Induction of diabetes led to significant increase in retinal expression of prorenin but not the (pro)renin receptor. Retinal adherent leukocytes were significantly suppressed with PRRB. Administration of PRRB inhibited diabetes-induced retinal expression of VEGF and ICAM-1. To clarify the role of signal transduction via the (pro)renin receptor in the diabetic retina, we used AT1-R-deficient mice in which the RAS was deactivated. Retinal adherent leukocytes in AT1-R-deficient diabetic mice were significantly suppressed with PRRB. PRRB suppressed the activation of ERK and the production of VEGF, but not ICAM-1, in AT1-R-deficient diabetic mice.
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AT1R and AT2R levels did not differ between BS/GS and healthy controls. Ang II induced ERK1/2 phosphorylation in BS/GS fibroblasts, but peak ERK1/2 phosphorylation declined more rapidly than that in control and BS/GS fibroblasts also exhibited increased MKP-1 levels at 30-min incubation. PD123319, an AT2R blocker in BS/GS fibroblasts, abolished the increased MKP-1 and ERK1/2 phosphorylation time course became same as that for control. Losartan, an AT1R blocker, alone altered the time course of control fibroblast MKP-1 to mimic the increase seen in BS/GS fibroblasts, whereas ERK1/2 declined concomitantly. Treatment with Losartan and PD123319 in controls reduced MKP-1 and elevated ERK1/2 phosphorylation to the level observed in BS/GS patients treated with PD123319.
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To evaluate the efficiency and safety of two treatment regimens using ramipril or losartan in combination with hydrochlorothiazide (HCT) and amlodipine in grade 1-2 arterial hypertension (AH).
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Thirty male Sprague-Dawley rats were randomly divided into Control group, ALI group (LPS), and Losartan group (LPS + Losartan). Bronchoalveolar lavage fluid (BALF) and lung tissue were obtained for analysis. The expressions of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), intercellular adhesion molecule-1 (ICAM-1) and caspase-3 were detected by reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting.
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In guinea pigs with descending aortic banding, treatment with losartan for 8 weeks neither attenuates progression of pressure overload hypertrophy nor significantly improves impaired mass-normalized pressure-derived indices of LV contraction and relaxation.
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The findings of LAARS, the first large study with an AII antagonist that examined IMT, suggest that AII antagonism reverses the early stages of vascular hypertrophy in patients with hypertension. Further studies are needed to delineate the relative importance of AII antagonism versus blood pressure reduction per se in mediating the beneficial vascular effects of losartan.
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Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady-state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A prospective, open-label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phase was 7 days of losartan (50 mg QAM), and the inhibition phase was 14 total days of fluvastatin (40 mg QHS), with the final 7 days including losartan. The authors found that fluvastatin did not significantly change the steady-state AUC0-24 or half-life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolism appears to require both CYP2C9 and CYP3A4 inhibition.
To observe the effects of different concentrations Angiotensin II on the transcription of LOX1 in culture human umbilical vein endothelial cells and to explore its mechanism.
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Treatment with losartan causes an increase in urinary Zn excretion and induces Zn deficiency in patients with hypertension. The addition of hydrochlorothiazide has an additive effect. Magnesium and nitric oxide metabolism are not affected by either treatment.
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The contribution of brain angiotensin II (ANG II) to thirst and Na+ appetite of sheep was evaluated. Thirst was stimulated by water deprivation, intracarotid or intracerebroventricular infusion of ANG II, or intracarotid or intracerebroventricular infusion of hypertonic solution. Intracerebroventricular infusion, over 1-3 h, of the ANG II type 1 (AT1) receptor antagonist, losartan, decreased or abolished water intake caused by all of the stimuli tested. Intracerebroventricular infusion of ZD-7155, another AT1-receptor antagonist, blocked ANG II-induced water intake. Neither losartan nor ZD-7155 infused intracerebroventricularly altered the Na+ appetite of Na(+)-depleted sheep. Intracerebroventricular infusion of losartan over 3 h, however, did block the increase in water intake and the decrease in Na+ intake caused by intracerebroventricular infusion of hypertonic NaCl in Na(+)-depleted sheep. Intracerebroventricular infusion of the ANG II type 2 (AT2) receptor antagonist, PD-123319, over 1-3 h, did not alter ANG II-induced water intake or Na+ depletion-induced Na+ intake. These results are consistent with the proposition that brain ANG II, working via AT1 receptors, is involved in the neural system controlling some aspects of physiological thirst and Na+ appetite. A role for AT2 receptors in physiological thirst or Na+ appetite is not supported by the present results.
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The ELITE II study will further define the role of losartan in the treatment of patients with symptomatic heart failure relative to the angiotensin-converting enzyme inhibitor captopril, an agent from a class currently considered standard treatment for this disease.
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The aim of the study was to compare the effects of long-term treatment with different types of antihypertensive drugs on left ventricular hypertrophy (LVH) and diastolic function in patients with essential hypertension. We examined 60 patients with mild to moderate hypertension from 35 to 55 years old (middle age 44.3 +/- 2.3 yrs) having no concomitant diseases. Patients were treated for six months with different types of antihypertensive drugs: 21 patient received nifedipine-retard 40 mg/day, 20--atenolol 100 mg/day, 10--losartan potassium 100 mg/day, 9--perindopril 4 mg/day. Cardiac structure and function was studied by echocardiography. For the left ventricle (LV) the diastolic mass normalised for body surface area (LVMI), the ratio of the early and atrial mitral inflow velocities (E/A), isovolumetric relaxation time (IVRT), relative wall thickness (RWT) were measured. After six months of treatment LVMI decreased by 9% in nifedipine group (P < 0.01), by 10.5% in atenolol group (P < 0.01), by 12% in losartan group (P < 0.01) and by 8.2% in perindopril group (NS). RWT decreased in all groups, while diastolic dimension index remained unchanged. The reversal of LVH was not related to blood pressure reduction. It was more significant in patients with initially higher values of LVMI. Antihypertensive effects of the drugs were comparable. Long-term treatment with all types of selected drugs improves cardiac structure and function independently of their antihypertensive action. Our data suggest that on the basis of the influence on cardiac remodelling no preference for any studied drug can be discerned. The work had the following source of support: the atenolol (Falitonsin) and nifedipine-retard (Corinfar-retard) were provided by the AWD Company (Germany), losartan potassium has been provided by Merck Sharp & Dohme Company and perindopril (Prestarium) by the Servier Group.
A total of 237 eligible patients with mean trough sitting diastolic blood pressure (SiDBP) 95-115 mmHg and a mean trough sitting systolic blood pressure (SiSBP) < 190 mmHg entered the baseline period of treatment with valsartan 80 mg/day for 4 weeks. Those (n = 165) whose SiDBP remained > 90 mmHg and who were not excluded for other reasons were then switched to a single-tablet formulation of losartan 50 mg/hydrochlorothiazide 12.5 mg combination once daily for a further 4 weeks.
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CATH.a cells were incubated with Ang II in combination with mitochondrial permeability transition pore (mPTP) inhibitors or angiotensin receptor antagonists, and apoptosis rate, caspase-3 activity, cytochrome c levels, and mPTP opening were assessed.
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White-coat hypertension (HT) and masked HT can be identified by home blood pressure (BP) measurement. The prevalence of these subtypes and the associated risk of cardiovascular disease have not been fully investigated among Japanese hypertensive patients. The risk of cardiovascular events due to HT and its relationship with home BP measurement were examined among Japanese hypertensive patients receiving treatment in the Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study, a nationwide prospective observational study. Both home and clinic BP were measured during treatment, and the occurrence of cardiovascular events was monitored in 4,596 Japanese patients (mean age of 60.8 years, 43.2% men, and mean follow-up period of 3.5 years). HT was defined as a systolic BP > or =140 mmHg for clinic BP and > or =135 mmHg for home BP while on treatment. The relative risk of all cardiovascular events and stroke increased along with higher clinic and home BP levels during treatment. The prevalence of white-coat HT, masked HT, well-controlled HT, and poorly controlled HT was 12.6%, 19.5%, 23.8%, and 44.1%, respectively. The relative risk of cardiovascular events was not significantly increased in the poorly controlled HT (relative risk [RR]: 2.05, 95% confidence interval [CI]: 0.77-5.45), white-coat HT (RR: 0.77, 95% CI: 0.15-3.96), and masked HT (RR: 2.00, 95% CI: 0.67-5.98) subgroups compared with the well-controlled-HT subgroup; however, the risk of masked HT was similar to that of poorly controlled HT. Monitoring both clinic and home BP is important to diagnose masked HT and to prevent cardiovascular disease in this subtype of HT. However, further investigation is required to fully characterize the cardiovascular risks associated with masked HT among Japanese patients receiving treatment.
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Mutations in sarcomere protein genes can cause hypertrophic cardiomyopathy (HCM), a disorder characterized by myocyte enlargement, fibrosis, and impaired ventricular relaxation. Here, we demonstrate that sarcomere protein gene mutations activate proliferative and profibrotic signals in non-myocyte cells to produce pathologic remodeling in HCM. Gene expression analyses of non-myocyte cells isolated from HCM mouse hearts showed increased levels of RNAs encoding cell-cycle proteins, Tgf-β, periostin, and other profibrotic proteins. Markedly increased BrdU labeling, Ki67 antigen expression, and periostin immunohistochemistry in the fibrotic regions of HCM hearts confirmed the transcriptional profiling data. Genetic ablation of periostin in HCM mice reduced but did not extinguish non-myocyte proliferation and fibrosis. In contrast, administration of Tgf-β-neutralizing antibodies abrogated non-myocyte proliferation and fibrosis. Chronic administration of the angiotensin II type 1 receptor antagonist losartan to mutation-positive, hypertrophy-negative (prehypertrophic) mice prevented the emergence of hypertrophy, non-myocyte proliferation, and fibrosis. Losartan treatment did not reverse pathologic remodeling of established HCM but did reduce non-myocyte proliferation. These data define non-myocyte activation of Tgf-β signaling as a pivotal mechanism for increased fibrosis in HCM and a potentially important factor contributing to diastolic dysfunction and heart failure. Preemptive pharmacologic inhibition of Tgf-β signals warrants study in human patients with sarcomere gene mutations.
Syndrome differentiation-based TCM treatment in addition to basic treatments can produce satisfactory therapeutic effects on proteinuria in patients with chronic kidney disease by improving the clinical symptoms, reducing TCM symptom scores and proteinuria, and protecting the renal functions.
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Angiotensin II (Ang II) plays an important role in cardiac remodeling through stimulation of proliferation and extracellular matrix (ECM) production in cardiac fibroblasts. Integrins are a family of transmembrane receptors that mediate the attachment of cells to ECM. We hypothesized that Ang II regulation of integrins further contributes to its role in cardiac remodeling. We cultured adult rat cardiac fibroblasts with and without Ang II (100 nmol/L) to determine the effects on mRNA and protein levels of integrins, as well as alpha-actinin and other cytoskeletal proteins that link to integrins at the site of focal adhesions. Ang II was also added in the presence of irbesartan (10 micromol/L), a specific Ang II type 1 (AT(1)) receptor antagonist, or PD 123319 (10 micromol/L), a specific Ang II type 2 receptor antagonist. To investigate the function of these integrins, we determined the effects of blocking antibodies on Ang II-induced adhesion to ECM. We also treated spontaneously hypertensive rats (SHR) with an AT(1) receptor blocker, losartan, or with hydralazine to investigate integrin and alpha-actinin expression in treated and untreated SHR. Ang II enhanced alpha(v), beta(1), beta(3), and beta(5) integrins; osteopontin; and alpha-actinin mRNA and protein levels in cardiac fibroblasts. All of these effects were inhibited by irbesartan but not by PD 123319. Pretreatment of cardiac fibroblasts with Ang II enhanced cell attachment to ECM proteins and induced focal adhesion kinase phosphorylation. Blocking antibodies to beta(3) and alpha(v)beta(5) attenuated Ang II-induced adhesion. In SHR, ventricular alpha(v) and beta(5) integrin expression and alpha-actinin were increased compared with those in Wistar-Kyoto rats. Although both losartan and hydralazine lowered mean arterial pressure and decreased peripheral vascular resistance, only losartan attenuated the increased integrin, alpha-actinin, fibronectin laminin, and osteopontin expression and the increased left ventricular mass (as determined with echocardiography). Hydralzine had none of these effects. Although both agents attenuated beta-myosin heavy chain expression, a marker of hypertrophy, losartan had a greater effect. These results suggest that integrins and alpha-actinin are upregulated by Ang II and in left ventricular hypertrophy and that the block of expression of these proteins through inhibition of the AT(1) receptor is associated with attenuation of the hypertrophic response. Ang II induces integrin and alpha-actinin expression in cardiac fibroblasts that is associated with adhesion and left ventricular hypertrophy and blocked through inhibition of the AT(1) receptor.
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To compare angiotensin receptor blocker utilization and expenditure patterns in Austria and Croatia following prescribing restrictions, as well as with other European countries introducing different supply- and demand-side measures. Lastly, to appraise the impact of generic losartan in Croatia on utilization of patented angiotensin receptor blockers.
To assess the efficacy of losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphe nyl-4-yl)methyl]imidazole, potassium salt), an angiotensin II receptor antagonist, on acute myocardial ischemia, 36 four-month-old spontaneously hypertensive rats were used. The animals underwent 45 min of left coronary artery occlusion and 1 h of reperfusion and were randomly assigned to control and losartan-treated groups (2, 5, and 10 mg/kg, intravenously). Losartan was administered 15 min before ischemia. Electrocardiograms (lead II) were monitored continuously throughout the experiment. To assess the anti-infarct effect of losartan, the area at risk was determined by methylene blue dye and the infarct size was determined by nitroblue tetrazolium chloride staining. The areas of risk and infarct were measured by computerized planimetry. Results demonstrated that the low and intermediate doses (2 and 5 mg/kg) of losartan significantly decreased the incidence of ventricular fibrillation and mortality during the ischemic period induced by left coronary artery occlusion. However, a significant reduction in infarct size, calculated as a percentage of the area at risk, was noted in all three losartan-treated groups (control: 41.5% +/- 5.2%, losartan, 2 mg/kg: 11.2% +/- 5.8%, 5 mg/kg: 8.5% +/- 2.7% and 10 mg/kg: 13.7% +/- 1.6%). The results suggest that losartan may be useful in the treatment of ventricular arrhythmias induced by acute myocardial infarction and attenuation of reperfusion injury in hypertension.
Cell culturing, ELISA, semi-quantitative RT-PCR, Western blotting.
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Calcium activated chloride channels (CaCCs) are critical in vascular smooth muscle function as they regulate proliferation/apoptosis of smooth muscle cells (SMCs) and vascular tone. Transmembrane protein 16A (TMEM16A) was demonstrated to encode CaCCs in basilar artery SMCs (BASMCs) and participate in basilar artery remodeling during hypertension. In addition, TMEM16A has recently been illustrated to contribute to pressure‑induced myogenic response in cerebral vasculature. However, whether TMEM16A is involved in cerebral vasoconstriction that is stimulated by other vasoconstrictors remains unclear. The aim of the present study was to establish whether TMEM16A is involved in the progression of angiotensin II (Ang II)‑induced basilar artery constriction and elucidate its potential role during hypertension. The study demonstrated that the specific inhibitor of TMEM16A, T16A‑inhA01 attenuated Ang II‑induced constriction in rat basilar arteries, and that this effect was weakened in parallel with the decline of TMEM16A expression in basilar arteries of 2‑kidney, 2‑clip hypertensive rats. Furthermore, it was found that 100 nM Ang II evoked a chloride current in cultured BASMCs with a basal 100‑nM intracellular Ca2+ ([Ca2+]i) level. In addition, the current could be abolished by TMEM16A small interfering RNA pretreatment and Ang II receptor type 1 (AT1) receptor blocker, losartan, while Ang II failed to cause a further increase to Ca2+‑dependent Cl‑ currents activated by 500 nM [Ca2+]i. In addition, in cultured BASMCs, Ang II induced phosphorylation of myosin phosphatase‑targeting subunit 1, and myosin light chains were significantly enhanced by TMEM16A overexpression, which were reversed by Rho‑associated protein kinase (ROCK) inhibitor, Y‑27632, while TMEM16A silencing demonstrated an opposing result. Furthermore, Ang II‑induced RhoA activation was enhanced by TMEM16A overexpression. In conclusion, the present study revealed that Ang II elicited a TMEM16A‑mediated current and TMEM16A participated in Ang II‑induced basilar constriction via the RhoA/ROCK signaling pathway.
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Diabetes mellitus (DM), which induces alterations in energy metabolism, is the leading cause of cardiovascular disease. We postulated that peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-alpha), a transcriptional coactivator that is the primary regulator of oxidative metabolism and mitochondrial biogenesis, and cardiac function are depressive in DM and simvastatin and losartan therapy can improve the affects of DM on mRNA expression of PGC-1alpha and cardiac function. An experimental model of DM (induced by streptozocin 60 mg/kg) in adult male rats (n = 24) was used to investigate the mRNA expression of PGC-1alpha in the left ventricular myocardium. These rats were divided into group I (insulin therapy only, n = 8), group II (insulin plus simvastatin 20 mg/kg/day orally, n = 8), and group III (insulin plus losartan 20 mg/kg/day orally, n = 8). Diabetic rats and 8 healthy rats (group IV) were sacrificed at 3 weeks following DM induction. The mRNA expression of PGC-1alpha was measured using real-time polymerase chain reaction (RT-PCR). Additionally, transthoracic echocardiography was performed on days 0 and 21. The experimental results indicated that the mRNA expression of PGC-1alpha and the left ventricular ejection fraction (LVEF %) were significantly lower in groups I, II and III than in group IV (all P < 0.001). However, the mRNA expression of PGC-1alpha and the LVEF were significantly higher in group III than in groups I and II (both P < 0.01). Conversely, mRNA expression of PGC-1alpha and LVEF did not differ between groups I and II (P > 0.5). In conclusion, DM induces suppression of mRNA expression of PGC-1alpha and LV function in diabetic rats. Losartan and not simvastatin therapy improved the LV function and the expression of this mitochondrial-biogenesis regulator.
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Renin-angiotensin-aldosterone system (RAAS) blockade improves prognosis in renal patients, but usually requires diuretic co-treatment. RAAS blockade can decrease erythropoietin (EPO) and/or haemoglobin (Hb) levels. Diuretics decrease EPO in rodents, but their effect on EPO and Hb in humans is unknown.
Tubulointerstitial fibrosis is considered to be common endpoint result of many forms of chronic renal diseases. Except for renal replacement, chronic renal fibrosis is presently incurable. This study demonstrates that the combination of hepatocyte growth factor (HGF) gene therapy with inhibition of the renin-angiotensin system produced synergistic beneficial effects leading to dramatic attenuation of renal tubulointerstitial fibrosis in obstructive nephropathy in mice. The combined treatment with human HGF gene and losartan, an angiotensin II (AngII) type I receptor blocker, preserved renal mass and gross morphology of the obstructed kidneys. Although HGF gene therapy alone inhibited the expression of alpha-smooth muscle actin (alpha SMA) by approximately 54% and 60% at day 7 and day 14 after surgery, respectively, its combination with losartan almost completely abolished alpha SMA induction in the obstructed kidneys. The combined therapy also synergistically inhibited the accumulation of interstitial matrix components, such as fibronectin and collagen I, and suppressed renal expression of transforming growth factor-beta1 (TGF-beta1) and its type I receptor. In vitro studies revealed that AngII by itself did not induce alpha SMA, but it drastically potentiated TGF-beta1-initiated alpha SMA expression in tubular epithelial cells. Furthermore, HGF abrogated de novo alpha SMA expression induced by TGF-beta1 plus AngII. These results suggest that many factors are implicated in the pathogenesis of renal interstitial fibrosis; therefore, a combined therapy aimed at simultaneously targeting multiple pathologic pathways may be necessary for halting the progression of chronic renal diseases. These findings may provide the basis for designing future therapeutic regimens for blocking progressive renal fibrosis in patients.
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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.
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Losartan and telmisartan, angiotensin AT1 receptor antagonists, are widely used antihypertensive drugs in patients. It is also known that arterial hypertension is often present in people with epilepsy, therefore, drug interactions between AT1 receptor antagonists and antiepileptic drugs can occur in clinical practice.
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Sodium hydrosulfide (NaHS, 56 µmol/kg/day) was administered intraperitoneally to the rats from the 7th day after 2K1C operation. Systolic blood pressure was significantly increased from the first week after the operation and was lowered after NaHS treatment for 4 weeks. H2S could also inhibit the ratio of left ventricle and septum weight to body weight, improve cross-sectional area, and ameliorate ventricular dysfunction. Additionally, the protein expression of AT1R and Ang II serum content were downregulated, whereas superoxide dismutase (SOD) protein was upregulated in 2K1C rats by NaHS treatment for 4 weeks. Furthermore, the reactive oxygen species level and AT1R protein were increased, whereas SOD protein was decreased in cardiomyocytes treated with Ang II compared with the control group. NaHS could reverse these changes. Losartan and N-acetylcysteine could also reverse Ang II-induced changes.