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Antihypertensive efficacy and safety of losartan/hydrochlorothiazide (HCTZ) combinations have not been adequately studied in Asians. In this open-label, 12-week study in seven Asian areas, patients on monotherapy with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) but not at blood pressure (BP) goal (sitting diastolic BP (SiDBP) <90 mm Hg in non-diabetics and <80 mm Hg in diabetics) were switched to losartan 50 mg/HCTZ 12.5 mg. At 4 and 8 weeks, the therapy for patients not at goal BP was titrated to losartan 100 mg/HCTZ 12.5 mg and to losartan 100 mg/HCTZ 25 mg, respectively. Data analysis included 430 patients with mean (s.d.) age 53.0 (10.1) years and 51.9% of the female gender. After 8 weeks (primary end point; titration up to losartan 100 mg/HCTZ 12.5 mg), 73.5% (95% confidence interval (CI): 69.0-77.6) of patients reached BP goal; 63.4 and 78.1% of patients reached BP goal at 4 weeks (titration up to losartan 50 mg/HCTZ 12.5 mg) and at 12 weeks (titration up to losartan 100 mg/HCTZ 25 mg). The mean changes from baseline (95% CI) in sitting systolic BP and SiDBP at 8 weeks were -16.7 (-18.0 to -15.4) mm Hg and -12.1 (-12.9 to -11.4) mm Hg, respectively. Clinical and laboratory adverse experiences (AEs) were reported in 27.5 and 21.0% of patients, respectively. Nine patients were discontinued because of drug-related clinical AEs. Switching Asian patients currently not at BP goal with ARB or ACEI monotherapy to a losartan/HCTZ combination achieved BP goal in the majority of patients. Losartan/HCTZ combinations were generally well tolerated.
Angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are known to prevent the onset of stroke and to attenuate neural damage. Additional beneficial effects of ARBs, independent of AT(1) receptor blockade, have been highlighted. Irbesartan is reported to act as an antagonist of the monocyte chemoattractant protein-1 (MCP-1) receptor, C-C chemokine receptor 2 (CCR2), due to its molecular structure. We examined the possible synergistic effects of co-administration of irbesartan with propagermanium, a CCR2 antagonist, on ischemic brain damage. Administration of propagermanium decreased ischemic brain area after middle cerebral artery occlusion (MCAO). To study the possible synergistic effects of propagermanium with ARBs, we employed non-effective lower doses of irbesartan and losartan. Administration of irbesartan with propagermanium decreased the ischemic brain area more markedly compared with propagermanium alone, but co-administration of losartan did not. MCP-1 mRNA level was significantly increased on the ipsilateral side after MCAO, and administration of irbesartan with propagermanium decreased the MCP-1 level, whereas co-administration of losartan did not. Similar results were obtained for MCP-1 protein level. CCR2 mRNA expression was significantly elevated on the ipsilateral side; however, no significant difference was observed between each group. mRNA levels of other inflammatory cytokines such as TNF-α and IL-1β also significantly increased on the ipsilateral side, but the expression levels were not changed by each drug treatment. Taking these findings together, irbesartan exerts more beneficial effects on ischemic brain damage with an MCP-1 receptor blocker, at least due to its inhibitory effects on MCP-1/CCR2 signaling beyond AT(1) receptor blockade.
Angiotensin II (Ang II) plays a critical role in the development of vascular lesions in hypertension, atherosclerosis, and several renal diseases. Because Ang II may contribute to the leukocyte recruitment associated with these pathological states, the aim of the present study was to assess the role of Ang II in leukocyte-endothelial cell interactions in vivo.
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Apart from being associated with a high BP burden, cardiovascular remodeling was associated with high levels of circulating epinephrine, aldosterone, as well as angiotensin II, suggesting a beneficial effect above and beyond the effect of BP reduction when using antihypertensive agents blocking the receptors of these neurohormonal factors.
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Compared with sham group, the sections of injured aorta showed marked intimal thickening with large numbers of VSMCs proliferation throughout intima and media, the level of Ang II obviously increased by 78.8% (P < 0.05), the expression of PDGF-beta receptor significantly increased by 83.9% (P < 0.05) at 14th day after operation. The expression of PDGF-beta receptor in cultured VSMC treated with Ang II was higher than that of control group (P < 0.01). The effect of Ang II was inhibited remarkably by pretreatment with losartan.
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The combined treatment with losartan and fluvastatin significantly inhibited atherosclerotic progress and reduced inflammation associated with atherosclerotic plaques.
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Overall there was a 7 +/- 2 mmHg fall (mean +/- SEM) in mean daytime systolic blood pressure at 4 weeks, and a 22 +/- 7% fall in protein/creatinine ratio (both P < 0.05), with no difference between groups A and B or between 4 and 8 weeks. These two changes were highly correlated (r = 0.64, P = 0.006, taking both groups together). Changes in diastolic pressure and in night-time systolic pressure did not reach statistical significance. Changes in renal plasma flow (measured by Tc 99m MAGIII), glomerular filtration rate and filtration fraction (measured by 51Cr EDTA) did not reach statistical significance, did not differ between the two groups and did not correlate with effects on proteinuria.
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Lorsartan, fosinopril inhibit myocardial fibrosis and reverse heart hypertrophy. Fosinopril may be more effective in these above effects than Lorsartan. The mechanism of the both drug's cardioprotective effects was related to inhibition of myocardium rennin-angiotension-aldsteron system.
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Mean ± SD systolic and diastolic BP decreased from 152 ± 13/87 ± 10 mmHg to 128 ± 14/74 ± 10 mmHg, respectively, after 12 months (p < 0.001). Mean ± SD plasma BNP levels decreased significantly from 46.0 ± 83.0 pg/mL to 40.8 ± 68.0 pg/mL (p < 0.05). The percentage of patients who achieved the JSH 2004 target BP was 51% after 12 months; the percentage was 63% in elderly patients aged ≥65 years without complications, and 43% in patients with concomitant diabetes mellitus or chronic kidney disease. No association was found between a decrease in plasma BNP levels and BP, age, body mass index or estimated glomerular filtration rate. There was a significant increase in serum uric acid and a decrease in serum potassium, but both were within the range of normal values. Adverse events were observed in 8.6% of the patients.
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Combined therapy decreased 24-hour proteinuria (-45.54% versus baseline) more effectively than either losartan (-28.17%; analysis of variance, P < 0.01) or benazepril (-20.19%; analysis of variance, P < 0.001) alone. Subgroup analysis showed that antiproteinuric effects of combination therapy, as well as losartan or benazepril alone, were significantly greater in patients with basal proteinuria greater than 2 g/24 h than in those with proteinuria less than this value (P < 0.001, P < 0.01, and P < 0.05, respectively). All therapies significantly decreased blood pressure (BP) compared with baseline, but there were no differences between treatments in BP changes.
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During phase I of the study, no statistically significant differences were observed between the low-dose losartan group and the control group. However, hearts treated with high-dose losartan demonstrated an increase in peak systolic pressure, maximum first derivative of pressure, pressure-time integral, coronary flow, and oxygen consumption (p < 0.0001). During phase II, hearts treated with losartan showed a significantly better recovery on reperfusion, as reflected by better contractility (p < 0.001), higher oxygen consumption (p < 0.001), higher coronary flow (p < 0.0001), and lower creatine phosphokinase levels (41.1 +/- 1.7 versus 73.3 +/- 5.6 U/L; p < 0.001).
The postlosartan ARR and PAC were shown to have better accuracy for the diagnosis of PA than the captopril test. With a postlosartan ARR >60, APAs can be adequately differentiated from IHA.
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Fingernail clubbing and discoloration frequently indicate serious pulmonary, cardiovascular, and gastrointestinal pathologies. A 76-year-old Caucasian man developed clubbing of the fingernails and discoloration of both the fingernails and toenails after 27 days of treatment with the angiotensin II receptor blocker (ARB) losartan 50 mg/day. Even though this therapy was switched to valsartan, the nail changes persisted for another 6 months. The patient's therapy then was changed to captopril, and the changes gradually subsided over 17 months. An extensive literature search revealed no reports of this effect in association with ARBs. However, one manufacturer had received spontaneous reports. Despite careful consideration of other possible causes of the patient's symptoms, the temporal association with the start and discontinuation of ARB therapy suggests a possible drug-related adverse event.
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Rat models of left ventricular hypertrophy induced by pressure overload was established by placing a band around the abdominal aortic of the rats, from which the hypertrophied cadiomyocytes were isolated and purified 8 weeks later. The isolated cardiomyocytes were treated with AngII plus losartan or AngII plus PD123319, and 36 h after the treatments, the expression levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-6 in the supernatant were detected using radioimmunoassay.
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Prospective, open-label, randomized, controlled study.
Modifiers of TGFβ signaling have been investigated as treatment options for several types of muscle diseases. The purpose of this review is to focus on the most recent studies that have used this treatment strategy for pathological muscle disorders. We also review the recent insight into the mechanistic processes by which TGFβ signaling contributes to these pathologies by promoting fibrosis formation.
While there have been reports on changes in the renin-angiotensin system and angiotensin II (AT) receptors in diabetes, there is no agreement on the nature of these changes. This study has characterised specific AT receptors in the heart, kidney, liver and adrenal glands of the streptozotocin (STZ)-diabetic rat using radioligand binding studies with the radioligand 125I-[Sar1, Ile8]-angiotensin II. Left ventricular AT receptor density increased by 135% 4 weeks after treatment and by 206% 12 weeks after treatment; in the liver, AT receptor density increased by 476% (4 weeks) and 263% (12 weeks) and in the adrenal gland by 236% (4 weeks) and 109% (12 weeks). In contrast, renal AT receptor density decreased by 49% (4 weeks) and 36% (12 weeks). Competition-displacement assays with losartan, an AT1-selective ligand, showed that the proportion of AT receptor subtypes remained unchanged. STZ treatment decreased plasma angiotensinogen by 72% (4 weeks) and 67% (12 weeks) and increased plasma renin concentration after 12 weeks; plasma renin activity and aldosterone concentrations remained unchanged. Treatment with human insulin (5 U/day) attenuated changes in plasma angiotensinogen and AT receptor density except in the left ventricle. We conclude that there are major changes in AT receptors in the STZ-diabetic rat that are tissue-specific and time-dependent. Plasma angiotensinogen and renin secretion change in directions that result in the maintenance of plasma renin activity and aldosterone concentration.
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Angiotensin II (Ang II) induces the pathological process of vascular structures, including renal glomeruli by hemodynamic and nonhemodynamic direct effects. In kidneys, Ang II plays an important role in the development of proteinuria by the modification of podocyte molecules. We have previously found that Ang II suppressed podocyte AMP-activated protein kinase (AMPK) via Ang II type 1 receptor and MAPK signaling pathway. In the present study, we investigated the roles of AMPK on the changes of p130Cas of podocyte by Ang II. We cultured mouse podocytes and treated them with various concentrations of Ang II and AMPK-modulating agents and analyzed the changes of p130Cas by confocal imaging and western blotting. In immunofluorescence study, Ang II decreased the intensity of p130Cas and changed its localization from peripheral cytoplasm into peri-nuclear areas in a concentrated pattern in podocytes. Ang II also reduced the amount of p130Cas in time and dose-sensitive manners. AMPK activators, metformin and AICAR, restored the suppressed and mal-localized p130Cas significantly, whereas, compound C, an AMPK inhibitor, further aggravated the changes of p130Cas. Losartan, an Ang II type 1 receptor antagonist, recovered the abnormal changes of p130Cas suppressed by Ang II. These results suggest that Ang II induces the relocalization and suppression of podocyte p130Cas by the suppression of AMPK via Ang II type 1 receptor, which would contribute to Ang II-induced podocyte injury.
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1. The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box. 2. The 5-HT2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box. 3. Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3 receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(-)-zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril. 4. The 5-HT4 receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone. 5. GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine. 6. It was concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor antagonists when administered alone to modify behaviour in the light/dark test indicates an absence of an endogenous 5-HT tone at the 5-HT2 and 5-HT4 receptors and (b) the enhancement by the 5-HT2 receptor antagonists and attenuation by the 5-HT4 receptor antagonists of drug-induced disinhibition indicates a plurality of 5-HT receptor involvement in the mediation of drug-induced disinhibitory profiles in the mouse.
Tubular atrophy is a common histological feature of chronic renal failure, and epithelial cell death by apoptosis might play an important role in its pathogenesis. Angiotensin II contributes to the progressive nature of many kidney diseases and treatment with angiotensin converting enzyme inhibitors preserves the structure of the tubulointerstitial compartment in human and experimental renal diseases.
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Atrial natriuretic peptide (ANP)/natriuretic peptide receptor-A (NPR-A) system is suggested as an endogenous anti-hypertrophic protective mechanism of the heart. We have shown previously that Angiotensin II (ANG II), an effector molecule of renin-angiotensin-aldosterone system, down-regulates NPR-A expression and its activity in vivo rat heart. However, the underlying mechanism by which ANG II down-regulates NPR-A expression in the heart is not well understood. Hence, the present investigation was aimed to determine whether ANG II-stimulated reactive oxygen species (ROS) and NF-κB are involved in the down-regulation of NPR-A activity in H9c2 (2-1) cardiac myoblast cells. The H9c2 (2-1) cardiac myoblast cells were exposed to ANG II (10(-7) M for 20 h) with/or without blocker treatment (losartan-10 µM, N-acetyl cysteine (NAC)-10 mM and pyrrolidine dithiocarbamate (PDTC)-100 µM). On exposure, ANG II induced a significant decrease (P < 0.001) in the expression of Npr1 (coding for NPR-A) gene and NPR-A receptor-dependent guanylyl cyclase (GC) activity. The level of expression of proto-oncogenes (c-fos, c-myc, and c-jun) and natriuretic peptides (ANP and BNP) was increased in ANG II-treated cells when compared with control cells. Interestingly, ANG II-dependent repression of Npr1 gene expression and guanylyl cyclase (GC) activity was completely restored on treatment with losartan, while only a partial reversal was observed in NAC- and PDTC-co-treated cells. In conclusion, the results of this study suggest that ROS-mediated NF-κB activation mechanism is critically involved in the ANG II-mediated down-regulation of NPR-A expression and its GC activity.
The efficacy and tolerability of AML/LOS 5/100 mg/d was found to have been noninferior to those of LOS/HCTZ 100/12.5 mg/d in these hypertensive patients nonresponsive to losartan 100-mg/d monotherapy.
A total of 1326 men and women aged 55 through 80 years (mean, 70 years) with systolic blood pressure of 160 to 200 mm Hg and diastolic blood pressure of less than 90 mm Hg (mean, 174/83 mm Hg) and ECG-LVH, recruited from 945 outpatient settings in the Nordic countries, the United Kingdom, and the United States.
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To determine whether angiotensin II type 1 receptors (AT1R) in vascular smooth muscle cells exert mechanosensitivity and identify the downstream ion channel mediators of myogenic vasoconstriction.
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Interindividual variation of blood pressure (BP) responses to antihypertensive drugs is extensive. Several clinical, laboratory, and genetic predictors of BP responses to blood pressure-lowering agents have been suggested. We describe here the principal findings from the GENRES Study which is primarily a pharmacogenetic study of antihypertensive drug responses but also includes analysis of certain clinical and laboratory predictors. In this placebo-controlled, double-blinded, and randomized study, more than 200 male subjects with essential hypertension were treated with four antihypertensive drug monotherapies (amlodipine, bisoprolol, hydrochlorothiazide, and losartan) in a cross-over fashion, resulting in more than 800 treatment periods. Generally, placebo BP level was the best predictor of BP responses. In addition, higher baseline plasma renin activity predicted better BP response to losartan and bisoprolol, and weaker response to hydrochlorothiazide. A number of candidate gene polymorphisms analysed so far have given negative results in relation to BP responses, with the exception of an STK39 variant associating with losartan responsiveness. In future, genome-wide association studies on antihypertensive pharmacogenetics may identify novel pathways of BP regulation and provide new tools for both basic research and clinical use.
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Angiotensin-converting enzyme inhibitors and AT1 blockers might slow the progression of hepatic fibrosis. Activated HSCs expressed AT1 receptors. Activation of RAS might be related to hepatic fibrogenesis induced by CCl4.
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It has been established that deoxycorticosterone acetate (DOCA)-salt hypertensive rats have an overactive brain angiotensin-system. The purpose of the present study was to identify the brain sites showing enhanced angiotensin-system activity responsible for the pathogenesis of hypertension in DOCA-salt hypertensive rats. The angiotensin receptor antagonist, losartan, was injected into brain ventricles or into tissues around the rostral parts of the third ventricle in conscious DOCA-salt hypertensive rats. Losartan (1 microg) injection into the lateral ventricle or into the rostral parts of the third ventricle produced a depressor response, whereas the agent did not affect blood pressure when injected into the caudal parts of the third ventricle or into the fourth ventricle. Losartan (0.1 microg) injection into the anterior hypothalamic preoptic area, anterior (AHA) produced a depressor response. Angiotensin II (0.1-1 ng) injection into the AHA produced a pressor response in sham-operated and DOCA-salt hypertensive rats, and the pressor response to angiotensin II (1 ng) was greater in DOCA-salt hypertensive rats than that in sham-operated rats. Release of angiotensin peptides in the AHA was greater in DOCA-salt hypertensive rats than that in sham-operated rats. These findings suggest that the angiotensin-system in the AHA is enhanced, and that this enhancement is involved in the maintenance of hypertension in DOCA-salt hypertensive rats. Both increased pressor reactivity to angiotensin II and increased release of angiotensin peptides in the AHA appear to be related to this enhancement of the angiotensin-system in DOCA-salt hypertensive rats.