ABSTRACT
In this work photo-electro-Fenton (PEF) processes using a dimensionally stable anode-gas diffusion electrode (DSA-GDE) system under light emission diodes (LED)-type radiation were used in the degradation of the angiotensin-II-receptor antagonists (ARA II), valsartan (VAL), and losartan (LOS), which are used in the treatment of hypertension diseases, and are considered among the emerging contaminants (ECs). Organic acids as citric, tartaric, and oxalic acids were used as complexing agents of iron ions in order to maintain the performance of the Fenton reaction at near-neutral pH value. The results show that at 3.42 mA/cm2 after 90 min of electro-Fenton (EF) treatment, degradation of 70% of VAL and 100% of LOS were observed. Total degradation of VAL and LOS was reached with a PEF process at the same time with mineralization of 30%. When citric and tartaric acids were used instead of oxalic acid, similar results were obtained, i.e., total degradation of both compounds, LOS and VAL, after 90 min of treatment. The degradation performance can be attributed to the increase of the initial dissolved iron in the system, facilitating the Fe3+/Fe2+ turnover in the catalytic photo-Fenton reaction and consequently, hydroxyl radical (â¢OH) production. In addition, the increased photo-activity of the complexes can be associated with their high capability to complex Fe3+ and to promote ligand-to-metal charge transfer, which is of key importance to feed Fe2+ to the Fenton process. The results show that the system evaluated was more efficient to eliminate sartan family compounds using LED lighting in comparison with traditional UV-A lamps used in this kind of work. Moreover, three transformation products of VAL degradation and two transformation products of LOS degradation were identified by high-resolution mass spectrometry (HRMS) using hybrid quadrupole-time-of-flight (QTOF) MS and, at the end of the PEF system, the several organic compounds accumulated and no mineralized were effectively treated in a subsequent aerobic biological system.
Subject(s)
Electrodes , Losartan/chemistry , Valsartan/chemistry , Water Pollutants, Chemical/chemistry , Antihypertensive Agents/chemistry , Antihypertensive Agents/metabolism , Biodegradation, Environmental , Citric Acid/chemistry , Diffusion , Hydrogen Peroxide/chemistry , Hydrogen-Ion Concentration , Hydroxyl Radical/chemistry , Iron/chemistry , Lighting/instrumentation , Lighting/methods , Losartan/metabolism , Oxidation-Reduction , Tartrates/chemistry , Valsartan/metabolism , Water Pollutants, Chemical/metabolismABSTRACT
BACKGROUND AND OBJECTIVE: The angiotensin type 1 (AT1) receptor has been implicated in the pathogenesis of inflammatory bone disorders. This study aimed to investigate the effect of an AT1 receptor antagonist in infection-induced and arthritis-associated alveolar bone loss in mice. MATERIAL AND METHODS: Mice were subjected to Aggregatibacter actinomycetemcomitans oral infection or antigen-induced arthritis and treated daily with 10 mg/kg of the prototype AT1 antagonist, losartan. Treatment was conducted for 30 d in the infectious condition and for 17 d and 11 d in the preventive or therapeutic regimens in the arthritic model, respectively. The mice were then killed, and the maxillae, serum and knee joints were collected for histomorphometric and immunoenzymatic assays. In vitro osteoclast assays were performed using RAW 264.7 cells stimulated with A. actinomycetemcomitans lipopolysacharide (LPS). RESULTS: Arthritis and A. actinomycetemcomitans infection triggered significant alveolar bone loss in mice and increased the levels of myeloperoxidase and of TRAP(+) osteoclasts in periodontal tissues. Losartan abolished such a phenotype, as well as the arthritis joint inflammation. Both arthritis and A. actinomycetemcomitans conditions were associated with the release of tumor necrosis factor alpha (TNF-α), interferon-gamma, interleukin-17 and chemokine (C-X-C motif) ligand 1 and an increased RANKL/osteoprotegerin ratio in periodontal tissues, but such expression decreased after losartan treatment, except for TNF-α. The therapeutic approach was as beneficial as the preventive one. In vitro, losartan prevented LPS-induced osteoclast differentiation and activity. CONCLUSION: The blockade of AT1 receptor exerts anti-inflammatory and anti-osteoclastic effects, thus protecting periodontal tissues in distinct pathophysiological conditions of alveolar bone loss.
Subject(s)
Alveolar Bone Loss/prevention & control , Anti-Inflammatory Agents/metabolism , Arthritis/complications , Losartan/metabolism , Pasteurellaceae Infections/complications , Receptor, Angiotensin, Type 1/metabolism , Aggregatibacter actinomycetemcomitans/pathogenicity , Animals , Arthritis/microbiology , Histocytochemistry , Knee Joint/pathology , Male , Maxilla/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Pasteurellaceae Infections/microbiology , RAW 264.7 Cells/drug effects , Serum/chemistryABSTRACT
To investigate the influence of central angiotensin AT1-receptors blockade on metabolic adjustments during graded exercise, Losartan (Los) was intracerebroventricularly injected in rats before running until fatigue. Oxygen consumption (VO2) was measured (n=6) and blood samples collected (n=7) to determine variations of glucose, lactate and free fatty acids (FFA). Los-rats exhibited a hyperglycemic response, already observed at 20% of maximal work, followed by a higher lactate levels and FFA mobilization from adipose tissue. Despite the reduced total time to fatigue and the higher VO2 associated with reduced mechanical efficiency, exercise led to the attainment of similar levels of effort in both groups. In summary, central AT1-receptor blockade during graded exercise induces hyperglycemia and higher FFA mobilization from adipose tissue at low exercise intensities in rats running at the same absolute exercise intensity. These data suggest that the central angiotensinergic system is involved in metabolic adjustments during exercise since central blockade of AT1-receptors shifts energy balance during graded exercise, similarly to situations of higher and premature sympathetic activation.
Subject(s)
Energy Metabolism , Oxygen Consumption/physiology , Physical Conditioning, Animal/physiology , Receptor, Angiotensin, Type 1/metabolism , Angiotensin II Type 1 Receptor Blockers/metabolism , Animals , Blood Glucose/metabolism , Fatty Acids, Nonesterified/blood , Lactic Acid/blood , Losartan/metabolism , Male , Random Allocation , Rats , Rats, Wistar , Running/physiologyABSTRACT
Losartan, the potassium salt of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazol, is an efficient antihypertensive drug. The vibrational FTIR and Raman spectra of Losartan (its anionic and protonated forms) are discussed. In addition, the copper(II) complex of Losartan was obtained and characterized as a microcrystalline powder. The metal center is bound to the ligand through the nitrogen atoms of the tetrazolate moiety as determined by vibrational spectroscopy. The compound is a dimer with the metal centers in a tetragonal distorted environment but the presence of a monomeric impurity has been determined by EPR spectroscopy. The antioxidant properties of the complex (superoxide dismutase mimetic activity) and its effect on the proliferation and morphology of two osteoblast-like cells in culture are reported. The new compound exerted more toxic effects on tumoral cells than the copper(II) ion and Losartan.
Subject(s)
Antihypertensive Agents/pharmacology , Cell Proliferation/drug effects , Copper/metabolism , Losartan/metabolism , Tetrazoles/metabolism , Animals , Antioxidants/pharmacology , Binding, Competitive , Cations, Divalent , Copper/chemistry , Disease Models, Animal , Electron Spin Resonance Spectroscopy , Ligands , Losartan/chemistry , Osteoblasts/cytology , Osteoblasts/metabolism , Osteoblasts/pathology , Rats , Spectroscopy, Fourier Transform Infrared , Spectrum Analysis, Raman , Structure-Activity Relationship , Superoxide Dismutase/metabolism , Tetrazoles/chemistry , Tumor Cells, CulturedABSTRACT
Angiotensin (Ang)-(1-7) is an endogenous peptide hormone of the renin-angiotensin system which exerts diverse biological actions, some of them counterregulate Ang II effects. In the present study potential effect of Ang-(1-7) on phosphoinositide (PI) turnover was evaluated in neonatal rat brain. Cerebral cortex prisms of seven-day-old rats were preloaded with [(3)H]myoinositol, incubated with additions during 30 min and later [(3)H]inositol-phosphates (IPs) accumulation quantified. It was observed that PI hydrolysis enhanced 30% to 60% in the presence of 0.01 nM to 100 nM Ang-(1-7). Neither 10 nM [D-Ala(7)]Ang-(1-7), an Ang-(1-7) specific antagonist, nor 10 nM losartan, an angiotensin II type 1 (AT(1)) receptor antagonist, blocked the effect of 0.1 nM Ang-(1-7) on PI metabolism. The effect of 0.1 nM Ang-(1-7) on PI hydrolysis was not reduced but it was even significantly increased in the simultaneous presence of [D-Ala(7)]Ang-(1-7) or losartan. PI turnover enhancement achieved with 0.1 nM Ang-(1-7) decreased roughly 30% in the presence of 10 nM PD 123319, an angiotensin II type 2 (AT(2)) receptor antagonist. The antagonists alone also enhanced PI turnover. Present findings showing an increase in PI turnover by Ang-(1-7) represent a novel action for this peptide and suggest that it exerts a function in this signaling system in neonatal rat brain, an effect involving, at least partially, angiotensin AT(2) receptors.
Subject(s)
Angiotensin I/metabolism , Cerebral Cortex/metabolism , Peptide Fragments/metabolism , Phosphatidylinositols/metabolism , Angiotensin I/pharmacology , Angiotensin II Type 1 Receptor Blockers/metabolism , Animals , Animals, Newborn , Antihypertensive Agents/metabolism , Cerebral Cortex/drug effects , Female , Hydrolysis/drug effects , Losartan/metabolism , Losartan/pharmacology , Male , Peptide Fragments/pharmacology , Rats , Rats, Inbred BB , Signal Transduction/drug effects , Signal Transduction/physiologyABSTRACT
OBJECTIVE: The LOTHAR study evaluated medium and long term (one year) efficacy, tolerability and metabolic effects of the fixed combination of amlodipine and losartan compared to amlodipine or losartan alone. METHODS: Brazilian multicenter, randomized, double-blind and comparative trial performed with 198 patients in stage 1 and 2 essential hypertension. RESULTS: The fixed combination has a high antihypertensive efficacy that is sustained in the long term with very low percentage of loss of blood pressure control. This percentage is incidentally lower than that of the two monotherapy comparative regimens. In the long term, more than 60% of the patients treated with the fixed combination remained with DBP < or = 85 mmHg, and the antihypertensive effect, when assessed by ABPM persisted for 24 hours with a trough-to-peak ratio of 76.7%. The frequency of adverse events was quite low in this group, and the long-term incidence of leg edema was approximately four-fold lower than that observed with amlodipine alone. The fixed combination did not change glucose and lipid metabolism in the medium or in the long term. CONCLUSION: Based on these results, we can say that the combination of amlodipine and losartan--the first fixed combination of a calcium channel blocker and an angiotensin II receptor blocker available in the pharmaceutical market, is an excellent option for the treatment of a wide range of hypertensive patients.
Subject(s)
Amlodipine/administration & dosage , Antihypertensive Agents/administration & dosage , Hypertension/drug therapy , Losartan/administration & dosage , Adult , Aged , Amlodipine/adverse effects , Amlodipine/metabolism , Antihypertensive Agents/adverse effects , Antihypertensive Agents/metabolism , Blood Pressure Monitoring, Ambulatory , Chi-Square Distribution , Double-Blind Method , Drug Therapy, Combination , Female , Glucose/metabolism , Humans , Hypertension/metabolism , Hypertension/physiopathology , Lipid Metabolism , Losartan/adverse effects , Losartan/metabolism , Male , Middle Aged , Statistics, Nonparametric , Time FactorsABSTRACT
OBJETIVO: O estudo LOTHAR avaliou a eficácia, tolerabilidade e os efeitos metabólicos em médio e longo prazo (um ano) da combinação fixa de anlodipino e losartana versus anlodipino e losartana isoladamente. MÉTODOS: Estudo multicêntrico brasileiro, randomizado, duplo-cego e comparativo realizado com 198 pacientes com hipertensão arterial primária em estágios 1 e 2. RESULTADOS: A combinação fixa apresenta alta eficácia anti-hipertensiva que se mantém em longo prazo com percentual reduzido de escape do controle pressórico, inferior a dos dois regimes monoterápicos de comparação. Em longo prazo, mais de 60 por cento dos pacientes tratados com a combinação fixa permaneceram com níveis da PAD < 85 mmHg e o efeito anti-hipertensivo quando avaliado pela MAPA persistiu nas 24 horas com relação vale-pico de 76,7 por cento. A freqüência de eventos adversos foi bastante reduzida neste grupo sendo a incidência em longo prazo de edema de membros inferiores cerca de quatro vezes menor que a observada com o anlodipino isolado. A combinação fixa não alterou os metabolismos da glicose e dos lípides tanto em médio quanto em longo prazos. CONCLUSAO: Estes resultados nos permitem afirmar que a combinação de anlodipino e losartana, a primeira combinação fixa de um antagonista dos canais de cálcio e um bloqueador do receptor da angiotensina II disponível no mercado farmacêutico constitui-se em excelente opção para o tratamento da hipertensão arterial em larga gama de pacientes hipertensos.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Amlodipine/administration & dosage , Antihypertensive Agents/administration & dosage , Hypertension/drug therapy , Losartan/administration & dosage , Amlodipine/adverse effects , Amlodipine/metabolism , Antihypertensive Agents/adverse effects , Antihypertensive Agents/metabolism , Blood Pressure Monitoring, Ambulatory , Chi-Square Distribution , Double-Blind Method , Drug Combinations , Drug Therapy, Combination , Glucose/metabolism , Hypertension/metabolism , Hypertension/physiopathology , Lipid Metabolism , Losartan/adverse effects , Losartan/metabolism , Statistics, Nonparametric , Time FactorsABSTRACT
We determined the effects of losartan and CGP42112A (selective ligands of the AT1 and AT2 angiotensin receptors, respectively) and salarasin (a relatively nonselective angiotensin receptor antagonist) on urinary volume and urinary sodium and potassium excretion induced by administration of angiotensin II (ANG II) into the paraventricular nucleus (PVN) of conscious rats. Both the AT1 and AT2 ligands and salarasin administered in the presence of ANG II elicited a concentration-dependent inhibition of urine excretion, but losartan inhibited only 75% of this response. The IC50 for salarasin, CGP42112A, and losartan was 0.01, 0.05, and 6 nM, respectively. Previous treatment with saralasin, CGP42112A and losartan competitively antagonized the natriuretic responses to PVN administration of ANG II, and the IC50 values were 0.09, 0.48, and 10 nM, respectively. The maximum response to losartan was 65% of that obtained with saralasin. Pretreatment with saralasin, losartan, and CGP42112A injected into the PVN caused shifts to the right of the concentration-response curves, but the losartan concentrations were disproportionately greater compared with salarasin or CGP42112A. The IC50 values were 0.06, 0.5, and 7.0 for salarasin, CGP42112A, and losartan, respectively. These results suggest that both AT1 and AT2 receptor subtypes in the PVN are involved in ANG II-related urine, sodium, and potassium excretion, and that the inhibitory responses to AT2 blockade are predominant.