental ischemic rats to 0.03±0.03 (compared to 0.03±0.004 in normal pregnant untreated rats). These results indicate that impaired CBF autoregulation in response to placental ischemia is due, at least in part, to increases in circulating AT1-AA. While AT1-AA infusion, by itself, did not alter brain water content at baseline blood pressures, the beneficial effects of losartan in placental ischemic rats suggests that the renin-angiotensin system may interact with other placental factors to promote cerebral vascular changes common to preeclampsia.

Abstract 254: Sirtuin-1 Activation Has no Effect on Aortic Root Dilatation in Marfan Mice

Rationale: Marfan syndrome (MFS) is an autosomal connective tissue disorder caused by mutations in the Fibrillin-1 (FBN1) gene. MFS patients are at risk for aortic aneurysm development and dissection, with often lethal consequences. Treatment consists of aortic root replacement surgery and beta-blocker medication. Losartan has been shown to inhibit aortic root dilatation in MFS patients. The beneficial effect of losartan suggests the detrimental involvement of angiotensin II receptor 1 (AT1R) signaling as a cause for aortic pathology. Angiotensin II (Ang-II) can induce cellular senescence, and downregulates sirtuin-1 (SIRT-1) expression. SIRT-1 is an NAD-dependent deacetylase which can prevent senescence. Among other functions, resveratrol can activate SIRT-1 and is effective in inhibiting aortic root dilatation in MFS mice. To further delineate the underlying mechanism, SIRT-1 activator SRT1720 is examined as therapeutic in MFS mice. Methodology: In the current study we investigated the effect of SRT1720 on aortic root dilatation in the Fbn1 C1039G/+ MFS mouse model. Eight week old mice were treated for two months with SRT1720. Aortic senescence and aortic root diameters were measured. Results: Effectiveness of the compound was established by measurement of body weight and granulocyte blood count. As expected, SRT1720-treated MFS mice showed decreased weight gain and increased granulocyte counts, confirming that SRT1720 was effective. While aortic senescence was decreased in the SRT1720-treated mice, this had no beneficial effect on aortic root dilatation. Conclusions: While SRT1720 prevented aortic senescence, this did not have an effect on aortic root dilatation in MFS mice. Thus the beneficial effect of resveratrol on aortic root dilatation can not be explained via its function as SIRT-1 activator.

AT1 receptor antagonism to reduce aortic expansion in Marfan syndrome: lost in translation or in need of different interpretation?

Marfan syndrome is an inherited autosomal dominant disorder of the connective tissue caused by mutations in the gene encoding fibrillin-1 ( FBN1 ).1,2 This disease has affected the ATVB community with the loss of 1 of our highly respected members, David Williams.3 The most devastating health issues of patients with Marfan syndrome are dissection and rupture of the proximal aorta. Aortic dimensions are routinely monitored in patients with Marfan syndrome, and surgical graft imposition is performed to sustain life. However, surgical intervention is a formidable process. To abrogate surgical repair, there is a desperate need for a medical approach for attenuating aortic expansion. Presently, patients with Marfan syndrome are routinely provided with β-adrenoceptor blockade. This standard of care is derived from the study of Shores et al.4 However, the benefit derived from administration of β-adrenoceptor blockade is far from established. Although FBN1 is a component of extracellular matrix, mutations in this protein do not directly promote the structural fragility that characterizes the specific aortic regions of patients with Marfan syndrome. Instead, a concept has developed that Fbn1 mutations lead to enhanced transforming growth factor β (TGF-β) activation that is the mechanistic basis of Marfan pathology. This concept originated from the demonstration that Fbn1 deficiency led to excessive activation of TGF-β signaling because of reduced binding, sequestration, and inactivation of TGF-β.5 Activation of TGF-β in Fbn1 -deficient mice was associated with a lung pathology similar to that observed in some patients with Marfan syndrome. This paradigm of FBN1 regulation of TGF-β activation was extended to aortic disease by generating heterozygous mice that express a C1039G mutation.6 These mice develop pronounced dilation of the ascending aorta associated with thickened media containing disrupted elastin fibers. In this model, the major proof of concept for the role of …

Role of nephrin in podocyte injury induced by angiotension II

Objective: To investigate the function of nephrin in podocytes and its relation to proteinuria in kidney diseases, and to study more clearly theoretical basis for the molecular mechanism of losartan anti-proteinuria and the special beneficial effects of losartan on podocyte injury. Methods: Experiment set up control, Ang II and losartan group. Cell morphology was observed perturbation, and using image processing software to analyze the cell body of cell morphology and size of the difference after 8 h, 24 h and 48 h. Detecting nephrin mRNA and protein expression changes by real time PCR (RT-PCR) and western blotting at different time points. Results: Podocyte cell bodies were significantly reduced after Ang II injury (p < 0.01), losartan directly reduces the rate of apoptotic podocytes induced by Ang. Apoptotic podocytes may related to the decrease of nephrin mRNA and protein expressions, losartan reduced the apoptosis and proteinuria by declining nephrin mRNA and protein expressions. Conclusion: Ang II induced podocyte injury caused abnormal expression and distribution of nephrin in podocytes, losartan maybe maintain the stability of nephrin expression and the integrity of hole diaphragm (SD) structure and function by blocking the signal path, playing a important role in protection mechanisms of anti-proteinuria. Our findings provide some possible clues for further exploring the pharmacological targets to the proteinuria. These novel findings provide new insights into the beneficial effects of losartan on podocytes directly.

Role of CD2-associated protein in podocyte apoptosis and proteinuria induced by angiotensin II

Podocytes are highly differentiated epithelial cells that form interdigitating foot processes with bridging slit diaphragms (SDs) that regulate renal ultrafiltration. Proteinuria is the most common clinical manifestation of glomerular diseases. Losartan is the traditional renin–angiotensin system (RAS). However; the precise mechanisms underlying the beneficial effects of Losartan on podocytes are still unknown. This study tested the hypothesis that podocytes were exposed to Angiotensin II (Ang II) to induce apoptosis and Proteinuria. Losartan directly reduces the rate of apoptotic podocytes induced by Ang II. Our results showed that apoptotic podocytes may be related to the decrease of CD2AP mRNA and protein expressions, Losartan reduced the apoptosis and Proteinuria by stabilizing the CD2AP mRNA and protein expressions. In this study, we explored the role of CD2-associated protein in podocyte apoptosis and Proteinuria induced by Ang II. Our findings provide some possible clues for further exploring the pharmacological targets to the proteinuria.

Abstract 487: Resveratrol as an Inhibitor of Aortic Root Dilatation in Marfan Mice

Rationale: Marfan syndrome (MFS) is an autosomal connective tissue disorder caused by mutations in the Fibrillin-1 (FBN1) gene. Marfan patients are at risk for aortic aneurysm development and dissection, with often lethal consequences. Treatment consists of aortic root replacement surgery and beta-blocker medication. Recently, losartan was proven to be effective in inhibition of aortic root dilatation in MFS patients. The beneficial effect of losartan suggests the involvement of angiotensin II receptor 1 (AT1R) signaling as a cause for aortic pathology. Angiotensin II (Ang-II) can induce cell senescence, in contrast to sirtuin-1 (SIRT-1), which is an NAD-dependent deacetylase and prevents senescence. Among other functions, resveratrol can activate SIRT-1, which prompted us to investigate the effectiveness of resveratrol treatment in MFS mice. Methodology: In the current study we investigate whether senescence plays a role in aortic dilatation and if resveratrol treatment inhibits aortic root dilatation in the Fbn1 C1039G/+ MFS mouse model. Eight week old mice were treated for two months with resveratrol. Aortic root diameter and senescence were measured. In addition, aortic root pathology was analyzed by different immunohistochemical stainings. Results: Senescence correlates positively with aorta dilatation. Resveratrol inhibits aortic root dilatation, even more efficiently than losartan. The number of inflammatory cells (CD45) and the signaling pathways involving phosphorylated (p-)SMAD2 or p-ERK1/2 are decreased in aortic root sections of losartan treated MFS mice. In contrast, these were not affected in the resveratrol treated MFS mice. Resveratrol did result in a diminished number of elastic lamina breaks and an increased number of nuclear SIRT-1 expressing cells. Conclusions: Senescence is involved in aortic dilatation in MFS mice. Resveratrol efficiently inhibits aortic root dilatation, yet via a different mechanism of action than is considered for losartan, which opens new possibilities for pharmacological treatment of MFS patients.

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.

Enhanced effect of losartan and rosuvastatin on neointima hyperplasia

The beneficial effects of losartan and rosuvastatin on neointimal formation have been well characterized, but little is known about the combined treatment benefit of these two drugs. This study was designed to investigate the synergistic effect of losartan combined with rosuvastatin on the magnitude of protective action in vascular injury mediated by cuff-induced neointimal formation model in vivo. Losartan at 20 mg/kg or rosuvastatin at 40 mg/kg significantly decreased both the neointimal formation and BrdU-positive cells in neointima, indicating the inhibition of cell proliferation including a progress of DNA synthesis. The combination treatment used lower doses of losartan with rosuvastatin (10 + 20 & 5 + 10 mg/kg, respectively) that proved to be significant in decreasing the neointimal formation and BrdU incorporation. These results were comparable to the diminution attained with monotherapy of either drug in higher doses. Interaction index measured by isobolar method indicated drug synergism in these two combinations of both drugs at lower doses. Therefore, the administration of losartan and rosuvastatin in combination with low doses synergistically decreased in cuff-induced neointimal formation by reducing cell proliferation, suggesting that this drug synergism may be fully effective with, lower adverse effects, for the treatment of vascular remodeling such as restenosis.

Beneficial effects of losartan on vascular injury induced by advanced glycosylation end products and their receptors in spontaneous hypertension rats

This study was designed to explore the role of losartan, an angiotensin II receptor blocker, in hypertensive injuries of blood vessels and the potential mechanisms related to the vascular advanced glycosylation end product (AGE)/receptor (RAGE) system, oxidative stress and endothelial proinflammatory factors. Spontaneously hypertensive rats (SHR) were employed for our study, and age-matched Wistar-Kyoto rats (WKY) were used for control experiments. After losartan treatment for 12 weeks, we observed by immunofluorescence that the vascular AGE level in the losartan group was significantly lower than that of the SHR group and that the vascular mRNA expression of RAGE, NF-kappaB, NADPH oxidase p47phox and ET-1, as detected by RT-PCR, was significantly lower in losartan group than in the SHR group. Meanwhile, we found that the expression of RAGE and NF-kappaB proteins in the losartan group and the WKY group was remarkably lower than that of the SHR group. Compared with the SHR group, the activities of plasma superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) and the NO level were robustly increased, while the plasma malondialdehyde (MDA) and ET-1 were substantially reduced. These findings suggest that losartan decreases the vascular AGE level, suppresses RAGE and NF-kappaB activation, and enhances the antioxidant capacity thereby improving the endothelial function, which induce hypertensive vascular remodeling.

Angiotensin II type 1 receptor antagonism improves endothelial vasodilator function in L-NAME-induced hypertensive rats by a kinin-dependent mechanism

This study was designed to investigate the ability of a chronic blockade of angiotensin II type 1 receptors with losartan to reverse the endothelial dysfunction present in N-nitro-L-arginine methyl ester (L-NAME)-treated hypertensive rats and the possible dependence of this effect on bradykinin B2-receptor activation. Rats treated with L-NAME alone (60 mg/kg per day for 8 weeks) or with L-NAME + losartan, L-NAME + icatibant (a bradykinin B2-receptor antagonist) and L-NAME + losartan + icatibant were studied. Losartan, icatibant or losartan + icatibant were co-administered with L-NAME during the last 4 weeks of the experiment. Endothelial nitric oxide synthase gene expression in aortic tissues, plasma nitrite/nitrate concentrations, the relaxant effect of acetylcholine on norepinephrine-precontracted aortic rings and 6-keto-PGF1alpha release from aortic rings were used as markers of the endothelial function. Rats treated with L-NAME alone and L-NAME + icatibant showed, as compared with untreated animals, a clear-cut increase in systolic blood pressure and a decrease of all the markers of endothelial function evaluated. In L-NAME-rats, administration of losartan reduced the systolic blood pressure and restored endothelial nitric oxide synthase gene expression, plasma nitrite/nitrate levels, the relaxant activity of acetylcholine on aortic rings and the generation of 6-keto-PGF1alpha from the aortic tissues. Co-administration of icatibant with losartan blunted the stimulatory effect of losartan on the markers of endothelial function evaluated. These results demonstrated that losartan is capable of reversing the endothelial vasodilator dysfunction in L-NAME-induced hypertensive rats, and that the beneficial effect of losartan is mediated by bradykinin B2-receptor activation.

Hospitalizations for New Heart Failure Among Subjects With Diabetes Mellitus in the RENAAL and LIFE Studies

We sought to study the risk factors for heart failure (HF) and the relation between antihypertensive treatment with losartan and the first hospitalization for HF in patients with diabetes mellitus in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) studies. We evaluated 1,195 patients with hypertension, left ventricular hypertrophy, and diabetes from the LIFE study and 1,513 patients with type 2 diabetes and nephropathy from the RENAAL study. The comparative treatments were atenolol in the LIFE study and placebo in the RENAAL study. Patients with a history of HF were excluded from this analysis. Losartan significantly reduced the incidence of first hospitalizations for HF versus placebo in the RENAAL study (hazard ratio 0.74, p=0.037) and versus atenolol in the LIFE study (hazard ratio 0.57, p=0.019). Patients enrolled in the RENAAL study were at a higher risk of developing HF (hazard ratio for RENAAL vs LIFE diabetics 3.0, p<0.0001). The significant, independent baseline risk factors for the development of HF in the RENAAL study were urinary albumin/creatinine ratio, age, peripheral vascular disease, the Cornell product, body mass index, and previous angina; in the LIFE study they were the Cornell product, previous myocardial infarction, peripheral vascular disease, baseline atrial fibrillation, alcohol use (inverse relation), and urinary albumin/creatinine ratio. The beneficial effect of losartan on the reduction of risk for hospitalization for new HF was demonstrated in patients who were at high renal and/or high cardiovascular risk.

Beneficial effect of losartan against proteinuria from the renal allograft

Beneficial effect of losartan against proteinuria from the renal allograft

DNA damage of lymphocytes in experimental chronic renal failure: Beneficial effects of losartan

DNA damage of lymphocytes in experimental chronic renal failure: Beneficial effects of losartan

DNA damage of lymphocytes in experimental chronic renal failure: Beneficial effects of losartan

Kidney diseases are associated with the accumulation of various uremic toxins increasing the oxygen free radical (OFR) activity with a number of serious consequences. One of them could be the impairment of DNA stability with the increased formation of DNA breaks. The study was performed in 4/6 kidney ablation rat nephropathy lasting for three months. The results of sham-operated (Sham), remnant kidney (Nx), and Nx treated by losartan (NxL) were compared. Nx significantly increased blood pressure, plasma creatinine, urea, hippurate, malondialdehyde (MDA), lipofuscin (LF), and the number of DNA breaks of lymphocytes. Losartan decreased the rise of blood pressure and inhibited the rise of creatinine plasma concentration but not of other variables, while it markedly inhibited the number of DNA breaks (Sham 15.9 +/- 1.1, Nx 54.5 +/- 1.7, P < 0.001; Nx/Sham, NxL 23.3 +/- 2.6 P < 0.001, NxL/Sham and P < 0.001 NxL/Nx). The 4/6 kidney ablation nephropathy increases the susceptibility of lymphocyte DNA to breaks, and losartan inhibits the number of breaks by a mechanism independent on glomerular filtration, accumulation of MDA or LF (markers of oxidative stress), and hippurate (marker of the accumulation of middle molecular substances). An independent mechanism, probably the interference with proliferation, is suggested.

EFFECT OF CHRONIC TREATMENT WITH LOSARTAN ON STREPTOZOTOCIN INDUCED DIABETIC NEPHROPATHY

Angiotensin converting enzyme (ACE) inhibitors produce a number of beneficial effects in a condition where diabetes - mellitus and hypertension co-exist. The present investigation was undertaken to study the effect of chronic treatment with losartan (2mg/kg, p.o.) on streptozotocin(STZ)-induced (45mg/kg, single dose, tail vein) diabetic nephropathy in rats. Treatment of ratswith STZ produced a significant loss of body weight, polyuria, polydipsia, hypoinsulinemia, hyperglycemia and increase in blood pressure. There was a significant increase in blood glucose levels in STZ-diabetic rats. Serum cholesterol, creatinine, urea and blood urea nitrogen (BUN) levels were found to be increased significantly in the STZ group diabetic rats. Treatment with losartan significantly prevented the raise in cholesterol, creatinine, urea and blood urea nitrogen levels. Creatinine clearance was significantly less in STZ-diabetic rats as compared to control animals and treatment with losartan significantly increased creatinine clearence. Our data suggest a beneficial effect of losartan in STZ - induced nephropathy in rats.