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The patterns of angiotensin II-receptor blocker (ARB) therapy in patients with and without a history of antihypertensive use were studied.
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Losartan is an angiotensin II receptor (AT-II-R) blocker that is widely used by human for blood pressure regulation. Also, it has antitumor property. In this study, we investigated the radiosensitizing effect of losartan on cellular toxicity induced by ionizing radiation on prostate cancer and non-malignant fibroblast cells. Human prostate cancer (DU-145) and human non-malignant fibroblast cells (HFFF2) were treated with losartan at different concentrations (0.5, 1, 10, 50 and 100 µM) and then these cells were exposed to ionizing radiation. The cell proliferation was determined using MTT assay. Our results showed that losartan exhibited antitumor effect on prostate cancer cells; it was reduced cell survival to 66% at concentration 1 µM. Losartan showed an additive killing effect in combination with ionizing radiation on prostate cancer cell. The cell proliferation was reduced to 54% in the prostate cancer cells treated with losartan at concentration 1 µM in combination with ionizing radiation. Losartan did not exhibit any toxicity on HFFF2 cell. This result shows a promising effect of losartan on enhancement of therapeutic effect of ionizing radiation in patients during therapy.
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This protocol has been approved by the CPRD's Independent Scientific Advisory Committee (ISAC). We will publish the results of the study as open-access peer-reviewed publications and disseminate findings through national and international conferences as are appropriate.
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Using Ang II I radioimmunoassay, real-time reverse transcription-PCR and western blot, we found that Ang II levels, and mRNA and protein expression of angiotension II type 1 receptor in nodose ganglia from CHF rats were higher than that from sham rats. Local microinjection of Ang II (0.2 nmol) into the nodose ganglia decreased the arterial baroreflex sensitivity in sham rats, whereas losartan (1 nmol, an angiotension II type 1 receptor antagonist) improved the arterial baroreflex sensitivity in CHF rats. Data from patch-clamp recording showed that Ang II (100 nmol/l) acutely inhibited Nav currents in the aortic baroreceptor neurons from sham and CHF rats. In particular, inhibitory effect of Ang II on Nav currents in the aortic baroreceptor neurons was larger in CHF rats than that in sham rats. Losartan (1 μmol/l) totally abolished the inhibitory effect of Ang II on Nav currents in sham and CHF aortic baroreceptor neurons.
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Fifteen patients aged 43.3 +/- 11.3 years with primary glomerulonephritis confirmed by renal biopsy were studied.
RT-PCR revealed two times higher prepro-TRH expression in left auricle than left ventricle. In transgenic rats with extra copy of mouse renin gene a marked increase of prepro-TRH expression in the heart was noted but the relative difference between left atrium and left ventricle persisted. The swelling stimulated TRH release from both left auricle and left ventricle and this stimulation could not be inhibited by bumetanide. Angiotensin II (10 nmol L-1) added into medium significantly decreased basal secretion of TRH. The inhibiting effect of Angiotensin II was prevented by 1 micromol L-1 losartan, an angiotensin II AT1 receptor blocker. When angiotensin II and hypotonicity were applied simultaneously, swelling-induced secretion persisted.
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The renin-angiotensin system may be implicated in the subtle sodium handling abnormality in preascitic cirrhosis.
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In the normal condition, AT2R in the IML tonically inhibits sympathetic activity through an NO/NOS dependent pathway and subsequent potassium channel activation.
ANG-(1-7) significantly attenuates ANGII-induced vasoconstriction and, although the Mas receptor is expressed in HMA, this effect seems to be independent of its activation. Additionally, AT2 receptor and endothelium are not involved in this mechanism, which suggests a direct effect on smooth muscle cells.
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We investigate whether combined treatment with losartan, an angiotensin II receptor blocker, and exercise training (ET) in spontaneously hypertensive rats (SHR) would have an additive effect in reducing hypertension and improving baroreflex sensitivity when compared with losartan alone. Male SHR (8 weeks old) were assigned to 3 groups: sedentary placebo (SP, N = 16), sedentary under losartan treatment (SL, N = 11; 10 mg kg-1 day-1, by gavage), and ET under losartan treatment (TL, N = 10). ET was performed on a treadmill 5 days/week for 60 min at 50% of peak VO2, for 18 weeks. Blood pressure (BP) was measured with a catheter inserted into the carotid artery, and cardiac output with a microprobe placed around the ascending aorta. The baroreflex control of heart rate was assessed by administering increasing doses of phenylephrine and sodium nitroprusside (iv). Losartan significantly reduced mean BP (178 16 vs 132 12 mmHg) and left ventricular hypertrophy (2.9 0.4 vs 2.5 0.2 mg/g), and significantly increased baroreflex bradycardia and tachycardia sensitivity (1.0 0.3 vs 1.7 0.5 and 2.0 0.7 vs 3.2 1.7 bpm/mmHg, respectively) in SL compared with SP. However, losartan combined with ET had no additional effect on BP, baroreflex sensitivity or left ventricular hypertrophy when compared with losartan alone. In conclusion, losartan attenuates hypertension and improves baroreflex sensitivity in SHR. However, ET has no synergistic effect on BP in established hypertension when combined with losartan, at least at the dosage used in this investigation.
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The LIFE study (Losartan Intervention For Endpoint reduction in hypertension) is a randomized, double-blind comparison of losartan and atenolol-based treatment. The study hypothesis was that losartan would reduce cardiovascular morbidity and mortality more than traditional antihypertensive treatment with atenolol.
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The present investigation determined that native angiotensins II and III (ANG II and III) were equipotent as pressor agents when ICV infused in alert rats, whereas native angiotensin IV (ANG IV) was less potent. An analogue of each of these angiotensins was prepared with a hydroxyethylamine (HEA) amide bond replacement at the N-terminus, yielding additional resistance to degradation. These three angiotensin analogues, HEA-ANG II, HEA-ANG III, and HEA-ANG IV, were equivalent with respect to maximum elevation in pressor responses when ICV infused; and each evidenced significantly extended durations of effect compared with their respective native angiotensin. Comparing analogues, HEA-ANG II had a significantly longer effect compared with HEA-ANG III, and HEA-ANG IV, whereas the latter were equivalent. Pretreatment with the AT1 receptor subtype antagonist, Losartan (DuP753), blocked subsequent pressor responses to each of these analogues, suggesting that these responses were mediated by the AT1 receptor subtype. Pretreatment with the specific AT4 receptor subtype antagonist, Divalinal (HED 1291), failed to influence pressor responses induced by the subsequent infusion of these analogues. These results suggest an important role for Ang III, and perhaps ANG IV, in brain angiotensin pressor responses mediated by the AT1 receptor subtype.
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Based on antihypertensive efficacy data versus irbesartan, the use of olmesartan medoxomil is expected to reduce the number of new cases of CV disease, resulting in a first-year reduction in cost in a cohort of 100,000 patients of 906,000 US dollars. Similarly, a reduction in new cases of coronary heart disease (CHD) resulted in a cost reduction of 701,000 US dollars; a cost reduction of 196,000 US dollars for fewer myocardial infarctions (MI); and a cost reduction of 28,000 US dollars for fewer strokes. Over 5 years, these estimates increase to 5,410,000 US dollars for fewer cases of CV disease; 3,975,000 US dollars for fewer cases of CHD; 1,430,000 US dollars for fewer MI; and 497,000 US dollars for fewer strokes. Compared with valsartan, the use of olmesartan medoxomil is estimated to reduce by 3,397,000 US dollars the expected cost of treating a cohort of 100 000 patients in the first year for fewer cases of CV disease; by 2,426,000 US dollars for fewer cases of CHD; by 565,000 US dollars for fewer MI; and by 124,000 US dollars for fewer strokes. Over 5 years, these estimates increase to 16,231,000 US dollars for CV disease; 11,955,000 US dollars for CHD; 4,505,000 US dollars for MI; and 1,741,000 dollars for stroke. Compared with losartan, the estimated reduction in first-year cost is 2,969,000 US dollars for CV disease for the cohort of 100,000 patients; 2,163,000 US dollars for CHD; 732,000 US dollars for MI; and 124,000 US dollars for stroke. Over 5 years, these estimates increase to 15,149,000 US dollars for CV disease; 11,107,000 US dollars for CHD; 4,057,000 US dollars for MI; and 1,437,000 dollars for stroke.
There are two major isoforms of the angiotensin II receptor, type 1 (AT1) and type 2 (AT2). AT2 is distinguished from AT1 with respect to its ligand selectivity, its insensitivity to non-hydrolyzable GTP analogues, and its as yet unidentified biological functions. In the present study we have expression-cloned AT2 cDNA from a cDNA library of a rat pheochromocytoma cell line (PC12w). Rat AT2 cDNA encodes a 363-amino acid protein that has seven transmembrane domains. AT1 is the closest in homology to AT2 but with only a 32% identity of amino acid sequence. Stably expressed in COS-7 cells, the receptor showed selective binding to AT2-specific ligands PD123319 and CGP42112A but not to the AT1-specific ligand, losartan. Northern blot analysis revealed that the mRNA of rat AT2 was expressed not only in PC12w cells but also in the adrenal glands and in the inferior olive of the brain, both of which are known to contain AT2 type binding sites. The expressed AT2 receptor mediated angiotensin II-induced inhibition of protein tyrosine phosphatase, an action that was dependent on a pertussis toxin-sensitive G-protein-coupled mechanism in COS-7 cells. The AT2-specific ligand CGP42112A was an agonist rather than antagonist in the inhibition of phosphotyrosine phosphatase. AT2 did not cause a decrease in cGMP in PC12w or COS-7 cells expressing AT2 stably. These results indicate that the AT2 receptor is structurally and functionally different from AT1 and suggest novel functional roles of the renin-angiotensin system in cross-talk with phosphotyrosine signaling by modulating protein phosphotyrosine levels.
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There were significant differences in the levels of CD62P, CD63, PAC-1, platelet microparticles, endothelial microparticles, sE-selectin, and sVCAM-1 between the hypertensive patients and healthy controls. These markers were all significantly increased in hypertensive and hyperlipidemic patients with Type 2 diabetes. In hypertensive patients with diabetes, CD62P, CD63, PAC-1, platelet and endothelial microparticles, and soluble adhesion markers were all decreased by losartan monotherapy. The decrease of each marker in hypertensive and hyperlipidemic patients given combined therapy with losartan plus simvastatin was greater among those with than without Type 2 diabetes. Low-density lipoprotein was decreased significantly by simvastatin and was correlated with CD62P or platelet microparticles in all of the patients.
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Diurnal blood pressure was significantly reduced after losartan compared with placebo (122/70 +/- 11/8 vs. 130/76 +/- 12/6 mmHg, p < 0.05). A significant decline in GFR (133 +/- 23 vs. 140 +/- 22 ml/min, p < 0.05) and filtration fraction (FF; GFR/RPF) (24.6 +/- 3.5 vs. 26.2 +/- 3.6%, p < 0.05) was observed in the losartan vs. placebo groups. RPF and UAE did not change. Isotopically determined glucose disposal rates were similar after losartan and placebo in the basal (2.61 +/- 0.53 vs. 2.98 +/- 0.93 mg/kg/min) and insulin-stimulated states (6.84 +/- 2.52 vs. 6.97 +/- 3.11 mg/kg/min). However, the glucose oxidation rate increased significantly after losartan vs. placebo in the basal state (1.72 +/- 0.34 vs. 1.33 +/- 0.18, mg/kg/min, p < 0.01) and during insulin stimulation (2.89 +/- 0.75 vs. 2.40 +/- 0.62 mg/kg/min, p < 0.03). Basal and insulin-stimulated non-oxidative glucose disposal tended to decrease after losartan; however, this was not significant. Endogenous glucose production and lipid oxidation were unchanged after treatment and similarly suppressed during hyperinsulinaemia. Glycaemic control, total cholesterol, high-density lipoprotein (HDL)-cholesterol and triglycerides were stable in both losartan and placebo groups.
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Urinary kallikrein excretion is positively correlated to renal function, serum and urinary inflammatory mediator MCP-1 in chronic kidney disease patients. These findings indicate that urinary kallikrein excretion may reflect the change of renal function and kidney inflammatory status.
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The serum EDLS levels increased significantly compared with a CSF group after SFO administration with Ang II; The Na+, K(+)-ATPase activities in PT segments decreased significantly at 30 min and 60 min after SFO administration with Ang II. There was a negative linear correlation between serum EDLS level and the Na+, K(+)-ATPase activity of PT segments in rats administrated with Ang II (r = -0.938).
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Although transient spironolactone treatment leads to prolonged blood pressure reduction and reduced collagen deposition, long-term organ protection only partially exists. Thus, transient spironolactone treatment is less effective than transient losartan treatment.
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Diabetic rats demonstrated baseline increases in GFR and FF. In contrast to similar decreases in BP in diabetic and control rats, renal vasodilator effects and a decrease in FF, following ROCK inhibition were observed only in diabetic rats. The vasodilator effects of Y27632 and a further decrease in FF, were also detected in diabetic rats pretreated with the angiotensin antagonist losartan. The effects of ROCK inhibitors in diabetic rats were modulated by prior protein kinase C (PKC)β inhibition with ruboxistaurin, which abolished their effects on FF. Consistent with the renal vasodilator effects, the ROCK inhibitors reduced phosphorylation of myosin light chain in diabetic kidneys.
The study is to investigate the effect of angiotensin II (Ang II) and its receptor blockers on migration and endothelin-1 (ET-1) expression of rat vascular adventitial fibroblast subpopulations. Vascular adventitial fibroblasts were individually expanded by using cloning rings, and the effects of Ang II on the migration of adventitial fibroblast subpopulations were evaluated by Transwell. Fluorescence quantitative-PCR detected the expression of preproET-1 mRNA induced by Ang II, and its receptor antagonists losartan and PD-123319. The concentration of ET-1 was determined by ELISA. It showed that spindle shaped and epithelioid shaped cells were isolated by using cloning rings, named as spindle cells and round cells. RT-PCR showed that fibroblast subpopulations did not have leukocytes, endothelial cells and smooth muscle cells, namely pure cell lines. Compared with respective control cells, two subpopulations had transferring ability. Ang II significantly improved round cells migration in a concentration-dependent manner, and had no obvious influence on spindle cells migration. Ang II (1 x 10(-8) - 1 x 10(-6) mol x L(-1)) significantly increased the expression of preproET-1 mRNA in round cells (P < 0.01), and had no significant effect on the expression of preproET-1 mRNA in spindle cells. Losartan blocked the expression of preproET-1 mRNA induced by Ang II in round cells, and had no significant effect on the expression of preproET-1 mRNA in spindle cells. The effects of Ang II and ET-1 receptor inhibitors on the release of ET-1 were similar to the expression of preproET-1 mRNA. The results indicate that there are two cell subpopulations: round cells and spindle cells in rat vascular adventitial fibroblasts. Ang II significantly improved cells migration, and increased the expression of ET-1 in round cell subpopulation. It suggested that there may be different migratory mechanisms in two cell subpopulations, and the two subpopulations may play a different role in vascular remodeling and reparative process.
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Actions of ANG II on electrical and synaptic behavior of enteric neurons in the guinea pig small intestine were studied. Exposure to ANG II depolarized the membrane potential and elevated neuronal excitability. The number of responding neurons was small, with responses to ANG II in 32% of submucosal neurons and 25% of myenteric neurons. Hyperpolarizing responses were evoked by ANG II in 45% of the neurons. The hyperpolarizing responses were suppressed by alpha2-noradrenergic receptor antagonists, which suggested that the hyperpolarizing responses reflected stimulation of norepinephrine release from sympathetic neurons. Exposure to ANG II enhanced the amplitude and prolonged the duration of noradrenergic inhibitory postsynaptic potentials and suppressed the amplitude of both fast and slow excitatory postsynaptic potentials. The selective ANG II(1) receptor (AT1R) antagonists, ZD-7115 and losartan, but not a selective AT2R antagonist (PD-123319), suppressed the actions of ANG II. Western blot analysis and RT-PCR confirmed expression of AT1R protein and the mRNA transcript for the AT1R in the enteric nervous system. No expression of AT2R protein or mRNA was found. Immunoreactivity for AT1R was expressed by the majority of neurons in the gastric antrum and small and large intestine. AT1R immunoreactivity was coexpressed with calbindin, choline acetyltransferase, calretinin, neuropeptide Y, and nitric oxide synthase in subpopulations of neurons. The results suggest that formation of ANG II might have paracrine-like actions in the enteric nervous system, which include alterations in neuronal excitability and facilitated release of norepinephrine from sympathetic postganglionic axons. The enhanced presence of norepinephrine is expected to suppress fast and slow excitatory neurotransmission in the enteric microcircuits and to suppress neurogenic mucosal secretion.
Asia is predicted to have the largest population of patients with diabetes who are at high risk for renal disease. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, approximately 17% of patients were Asians. In this subgroup analysis, we examined the characteristics, response, and adherence to treatment of the Asian population, as well as their baseline predictors of risk of renal end points.
Using radioligand binding studies, we have defined the angiotensin II receptors present on these cells as being predominantly of the AT1 subtype. Angiotensin II increased peak intracellular calcium levels by 126 +/- 16 nmol/l (mean +/- SEM) in 17/49 cultures. Angiotensin II induced c-fos expression in a concentration-dependent manner only in cultures that exhibited an intracellular calcium transient in response to stimulation with angiotensin II. The induction of c-fos was inhibited by the selective AT1 antagonist losartan in accordance with the binding studies. Angiotensin II stimulated DNA synthesis with a maximal increase of 66.4% +/- 20.5% over serum-free levels at 1 nmol/l (mean +/- SEM, n = 6, P < 0.05). DNA synthesis declined with increasing angiotensin II concentration, falling to control values at 1 mumol/l, suggesting that a growth-inhibitory influence may counter-balance the stimulatory effect that is observed at lower concentrations.
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In cultured RPMCs, Ang II upregulated profibrotic signaling pathways through AT1-mediated ERK1/2 phosphorylation.
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We tested the hypothesis that the combination of converting enzyme inhibitor (CEI) with losartan (LOS) produces a more profound antiproteinuric effect than either drug alone in normotensive patients with immunoglobulin A (IgA) nephropathy. Eight normotensive (mean blood pressure, 88.9 +/- 2.1 mm Hg) patients with biopsy-proven IgA nephropathy, nonnephrotic proteinuria (protein, 1 to 3 g/d), and normal or slightly reduced creatinine clearance (range, 69 to 119 mL/min) were studied. Clinical evaluations and laboratory tests were performed (1) before CEI treatment (basal) and after (2) CEI alone (CEI, 12 weeks); (3) the combination of CEI and LOS, the latter at a dosage of 50 mg/d (CEI + LOS, 4 weeks); (4) LOS alone (LOS; 50 mg/d; 12 weeks); (5) the combination of LOS and CEI (LOS + CEI, 4 weeks, at the same dosage as CEI + LOS); and (6) a doubled dose of either CEI alone or LOS alone for 4 weeks. CEI and LOS as monotherapy significantly reduced proteinuria by 38% and 30%, respectively. No further reduction of proteinuria was achieved by doubling the dose of CEI or LOS. Both combinations induced a more remarkable reduction of proteinuria (73%; P < 0.05 v other periods) than either drug administered alone. The antiproteinuric effect of CEI or LOS and the more remarkable effect achieved with both combinations was not dependent on the reduction of blood pressure and/or creatinine clearance. In conclusion, this study provides first-time evidence that the combination of CEI and LOS in normotensive patients with IgA nephropathy produces a more profound decrease in proteinuria than either drug. This additive antiproteinuric effect is not dependent on changes in systemic blood pressure and creatinine clearance. Nevertheless, a larger controlled study is required to confirm this novel observation.
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The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV.