RT-PCR showed that high glucose and AngII up-regulated the expression of CTGF mRNA, and AngII stimulated the expression in a dose-dependent manner. Expression of CTGF mRNA induced by AngIIwas partially suppressed by 10(-5) mol/L Losartan (P < 0.05).
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Genotype was determined in 57 CGN patients and 113 subjects free of chronic diseases. Effects of ACE gene polymorphism on antihypertensive and antiproteinuric efficiency of ACEI and cozaar were studied in 35 CGN patients on monotherapy. 24-h proteinuria, levels of creatinine, potassium in the serum, arterial pressure, glomerular filtration rate were measured in all the patients.
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In the second liver biopsy after 1 year, the decrease in fibrosis stage was significantly different between losartan group and silymarin group (a decrease of 1.88±0.96 (50.9%) vs. 0.45±0.93 (11.7%), respectively; P<0.01). In patients treated with losartan, regression in fibrosis stage was observed in 14/16 patients vs. 2/11 in silymarin group (P<0.01). No differences were observed in inflammation grades in both groups. A significant increase in albumin and prothrombin levels and a decrease in systolic blood pressure were found in losartan but not in silymarin group (P=0.009, 0.001 & 0.018 respectively and P=0.158, 0.603 & 0.288, respectively).
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Structure-activity relationships are reported for a novel class of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid derivatives that displace 125I-labeled angiotensin II from a specific subset of angiotensin II (Ang II) binding sites in rat adrenal preparations. This binding site is not the Ang II receptor mediating vascular contraction or aldosterone release, but, rather, is one whose function has not yet been fully elucidated. It has been identified in a number of tissues and has a similar affinity for Ang II and its peptide analogues as does the vascular receptor. The non-peptide compounds reported here are uniquely specific in displacing Ang II at this binding site and are inactive in antagonizing Ang II at the vascular receptor or in pharmacological assays measuring vascular effects. PD 123,319 (79), one of the most potent compounds, has an IC50 of 34 nM. Certain of these compounds may have utility in the definition and study of Ang II receptor subtypes.
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Intracerebroventricular injection of Los increased 5-HT content in the preoptic area and hypothalamus. Such results correlated positively with body heating rate and inversely with time to fatigue. On the other hand, time to fatigue was directly correlated with the diminished concentration of 5-HT in the hippocampus of Los rats. Although the levels of DA were not affected by Los treatment during exercise in any of the brain areas studied, a higher 5-HT/DA ratio was seen in the hypothalamus of Los animals. This higher hypothalamic 5-HT/DA ratio correlated positively with body heating rate and negatively with time to fatigue.
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A Simple high-performance thin layer chromatography (HPTLC) method for separation and quantitative analysis of losartan potassium, amlodipine, and hydrochlorothiazide in bulk and in pharmaceutical formulations has been established and validated. After extraction with methanol, sample and standard solutions were applied to silica gel plates and developed with chloroform : methanol : acetone : formic acid 7.5 : 1.3 : 0.5 : 0.03 (v/v/v/v) as mobile phase. Zones were scanned densitometrically at 254 nm. The R(f) values of amlodipine besylate, hydrochlorothiazide, and losartan potassium were 0.35, 0.57, and 0.74, respectively. Calibration plots were linear in the ranges 500-3000 ng per spot for losartan potassium, amlodipine and hydrochlorothiazide, the correlation coefficients, r, were 0.998, 0.998, and 0.999, respectively. The suitability of this method for quantitative determination of these compounds was by validation in accordance with the requirements of pharmaceutical regulatory standards. The method can be used for routine analysis of these drugs in bulk and in formulation.
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Maximum CRIP uptake was observed in the infarct area; quantitative uptake (percent injected dose/g) was highest at 2 weeks (2.75 +/- 0.46%), followed by 4 (2.26 +/- 0.09%) and 12 (1.74 +/- 0.24%) weeks compared with that in unmanipulated mice (0.59 +/- 0.19%). Uptake was higher at 12 weeks in the remote areas. CRIP uptake was histologically traced to myofibroblasts. Captopril alone (1.78 +/- 0.31%) and with losartan (1.13 +/- 0.28%) significantly reduced tracer uptake; scrambled CRIP uptake in infarct area (0.74 +/- 0.17%) was similar to CRIP uptake in normal myocardium.
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Mean arterial pressure, measured 4 h after the dose, fell from 113.8 +/- 2.1 mmHg (placebo) to 99.2 +/- 2.4 mmHg (50-mg dose) and 96.5 +/- 2.4 mmHg (100-mg dose). This blood pressure lowering effect was sustained for 24 h 116.3 +/- 2.3 mmHg (placebo) versus 105.5 +/- 1.8 mmHg (50-mg dose) and 103.3 +/- 1.9 mmHg (100-mg dose)]. The glomerular filtration rate remained stable, while the effective renal plasma flow increased by 12.5 +/- 2.9% (100-mg dose). The systemic and renal hemodynamic effects were similar at the 50- and 100-mg doses. Urinary excretion of total protein, albumin and immunoglobulin G decreased dose-dependently by a maximum of +/- 50% (100-mg dose). With the high dose, serum uric acid fell from 0.43 +/- 0.02 mmol/l to 0.39 +/- 0.02 mmol/l, and potassium increased from 4.2 +/- 0.1 to 4.6 +/- 0.1 mmol/l.
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Alterations in the podocyte actin cytoskeleton have been implicated in the development of proteinuric kidney diseases. In the present study, we evaluated the effect of HIV on the podocyte actin cytoskeleton and the mechanism involved. We hypothesized that HIV may be compromising the actin cytoskeleton via downregulation of the vitamin D receptor (VDR) of conditionally immortalized differentiated human podocytes (CIDHPs). HIV-transduced podocytes (HIV/CIDHPs) not only displayed downregulation of VDR but also showed activation of the renin-angiotensin system (RAS) in the form of enhanced expression of renin and increased production of ANG II. Moreover, CIDHPs lacking VDR displayed enhanced ANG II production, and treatment of HIV/CIDHPs with EB1089 (vitamin D3; VD) attenuated ANG II production. HIV/CIDHPs as well as ANG II-treated CIDHPs exhibited enhanced expression of cathepsin (CTS) L. Additionally, losartan (an ANG II type I receptor blocker) inhibited both HIV- and ANG II-induced podocyte cathepsin L expression. Furthermore, VD downregulated HIV-induced podocyte CTSL expression. Both losartan and free radical scavengers attenuated HIV- and ANG II-induced podocyte reactive oxygen species (ROS) generation. HIV also led to cytosolic CTSL accumulation through enhancement of podocyte lysosomal membrane permeabilization; on the other hand, VD, losartan, and superoxide dismutase (SOD) attenuated HIV-induced enhanced podocyte cytosolic CTSL accumulation. Morphological evaluation of HIV/CIDHPs revealed sparse actin filaments and attenuated expression of dynamin. Interestingly, podocytes lacking CTSL displayed enhanced dynamin expression, and HIV/CIDHPs expressing CTSL exhibited downregulation of dynamin. These findings indicate that HIV-induced downregulation of podocyte VDR and associated RAS activation and cytosolic CTSL accumulation compromised the actin cytoskeleton.
Dahl-salt sensitive rats fed high salt diet developed malignant hypertension, resulting in heart failure with inappropriately increased plasma aldosterone level. The gene expression pattern of the adrenal gland from heart failure rats showed strikingly upregulated b3-Adrenergic receptor (b3-AR) expression. Using Dahl-salt sensitive rats and H295R human adrenocortical carcinoma cells, we conducted immunohistochemical and molecular biological studies to assess whether b3-AR contribute to aldosterone production in heart failure.
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A total of 65,358 incident diabetes cases were identified out of 1,771,173 person-years. Olmesartan initiators had a small but significantly increased risk of developing diabetes after adjusting for baseline characteristics and mean daily dose (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.03-1.12). After excluding those followed for less than one year, the increase in diabetes risk are more pronounced (HR, 1.09; 95% CI, 1.05-1.14). This association was consistent across all subgroup analyses. Similar results were observed when a more strict definition of diabetes combining both diabetes diagnosis and anti-diabetic treatment was used. On the other hand, there was no difference in diabetes risk between telmisartan and losartan.
The role of ANG II in the arterial baroreflex control of renal sympathetic nerve activity (RSNA) in eight term-pregnant (P) and eight nonpregnant (NP) conscious rabbits was assessed using sequential intracerebroventricular and intravenous infusions of losartan, an AT1 receptor antagonist. The blood pressure (BP)-RSNA relationship was generated by sequential inflations of aortic and vena caval perivascular occluders. Pregnant rabbits exhibited a lower maximal RSNA reflex gain (-44%) that was primarily due to a reduction in the maximal sympathetic response to hypotension (P, 248 +/- 20% vs. NP, 357 +/- 41% of rest RSNA, P < 0.05). Intracerebroventricular losartan decreased resting BP in P (by 9 +/- 3 mmHg, P < 0.05) but not NP rabbits, and had no effect on the RSNA baroreflex in either group. Subsequent intravenous losartan decreased resting BP in NP and further decreased BP in P rabbits, but had no significant effect on the maximal RSNA reflex gain. ANG II may have an enhanced role in the tonic support of BP in pregnancy, but does not mediate the gestational depression in the arterial baroreflex control of RSNA in rabbits.
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In the Losartan Intervention for Endpoint Reduction (LIFE) echocardiography substudy, 939 hypertensive patients with measurable LVM at baseline were randomized to a mean of 4.8 years of losartan- or atenolol-based treatment. Patients with LVH (LVM/body surface area ≥116 and ≥96 g/m(2) in men and woman, respectively) were divided into 4 groups-concentric nondilated (increased M/EDV, normal EDV), eccentric dilated (increased EDV, normal M/EDV), concentric dilated (increased M/EDV and EDV), and eccentric nondilated (normal M/EDV and EDV)-and compared with patients with normal LVM. Time-varying LVH classes were tested for association with all-cause and cardiovascular mortality and a composite end point of myocardial infarction, stroke, heart failure, and cardiovascular death in multivariable Cox analyses. At baseline, the LVs were categorized as eccentric nondilated in 12%, eccentric dilated in 20%, concentric nondilated in 29%, concentric dilated in 14%, and normal LVM in 25%. Treatment changed the prevalence of 4 LVH groups to 23%, 4%, 5%, and 7%; 62% had normal LVM after 4 years. In time-varying Cox analyses, compared with normal LVM, those with eccentric dilated and both concentric nondilated and dilated LVH had increased risks of all-cause or cardiovascular mortality or the composite end point, whereas the eccentric nondilated group did not.
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Changes in systolic blood pressure (SBP), albuminuria, potassium, haemoglobin, cholesterol and uric acid after 6 months of losartan treatment were assessed in the RENAAL database. Improvement in predictive performance of renal outcomes (ESRD or doubling serum creatinine) for each individual using ARB-induced changes in all risk markers was assessed by the relative integrative discrimination index (RIDI).
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To investigate the regulating role of protein kinase C(PKC) and the effects of losartan intervention on the expression of pulmonary arterial collagen in chronic hypoxic rat models.
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Exercise training markedly improves aerobic capacity and cardiac function after myocardial infarction, either alone or in combination with angiotensin inhibition. The two interventions appear to act by complementary mechanisms; whereas exercise training restores cardiac energy metabolism, mainly at the level of energy transfer, losartan unloads the heart by lowering filling pressure and afterload.
Angiotensin II receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics have an accepted place in the management of hypertension. Most patients require combination therapy with two or more drugs to adequately control blood pressure to targets recommended by European and international guidelines. ARBs and the thiazide diuretic hydrochlorothiazide have complementary modes of action. Fixed-dose combinations of an ARB and low-dose hydrochlorothiazide provide a convenient and effective treatment option for patients who do not achieve blood pressure targets on monotherapy, without compromising the placebo-like tolerability of ARBs. In Europe, fixed-dose combinations with hydrochlorothiazide currently are available for the ARBs candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan. Recently, a number of studies have focused on the use of ARBs in monotherapy and in combination therapy, in conditions including congestive heart failure, post-myocardial infarction management, hypertension with cardiovascular risk factors, and diabetic and non-diabetic nephropathy. Evidence from these studies suggests a beneficial role beyond the antihypertensive effect of these therapies in providing protection against cardiovascular, renovascular, and cerebrovascular events.
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Among children and young adults with Marfan's syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364.).
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Adult male Wistar rats received lisinopril, losartan, bradykinin, or saline solution in a proportional volume, intraperitoneally, before and after 70% partial hepatectomy. Animals from the experimental and saline groups were sacrificed at 36 hours after partial hepatectomy. The alpha-smooth muscle actin labelled stellate cells population was counted in the periportal and pericentral zones of the liver specimen.
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Treatment of hypertensive patients with fixed-dose combination therapy consisting of losartan and hydrochlorothiazide (HCTZ) has several potential benefits over monotherapy with each of the individual components: more effective blood pressure control, a reduction in the likelihood of adverse effects, and facilitation of patients staying on therapy due to a simple once-daily regimen. Losartan plus HCTZ fixed-dose combination therapy lowers blood pressure in mild to moderate or severe hypertensive patients to a level comparable with other classes of antihypertensive drugs in combination with HCTZ. Fixed-dose combination therapy with losartan plus HCTZ is therefore an excellent choice for hypertensive patients in whom combination therapy is necessary to achieve additional blood pressure reductions.
Suppression of the formation of angiotensin II (A II) is thought to be a major contributor to the hemodynamic response to angiotensin-converting enzyme inhibition (ACE-inhibitor) therapy. However, during ACE-inhibitor treatment, A II plasma levels may also recover through tissue chymase. This study has attempted to verify the feasibility, safety and tolerability of a combined treatment using captopril (75 mg/day) and losartan (25 mg/day), and to ascertain its ability to reduce the formation and action of A II in the early post-infarction phase of reperfused anterior myocardial infarction (AMI).
Forty hypertensive patients on hemodialysis therapy were randomly assigned to the losartan treatment group (n=20) or the control treatment group (n=20). At baseline and 6 and 12 months after the treatment, 24-h ambulatory BP monitoring was performed. Echocardiography and measurements of brachial-ankle pulse wave velocity (baPWV) and biochemical parameters were also performed before and after therapy.
Angiotensin I (AI) and angiotensin II (AII) induce a portal hypertensive response (PHR) and the liver is able to convert AI into AII to trough the action of the angiotensin-converting enzyme (ACE). Our purpose was to characterize angiotensin I liver conversion.
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Losartan is a 4-chloro-5-hydroxymethylimidazole derivative that is a potent and highly selective angiotensin II receptor antagonist. Losartan is metabolized in vivo in rats, monkeys, and humans to a carboxylic acid derivative E3174 that is pharmacologically more active than the parent compound. We have investigated the mechanism of this biotransformation in human liver preparations. The oxidation of both losartan and the putative aldehyde intermediate E3179 was catalyzed by the microsomal fraction, required both NADPH and molecular oxygen, and was inhibited by SKF 525-A, implicating cytochrome P450 (CYP). When incubations with each substrate were performed under an atmosphere of 18O2, the extent of 18O incorporation into the carboxylic acid product was consistent with a mechanism for losartan oxidation involving an aldehyde intermediate. To substantiate the involvement of CYP in these reactions, incubations with losartan and the aldehyde E3179 were performed in the presence of isoform-selective inhibitors. Inhibitors of CYP3A4/5 (gestodene and ketoconazole) and CYP2C9/10 (sulfaphenazole) attenuated the oxidation of both substrates. It was then demonstrated that microsomes containing either recombinant human liver CYP2C9 or CYP3A4 were capable of oxidizing both losartan and the aldehyde E3179 to the carboxylic acid E3174. Subsequently, it was shown that rabbit anti-CYP2C9 and anti-CYP3A3/4 inhibited the oxidation of losartan to E3174 in incubations with human liver microsomes. These studies support the hypothesis that the aldehyde E3179 is an intermediate in the oxidation of losartan and that this two-step reaction is catalyzed in human liver microsomes by members of the CYP3A and CYP2C subfamilies.
Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli including stress and hyperosmolarity. However, it is unclear whether BDNF in the PVN contributes to increases in blood pressure (BP). We tested the hypothesis that increased BDNF levels within the PVN would elevate baseline BP and heart rate (HR) and cardiovascular stress responses by altering central angiotensin signaling. BP was recorded using radiotelemetry in male Sprague-Dawley rats after bilateral PVN injections of adeno-associated viral vectors expressing green fluorescent protein (GFP) or myc epitope-tagged BDNF fusion protein. Cardiovascular responses to acute stress were evaluated 3 to 4 wk after injections. Additional GFP and BDNF-treated animals were equipped with osmotic pumps for intracerebroventricular infusion of saline or the angiotensin type-1 receptor (AT1R) inhibitor losartan (15 μg·0.5 μl(-1)·h(-1)). BDNF treatment significantly increased baseline BP (121 ± 3 mmHg vs. 99 ± 2 mmHg in GFP), HR (394 ± 9 beats/min vs. 314 ± 4 beats/min in GFP), and sympathetic tone indicated by HR- and BP-variability analysis and adrenomedullary tyrosine hydroxylase protein expression. In contrast, body weight and BP elevations to acute stressors decreased. BDNF upregulated AT1R mRNA by ∼80% and downregulated Mas receptor mRNA by ∼50% in the PVN, and losartan infusion partially inhibited weight loss and increases in BP and HR in BDNF-treated animals without any effect in GFP rats. Our results demonstrate that BDNF overexpression in the PVN results in sympathoexcitation, BP and HR elevations, and weight loss that are mediated, at least in part, by modulating angiotensin signaling in the PVN.
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It is well recognized that ANG II interacts with arginine vasopressin (AVP) to regulate water reabsorption and urine concentration in the kidney. The present study used ANG II type 1a (AT(1a)) receptor-deficient (Agtr1a(-/-)) mice to test the hypothesis that AT(1a) receptor signaling is required for basal and water deprivation-induced urine concentration in the renal medulla. Eight groups of wild-type (WT) and Agtr1a(-/-) mice were treated with or without 24-h water deprivation and 1-desamino-8-d-AVP (DDAVP; 100 ng/h ip) for 2 wk or with losartan (10 mg/kg ip) during water deprivation. Under basal conditions, Agtr1a(-/-) mice had lower systolic blood pressure (P < 0.01), greater than threefold higher 24-h urine excretion (WT mice: 1.3 ± 0.1 ml vs. Agtr1a(-/-) mice: 5.9 ± 0.7 ml, P < 0.01), and markedly decreased urine osmolality (WT mice: 1,834 ± 86 mosM/kg vs. Agtr1a(-/-) mice: 843 ± 170 mosM/kg, P < 0.01), without significant changes in 24-h urinary Na(+) excretion. These responses in Agtr1a(-/-) mice were associated with lower basal plasma AVP (WT mice: 105 ± 8 pg/ml vs. Agtr1a(-/-) mice: 67 ± 6 pg/ml, P < 0.01) and decreases in total lysate and membrane aquaporin-2 (AQP2; 48.6 ± 7% of WT mice, P < 0.001) and adenylyl cyclase isoform III (55.6 ± 8% of WT mice, P < 0.01) proteins. Although 24-h water deprivation increased plasma AVP to the same levels in both strains, 24-h urine excretion was still higher, whereas urine osmolality remained lower, in Agtr1a(-/-) mice (P < 0.01). Water deprivation increased total lysate AQP2 proteins in the inner medulla but had no effect on adenylyl cyclase III, phosphorylated MAPK ERK1/2, and membrane AQP2 proteins in Agtr1a(-/-) mice. Furthermore, infusion of DDAVP for 2 wk was unable to correct the urine-concentrating defects in Agtr1a(-/-) mice. These results demonstrate that AT(1a) receptor-mediated ANG II signaling is required to maintain tonic AVP release and regulate V(2) receptor-mediated responses to water deprivation in the inner medulla.
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The fluorescence intensity of labeled HPS70 in the NPY group was 1,825.10 +/- 115.55, significantly stronger than that in the control group (1595.83 +/- 186.54, P < 0.05) and the fluorescence intensity of labeled HPS70 in the NPY + losartan group (1 658.54 +/- 183.78) was not significantly different from that in the control group (P > 0.05). The MTT-OD in NPY group was 0.2626 +/- 0.0025, significantly higher than that in the control group (0.2239 +/- 0.0010, P < 0.01). and the MTT-OD in NPY + losartan group was 0.2440 +/- 0.0013, significantly lower than that in the control group (P < 0.05).