The long-term effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on ambulatory blood pressure and cardiac performance have never been examined comparatively.
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A TP receptor (TP-R) mimetic causes salt-sensitive hypertension and renal afferent arteriolar vasoconstriction. TP-Rs mediate effects of ANG II on renal vascular resistance and drinking. Therefore, we investigated the hypothesis that thromboxane A(2) synthase (TxA(2)-S) and/or TP-R expression is regulated by salt and/or ANG II. Rats (n = 6) received high-salt (HS) or low-salt (LS) diets. Additional HS-diet rats received ANG II while other HS- and LS-diet rats received the AT(1) receptor (AT(1)-R) antagonist losartan. Excretion of thromboxane B(2) by conscious rats was increased with the HS diet compared with the LS diet (126 +/- 10 vs. 48 +/- 5 pmol/24 h, respectively; P < 0.01). The mRNA abundance for TP-Rs (relative to beta-actin) in the kidney cortex was enhanced 30% by the HS diet (P < 0.001) and was reduced 50% by the addition of ANG II (P < 0.001). However, during losartan administration, the effects of salt were reversed; mRNA more than doubled during the LS diet (P < 0.001). Similarly, the mRNA abundance for TP-Rs in the brain stem was reduced by 50% with the addition of ANG II (P < 0.001) and during losartan administration was almost doubled by the LS diet (P < 0.001). The mRNA abundance for TxA(2)-S in the kidney cortex also was increased many times with the HS diet (P < 0.001). In contrast, the mRNA for TxA(2)-S in the brain was unaffected by salt. ANG II did not affect TxA(2)-S at either site. During losartan administration, TxA(2)-S increased modestly in the brain stem with the LS diet. mRNA abundance for TP-Rs in the kidney cortex and brain stem is suppressed by ANG II acting on AT(1)-Rs. In the absence of AT(1)-Rs, expression of TP-Rs at both sites is enhanced by LS intake. In contrast, ANG II does not affect the mRNA abundance for TxA(2)-S. Expression of TxA(2)-S is enhanced by HS intake in the kidney cortex but by LS intake in the brain stem only during losartan administration. Thus TP-Rs are strongly dependent on ANG II acting on AT(1)-Rs, whereas TxA(2)-S is regulated differentially in the kidney cortex and brain stem by salt intake.
The angiotensin II (Ang II)-binding sites in rat adrenal gland membranes were characterized using 125I-radiolabelled Ang II. While Scatchard analysis identified a single population of Ang II receptor sites, isoelectric focusing (IEF) on polyacrylamide gels revealed four peaks of specific Ang II binding which migrated to isoelectric points (pI values) 6.8, 6.7, 6.5 and 6.3. In binding assays in the presence of an excess of the Ang II receptor AT1 subtype antagonist DuP 753, a monophasic dose-dependent displacement of 125I-labelled Ang II binding by the Ang II receptor AT2 subtype antagonist CGP42112A was observed, and vice versa. In this system, reduction of disulphide bridges using 1 mmol dithiothreitol (DTT)/l markedly increased the number of binding sites in the adrenal zona glomerulosa without affecting receptor affinity. Using IEF, it was found that both DuP 753 and CGP42112A were able to reduce specific binding of each of the four peaks to some extent. However, the predominant effect of DuP 753 was to reduce the labelling of the isoform at pI 6.7 substantially, while CGP42112A significantly inhibited the specific 125I-labelled Ang II binding to the pI 6.3 isoform. When DuP 753 and CGP42112A were used together, specific binding of 125I-labelled Ang II to the isoforms of pI values 6.8, 6.7 and 6.3 was completely eliminated. These data suggest that the four peaks of specific binding found may be composed of different isoforms of both AT1 and AT2 receptor subtypes and that the Ang II receptor isoforms which migrated to pI 6.7 and pI 6.3 are predominantly composed of AT1 and AT2 receptor subtypes respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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Proliferating IH samples from six patients were cultured in vitro in the presence of angiotensin I (ATI) alone, or AT1 and the ACE inhibitor, ramipril, or ATII alone, or ATII with the ATII receptor 1 (ATIIR1) blocker, losartan, or ATII with the ATIIR2 blocker, PD123319, or the ATIIR2 agonist, CGP42112. After 6 days in culture, the IH tissue pieces were harvested, formalin-fixed and paraffin-embedded. The effect of each treatment type on cellular proliferation was evaluated by immunohistochemical staining of these tissue pieces using the proliferation marker, Ki67.
Cardiac hypertrophy as an adaptation to increased blood pressure leads to an increase in ventricular expression of transforming growth factor Cardiac hypertrophy as an adaptation to increased blood pressure leads to an increase in ventricular expression of transforming growth factor b (TGF-b), probably via the renin-angiotensin system. We studied in vivo to determine whether angiotensin II affects TGF-b expression independent from mechanical effects caused by the concomitant increase in blood pressure and in vitro intracellular signaling involved in angiotensin II-dependent TGF-b1 induction. In vivo, the AT1 receptor antagonist losartan, but not reduction of blood pressure by hydralazine, inhibited the increase in TGF-b1 expression caused by angiotensin II. In vitro, angiotensin II caused an induction of TGF-b1 expression in adult ventricular cardiomyocytes and induced AP-1 binding activity. Transfection with "decoys" directed against the binding site of AP-1 binding proteins inhibited the angiotensin II-dependent TGF-b induction. Angiotensin II induced TGF-b expression in a p38-MAP kinase-dependent way. p38-MAP kinase activation was diminished in presence of the antioxidants or diphenyleneiodium chloride, or by pretreatment with antisense nucleotides directed against phox22 and nox, components of smooth muscle type NAD(P)H oxidase. Thus, our study identifies a previously unrecognized coupling of cardiac AT receptors to a NAD(P)H oxidase complex similar to that expressed in smooth muscle cells and identifies p38-MAP kinase activation as an important downstream target.
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Periodic risk assessment using lower risk thresholds is unlikely to be cost-effective. The polypill would become cost-effective if drug prices were reduced.
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Since March 2013, the emergence of an avian-origin influenza A (H7N9) virus has raised concern in China. Although most infections resulted in respiratory illness, some severe cases resulted in acute respiratory distress syndrome (ARDS), which is a severe form of acute lung injury (ALI) that further contributes to morbidity. To date, no effective drugs that improve the clinical outcome of influenza A (H7N9) virus-infected patients have been identified. Angiotensin-converting enzyme (ACE) and ACE2 are involved in several pathologies such as cardiovascular functions, renal disease, and acute lung injury. In the current study, we report that ACE2 could mediate the severe acute lung injury induced by influenza A (H7N9) virus infection in an experimental mouse model. Moreover, ACE2 deficiency worsened the disease pathogenesis markedly, mainly by targeting the angiotensin II type 1 receptor (AT1). The current findings demonstrate that ACE2 plays a critical role in influenza A (H7N9) virus-induced acute lung injury, and suggest that might be a useful potential therapeutic target for future influenza A (H7N9) outbreaks.
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In a cross-over randomized controlled trial, 33 non-diabetic CKD patients (proteinuria 3.8 ± 0.4 g/24 h, blood pressure 143/86 ± 3/2 mmHg, creatinine clearance 89 ± 5 mL/min) were treated during 6-week periods with placebo, angiotensin receptor blockade (ARB; losartan 100 mg/day) and ARB plus diuretics (losartan 100 mg/day plus hydrochlorothiazide 25 mg/day), combined with LS (93 ± 52 mmol Na(+)/24 h) and regular sodium diet (RS; 193 ± 62 mmol Na(+)/24 h, P < 0.001 versus LS), in random order. As controls, 27 healthy volunteers were studied.
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The results suggest an important clinical function in hypertension therapy, as S. nutans could decrease the blood pressure in hypertensive mice by decreasing the HR and contractility, leading to a reduction in myocardial oxygen demand.
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Arterial hypertension, which represents a common problem in patients with renal transplant, contributes to the cardiovascular morbidity and mortality of these patients. The most usual immunosuppressive drugs (cyclosporine and FK-506) collaborate on the development of hypertension. Calcium channel blockers are the most habitually used antihypertensive drugs in this population, although its long-term hemodimamycs effects could be deleterious especially in transplanted patients with chronic graft nephropathy. Losartan, a specific blocker of angiotensin II (AT1) receptors, has demonstrated a potent antihypertensive effect with a good safety and tolerance profile. The glomerular effects of losartan could be useful in transplanted patients. The present open, prospective and multicenter study evaluated the efficacy and safety of losartan in the treatment of hypertension in a group of patients with a renal transplant. Seventy-six patients with systolic blood pressure > or = 140 and/or diastolic blood pressure > or = 90 mm Hg, and/or patients on therapy with one antihypertensive drug and related side effects were included. After inclusion, therapy with losartan 50 mg/24 hr was started, discontinuing the previous antihypertensive therapy and/or therapy which caused the side effects. At four weeks, if blood pressure (BP) was not controlled, hydrochlorothiazide 25 mg or furosemide 40 mg/24 hr was added. At baseline and at weeks 2, 4, 8 and 12, the following parameters were monitored: BP, creatinine, hematocrit, hemoglobin, glucose, ions, uric acid, cholesterol, triglycerides, bilirubin, SGOT, SGPT, GGT, LDH, calcium, phosphate, alkaline phosphatase, proteinuria, and both cyclosporine and FK-506 levels in whole blood. Sixty-seven patients completed the 12-week study period. Mean blood pressure decreased from 113 +/- 10 to 102 +/- 9 mm Hg at the end of the study (P < 0.0001); 38 of the 67 patients (56.7%) who completed the study had a SBP lower than 140 mm Hg and a DBP lower than 90. These blood pressures were obtained in 30 patients on monotherapy with losartan (78.9%). Proteinuria decreased significantly at week 4 and was confirmed at week 12, especially in patients with proteinuria > or = 300 mg/24 hr. Nine patients were withdrawn during the study period for different reasons. Serum creatinine showed a slight, non-clinically significant increase at week 4, remaining stable until the end of the study. Two patients developed a mild normocytic anemia, and three others presented a mild impairment of pre-existent anemia. No interactions with cyclosporine or FK-506 were described. These results indicate that losartan is effective in reducing BP in hypertensive patients with a renal transplant. It has a good tolerance profile and does not interfere with immunosuppressive therapy.
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In a patient with type 2 diabetes mellitus, the addition of the incretin mimetic exenatide and the dipeptidyl peptidase-4 inhibitor sitagliptin to glipizide therapy appeared effective and safe.
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Two hundred and twenty-one patients with hypertension and AF of duration >48 h were randomly assigned to either the rhythm (n=155) or rate (n=66) control group. Exercise capacity was improved in the rhythm control group in the 1st year of the study (p<0.0001). There were no statistically significant differences in the embolic event rate and the total mortality between the 2 groups at the end of the study (p=NS).
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The monocyte chemoattractant protein-1 (MCP-1) plays an important role in the pathogenesis of progression of renal failure. This is based on the observations done both in various animal models of renal damage and in different types of human renal disease. During the development of non-infectious kidney stones, crystals are formed and deposited on the kidneys and the kidneys are surrounded by monocytes/macrophages. We have proposed that in response to crystal exposure, renal epithelial cells produce chemokines, which attract the monocytes/macrophages to the sites of crystal deposition. In this study, we investigated the expression of MCP-1 protein by SD rats exposed to oxonic acid (OA). Our study showed that hyperuricemia accelerates renal progression via a mechanism linked to high MCP-1 which may mediate the inflammation reaction of renal diseases induced by hyperuricemia. Losartan may retard the progression of advanced renal dysfunction, and the mechanism was partly due to blocking of renal inflammation induced by the uric acid. Because the number of experiments performed here is very few, results must be confirmed by more extensive studies with a larger sample size.
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Sixty adult male Wistar Albino rats were divided into three groups. After undergoing surgical femoral fracture and fixation, the ACEI group received 10 mg/kg of Enalapril, the ARB group received 10 mg/kg of Losartan and the Control group did not receive any medication. Fracture healing was evaluated at second and fifth postoperative weeks by the Lane-Sandhu radiological staging system and by histological scoring system of Huoet al. ACE expression in fracture callus was studied by immunohistochemistry.
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To investigate the potency of LC-MS/MS by means of sensitivity and the applicability for cassette dosing in microdose clinical trials.
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The angiotensin II receptor blockers irbesartan and losartan effectively reduce blood pressure and proteinuria in childhood. We were impressed by the neutral taste and the small size of the candesartan cilexetil tablets. This angiotensin II receptor blocker was used during 4 months in 17 pediatric patients (aged 0.5-16, median 4.5 years) with chronic arterial hypertension (n=6), overt proteinuria (n=2), or both (n=9). The initial candesartan dose of 0.23 (0.16-0.28) mg/kg body weight once daily (median and interquartile ranged) was doubled in ten patients [final dose 0.35 (0.22-0.47) mg/kg body weight]. No adverse clinical experiences were noted on candesartan. Candesartan increased plasma potassium by 0.3 (0.0-0.8) mmol/l (P<0.01). In children with arterial hypertension, blood pressure decreased by 9 (3-13)/9 (3-18) mmHg (P<0.01); in those with overt proteinuria the urinary albumin/creatinine ratio decreased by 279 (33-652) mg/mmol (P<0.05). In conclusion, in children candesartan reduces blood pressure and proteinuria with an excellent short-term tolerability profile.
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In SHR-SP, losartan prevented stroke and improved the cerebral artery's smooth muscle and endothelial cell functions, which are altered during ageing and impaired even more dramatically by stroke occurrence.
No analytical interferences with endogenous compounds were found, and the extraction recoveries were over 88%. Limits of quantification of 2 ng mL-1 for losartan and 5 ng mL-1 for E-3174 were achieved, as well as good reproducibility with coefficients of variation of <9% in all cases. Analyses with the present HPLC method show significant differences (p<0.05) in losartan MRs between the four CYP2C9 genotype groups in 13 Spanish healthy volunteers.
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Due to the current analytical processes that are not able to measure all the pharmaceutical molecules and to the high costs and the consumption of time to sample and analyze PhACs, models to calculate Predicted Environmental Concentrations (PECs) have been developed. However a comparison between MECs and PECs, taking into account the methods of calculations and peculiarly the parameters included in the calculation (consumption data, pharmacokinetic parameters, elimination rate in STPs and in the environment), is necessary to assess the validity of PECs. MEC variations of sixteen target PhACs [acetaminophen (ACE), amlodipine (AML), atenolol (ATE), caffeine (CAF), carbamazepine (CAR), doxycycline (DOX), epoxycarbamazepine (EPO), fluvoxamine (FLU), furosemide (FUR), hydrochlorothiazide (HYD), ifosfamide (IFO), losartan (LOS), pravastatin (PRA), progesterone (PROG), ramipril (RAM), trimetazidine (TRI)] have been evaluated during one hydrological cycle, from October 2011 to October 2012 and compared to PECs calculated by using an adaptation of the models proposed by Heberer and Feldmann (2005) and EMEA (2006). Comparison of PECs and MECS has been achieved for six molecules: ATE, CAR, DOX, FUR, HYD and PRA. DOX, FUR and HYD present differences between PECs and MECs on an annual basis but their temporal evolutions follow the same trends. PEC evaluation for these PhACs could then be possible but need some adjustments of consumption patterns, pharmacokinetic parameters and/or mechanisms of (bio)degradation. ATE, CAR and PRA are well modeled; PECs can then be used as reliable estimation of concentrations without any reserve.
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This study demonstrates that losartan significantly improved endothelial function in type 2 diabetes patients with hypertension compared with atenolol. This must be independent of the blood pressure-lowering effect of losartan and is probably caused by an antioxidative effect of the angiotensin receptor blocker.
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Systemic N(G)-nitro-L-arginine methyl ester (L-NAME) infusions (12.5 microg/kg per min for 40 min) were given to eight hypertensive subjects (age 53 +/- 6 years) during placebo, and during pretreatment with HCT (25 mg once daily) or HCT and losartan (LOS) (50 mg twice daily), both for 9 days. The glomerular filtration rate (GFR) and renal plasma flow were estimated from the clearances of radiolabeled thalamate and hippuran. Renal blood flow (RBF) was calculated as renal plasma flow/1 - hematocrit and the renal vascular resistance (RVR) as mean arterial pressure (MAP) divided by RBF.
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Mean arterial pressure (MAP) was measured by tail-cuff plethysmography and the plasma levels of total 8-isoprostane, nitric oxide, prostacyclin, thromboxane A(2), angiotensin II, aldosterone, and aortic cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were determined by enzyme immunoassay. Plasma, heart, and kidney GSH were analyzed by high-performance liquid chromatography. Aortic and renal superoxide production was determined by fluorescence spectrometry.
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We evaluated the effect of physical training on the cardiovascular responses produced by angiotensin peptides at the rostroventrolateral medulla (RVLM) of non-anesthetized normotensive rats. The RVLM pressor effect induced by Ang II was significantly greater in trained rats, while, in contrast, the Ang-(1-7) pressor effect was significantly smaller in trained in comparison to sedentary rats. In addition, the RVLM microinjection of Losartan (AT1 Ang II receptor antagonist) or A-779 (Ang-(1-7) receptor antagonist) induced opposite effect in trained rats. These results show that exercise training induces a differential RVLM responsiveness to Ang peptides, which was corroborated by the selective antagonists, indicating that the RVLM is a site in the central nervous system involved in the adaptive mechanisms triggered during exercise training.
Interleukin (IL)-6 is an autocrine growth factor for mesangial cells. It is not known whether high glucose influences IL-6 production in mesangial cells. Angiotensin II (AGII) is involved in the progression of renal diseases including diabetic nephropathy. Therefore, we evaluated the effects of high glucose in concert with AGII on IL-6 production in human mesangial cells and the modulation by blocking AGII. After 48 hr of culture, IL-6 mRNA expression was analyzed by reverse transcription and polymerase chain reaction (PCR). Quantitative determination of IL-6 concentrations in the culture supernatants of mesangial cells was performed using a sandwich enzyme immunoassay kit. Incubation of mesangial cells with high glucose (450 mg/dL) reduced the ratio of PCR products for IL-6 to beta-actin on densitometric results, while AGII (10(-7)M) increased it. The IL-6 secretion in the supernatant was also increased by AGII and decreased by high glucose. The IL-6 mRNA expression and IL-6 secretion in combination of high glucose and AGII were higher than those in high glucose and similar with those in control media. The addition of losartan (10(-6)M) or captopril (10(-6)M) to high glucose had no additional effects on IL-6 production. These results suggest that whereas AGII increases IL-6 production, high glucose decreases it. The IL-6 production of mesangial cells in diabetic milieu may be complicated and depend on the local effects of high glucose and/or AGII.
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Diabetic subjects have a high prevalence of hypertension, increased total body exchangeable sodium levels, and an impaired ability to excrete a sodium load. This study assessed the effect of dietary sodium restriction on the efficacy of losartan in hypertensive subjects with type 2 diabetes and albumin excretion rates of 10-200 microg/min.