RESUMO
BACKGROUND & AIM: Congestive heart failure (CHF) and anemia were reported to affect resting energy expenditure (REE). The aim of this study was to evaluate the effect of the correction of anemia on REE in subjects with CHF. PATIENTS AND METHODS: Nine anemic patients with compensated CHF and CRF were studied before and after correction of anemia. REE was studied by an open circuit indirect calorimeter, body composition by dual-energy-X-ray absorption and total body and extracellular water by multi-frequency bioelectrical impedence. Four anemic and 5 non-anemic CHF patients who did not receive any new treatment served as controls. RESULTS: After the correction of their anemia patients tended to increase weight (P<0.06), but no significant changes were observed in body composition. Daily caloric intake increased significantly (P<0.02). Ejection fraction increased (P<0.05) and pulse rate decreased significantly (P<0.001). REE and REEPP were in the normal range before correction but increased significantly afterwards (1402+/-256 vs. 1496+/-206 kcal/d, and 101+/-9 vs. 109+/-8, P<0.023 and P<0.006, respectively). CONCLUSION: Correction of anemia in patients with CHF increases their REE. This can be related either to improved tissue oxygenation and/or to increased caloric intake.
Assuntos
Anemia/metabolismo , Metabolismo Basal/fisiologia , Composição Corporal/fisiologia , Ingestão de Energia , Insuficiência Cardíaca/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anemia/complicações , Anemia/terapia , Calorimetria Indireta , Impedância Elétrica , Eritropoetina/uso terapêutico , Feminino , Insuficiência Cardíaca/complicações , Humanos , Ferro/administração & dosagem , Ferro/uso terapêutico , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Aumento de PesoRESUMO
BACKGROUND: Growing evidence suggests that inducible nitric oxide synthase (iNOS) is the main source of the high output of exhaled nitric oxide (NO) in asthma. Treatment of asthmatic patients with glucocorticoids reduces high levels of exhaled NO mainly by inhibiting the transcription of iNOS. A similar reduction in exhaled NO was recently observed in patients treated with the leukotriene receptor antagonists, but the exact interaction between these drugs and iNOS remains obscure. OBJECTIVE: The purpose of this study was to evaluate the effect of a leukotriene receptor antagonist, montelukast, on the expression and activity of iNOS in a murine model of allergic asthma. METHODS: Twenty-four BALB/c mice were sensitized to OVA and were equally divided into 3 groups (Groups 1-3). Eight additional mice were sham sensitized and served as a negative control group (Group 4). Group 1 received montelukast 1 mg/kg/day in their drinking water, Group 2 received dexamethasone 1 mg/kg/day in their drinking water and Groups 3 and 4 received plain tap water. After 1 week, the animals were challenged by inhalation of OVA and, 3 h later, they were killed and their lung cells were isolated by enzymatic tissue digestion. NO generation was measured by a Griess assay, and iNOS mRNA was studied by RT-PCR. RESULTS: A significant increase in iNOS mRNA expression and in NO generation was evident after allergen challenge compared with the controls. Pretreatment with montelukast mildly decreased NO production without producing a concomitant significant decrease in iNOS mRNA expression. CONCLUSION: Unlike pretreatment with glucocorticoids, we failed to find compelling evidence for a major role for montelukast treatment in the modulation of iNOS mRNA in a murine model of acute asthma.
Assuntos
Acetatos/uso terapêutico , Asma/metabolismo , Antagonistas de Leucotrienos/uso terapêutico , Pulmão/enzimologia , Óxido Nítrico Sintase/genética , Quinolinas/uso terapêutico , RNA Mensageiro/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Antígenos , Ciclopropanos , Dexametasona/uso terapêutico , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Nitratos/análise , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II , Nitritos/análise , Testes Cutâneos , SulfetosRESUMO
The offspring of coronary heart disease (CHD) patients are at particularly high risk for developing CHD. Endothelial dysfunction is present in the majority of CHD and atherosclerosis patients. Fish oil, rich in n-3 fatty acids has been shown to augment endothelium-dependent vasodilatation in human peripheral and coronary arteries. The aims of this study are to investigate presence of endothelial dysfunction determined by the brachial flow-mediated diameter, nitric oxide, plasma lipids and fibrinogen, and the effect of high doses of fish oil on these parameters. Twenty-four healthy offspring of CHD patients (study group) were supplemented with 9 g/day Alsepa fish oil (each gram containing 180 mg EPA and 120 mg DHA), for a period of two weeks. Plasma nitric oxide, urine nitric oxide, fibrinogens and flow-mediated vasodilatation (FMD) were determined prior to fish oil therapy, two weeks into therapy and four weeks after the end of therapy with fish oil. Twelve healthy subjects (control group) with no family history of heart disease were studied as controls (day one only). The offspring had a lower increase in FMD and lower nitric oxide production, compared with the control group. No other parameters varied between the two groups. The administration of fish oil did not result in any changes in the studied parameters. In healthy offspring of CHD patients, early endothelial dysfunction was documented before evidence of atherosclerosis. Ingestion of fish oil over a 13-day period did not improve endothelial dysfunction.
Assuntos
Endotélio Vascular/fisiopatologia , Óleos de Peixe/farmacologia , Isquemia Miocárdica/genética , Óxido Nítrico/biossíntese , Adulto , Artéria Braquial/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/prevenção & controle , Vasodilatação/efeitos dos fármacosRESUMO
Anemia (Hemoglobin of < 12 to 13 g/dl) is frequently encountered in patients with congestive heart failure (CHF). This anemia may be partly due to hemodilution, partly to the associated reduction in renal function, and partly to the use of ACE inhibitors and aspirin. However, there is evidence that CHF alone--through excessive cytokine production may also reduce the bone marrow and cause anemia. In several recent studies anemia has been found to be associated with a more severe degree of CHF, a higher rate of death, renal failure, hospitalization and evidence of malnutrition. In both uncontrolled and controlled studies correction of anemia with erythropoietin with or without the addition of i.v. iron has been attempted. The correction of anemia has been associated with a marked improvement in New York Heart Association (NYHA) functional cardiac class and Left Ventricular Ejection Fraction, a marked reduction in the need for hospitalization and high dose oral and i.v. diuretics, and an improvement in exercise capacity, peak exercise oxygen utilization and quality of life. The serum creatinine, which had been increasing steadily before treatment, stabilized with the correction of anemia. All this suggests that control of anemia in CHF could become a valuable addition to the therapeutic armamentarium of CHF and might also play a major role in the prevention of progressive renal failure.
Assuntos
Anemia/complicações , Anemia/terapia , Insuficiência Cardíaca/complicações , Hospitalização , Nefropatias/complicações , Falência Renal Crônica/prevenção & controle , Anemia/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Nefropatias/fisiopatologia , Nefropatias/terapia , Falência Renal Crônica/fisiopatologia , SíndromeRESUMO
Anemia is seen in chronic kidney insufficiency (CKI), dialysis patients, congestive heart failure (CHF), and renal transplantation. Anemia can lead to progressive cardiac damage as well as progressive renal damage. It is not generally appreciated that CHF itself may be a very common contributor to both the production of anemia as well as to the progression of the renal failure. Correction of the anemia with erythropoietin and, as necessary, intravenous iron, may prevent the deterioration of both the heart and the kidneys. We suggest that there is a triangular relationship, a vicious circle, between CHF, CKI and anemia where each of these three can both cause and be caused by the other. We call this syndrome the cardio-renal anemia (CRA) syndrome. All physicians, especially cardiologists and internists who treat CKI and CHF, should be made aware of the dangers of anemia in CKI and CHF and should work with nephrologists to correct it.
Assuntos
Anemia/etiologia , Insuficiência Cardíaca/complicações , Falência Renal Crônica/complicações , Anemia/terapia , Eritropoetina/uso terapêutico , Insuficiência Cardíaca/terapia , Humanos , Ferro/uso terapêutico , Falência Renal Crônica/terapiaRESUMO
BACKGROUND: Contrast media (CM) are nephrotoxic and might further worsen renal function in patients with chronic renal failure. L-Arginine, the substrate of nitric oxide, protects kidney function and may improve endothelial function in patients with coronary artery disease. HYPOTHESIS: Acute administration of L-arginine in a subset of patients with combined coronary artery disease and impaired kidney function during coronary angiography might prevent superimposed acute renal failure. METHODS: A double-blind study of patients with mild/moderate chronic renal failure (Cr >1.7 mg/dl) undergoing coronary angiography (meglumine ioxaglate) was conducted. Patients received either L-arginine (300 mg/kg) or placebo and were followed for 48 h. Cardiac hemodynamic parameters, renal function and nitric oxide production were sequentially recorded. RESULTS--PRIMARY AND SECONDARY: Both groups experienced a decrease of creatinine clearance 48 h following the procedure (p < 0.05). Creatinine levels slightly increased following the administration of L-arginine (p < 0.05) but not in the placebo treated group. No changes of systemic and cardiac pressures, total peripheral resistance or cardiac output were recorded within and between the treatment and placebo groups. CONCLUSION: CM injection causes an impairment of renal function. Addition of intravenous L-arginine during cardiac catheterizations in patients with chronic renal failure does not prevent CM-induced nephrotoxicity and does not affect endothelial dysfunction in the particular population studied by the authors, i.e. patients with coronary artery disease (CAD) of various degrees, or suspicion of CAD and chronic mild renal failure.
Assuntos
Injúria Renal Aguda/prevenção & controle , Arginina/uso terapêutico , Meios de Contraste/efeitos adversos , Doença da Artéria Coronariana/complicações , Falência Renal Crônica/complicações , Injúria Renal Aguda/induzido quimicamente , Idoso , Análise de Variância , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Angiografia Coronária/efeitos adversos , Doença da Artéria Coronariana/fisiopatologia , Creatinina/sangue , Creatinina/urina , Método Duplo-Cego , Feminino , Humanos , Injeções Intravenosas , Falência Renal Crônica/fisiopatologia , Masculino , Óxido Nítrico/sangue , Óxido Nítrico/urina , Resistência Vascular/efeitos dos fármacosRESUMO
Both Congestive Heart Failure (CHF) and Chronic Renal Failure (CRF) are increasing steadily in the community. We propose that there is a vicious circle established whereby CHF and CRF both cause anemia and the anemia then worsens both the CHF and CRF causing more anemia and so on. We call this the Cardio Renal Anemia (CRA) syndrome. By the combination of active treatment of the CHF and control of the anemia with subcutaneous erythropoietin and intravenous iron, the progression of both the CHF and the CRF can be slowed or stopped in most cases, the quality of life improved and the need for recurrent hospitalization reduced. This will involve cooperation between internists, cardiologists, and nephrologists to allow early and maximal therapy of both the CHF and the anemia.
Assuntos
Anemia/tratamento farmacológico , Eritropoetina/administração & dosagem , Compostos Férricos/administração & dosagem , Insuficiência Cardíaca/complicações , Falência Renal Crônica/complicações , Idoso , Anemia/complicações , Progressão da Doença , Quimioterapia Combinada , Feminino , Óxido de Ferro Sacarado , Ácido Glucárico , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Hospitalização , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Falência Renal Crônica/terapia , Masculino , Consumo de Oxigênio , Proteínas Recombinantes , Volume SistólicoRESUMO
BACKGROUND: We investigated the role of tumor necrosis factor alpha (TNF-alpha) in protamine-induced cardiotoxicity and the possibility of preventing or decreasing this effect by anti TNF-alpha antibodies and heparin. METHODS: Isolated rat hearts were perfused for 60 min with Krebs-Henseleit solution (KH). The control group was perfused with KH alone, the KH > protamine > KH group was treated from the 20th to the 40th minute with protamine, and the KH + anti-TNF > protamine + anti-TNF > KH + anti-TNF group was treated the same as the KH > protamine > KH group but with anti-TNF-alpha antibodies added throughout perfusion. The KH + heparin > protamine + heparin > KH + heparin group was treated the same as the KH > protamine > KH group but with heparin added to KH throughout perfusion. The KH > protamine > KH + heparin was perfused the same as the KH> protamine > KH group but with heparin added to KH for the last 20 min. Left ventricular (LV) function and coronary flow were measured every 10 min. TNF-alpha was measured in the coronary sinus effluent. Left ventricular TNF messenger RNA was determined in the control and KH > protamine > KH groups at baseline and after the 40-min perfusion. RESULTS: Protamine caused a significant decrease of peak systolic pressure and dP/dt (to 25% of baseline). Significant amounts of TNF-alpha in the effluent in the KH > protamine > KH group (102.3 +/- 15.5 pg/min) and TNF messenger RNA expression in left ventricular samples were detected. TNF-alpha was below detectable concentrations in the control, KH + anti-TNF > protamine + anti-TNF > KH + anti-TNF, and KH + heparin > protamine + heparin > KH + heparin groups. TNF-alpha concentrations correlated with depression of LV peak systolic pressure (r = 0.984; P = 0.01) and first derivate of the increase of LV pressure (r = 0.976; P = 0.001). Heparin improved LV recovery and decreased protamine-induced TNF-alpha release (KH > protamine > KH + heparin group). CONCLUSIONS: Anti-TNF-alpha antibodies and heparin prevent protamine-induced TNF-alpha release and depression of LV function. Heparin improves protamine-induced depression of cardiac function.
Assuntos
Anticorpos Bloqueadores/uso terapêutico , Anticoagulantes/uso terapêutico , Cardiopatias/prevenção & controle , Antagonistas de Heparina/toxicidade , Heparina/uso terapêutico , Protaminas/toxicidade , Fator de Necrose Tumoral alfa/imunologia , Animais , Cardiopatias/induzido quimicamente , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Masculino , Protaminas/antagonistas & inibidores , RNA Mensageiro/biossíntese , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/biossínteseRESUMO
UNLABELLED: Nitric oxide (NO), generated by inducible nitric oxide synthase (NOS) following lipopolysaccharide (LPS) administration, produces renal failure through autoinhibition of glomerular endothelial NOS activity. Preadministration of selective iNOS inhibitors abolishes this effect. Although nonselective NOS inhibitors further decrease GFR, current clinical trials investigate the effect of nonselective NOS inhibition in septic patients. The goals of our study were to determine whether treatment with selective NOS inhibitors can reverse the decrease in GFR in LPS treated rats with already established renal failure and to define the outcome of LPS treated rats following nonselective NOS inhibition. Four hours following the administration of LPS (4 mg/kg), we measured creatinine clearance (CrCl) before and after the administration of either L-NIL (selective iNOS inhibitor, 3 mg every 20 minutes) or saline. Selective iNOS inhibition attenuated the decrease in blood pressure [ CONTROLS: 105 +/- 6 to 98 +/- 5, LPS: 92 +/- 5* to 83 +/- 4*, LPS + L-NIL: 88 +/- 6* to 94 +/- 6 mm Hg; *p < 0.05, vs controls (n = 6)], and reversed the decrease in GFR after LPS [ CONTROLS: 2.21 +/- 0.13 to 2.07 +/- 0.11, LPS: 0.82 +/- 0.18* to 0.66 +/- 0.22*, LPS + L-NIL: 0.76 +/- 0.15* to 1.86 +/- 0.15 ml/min; *p < 0.05 vs controls (n = 6)]. We next studied the effect of complete non-selective NOS inhibition (L-NAME 200 mg, 2 hours after LPS) on LPS treated rats. All (6/6) animals treated with both LPS and L-NAME died within 2 hours following LPS, while rats treated with either LPS, L-NAME, or LPS + L-NIL survived. Histologic studies performed in all experimental groups were unremarkable. Overnight mortality was studied using smaller doses of L-NAME. All LPS + L-NAME (10/10) and 1/10 LPS treated rats died. L-NAME, control, and LPS + L-NIL animals survived. The characteristic histologic findings in LPS + L-NAME rats were diffuse ischemic changes, most importantly acute myocardial infarction. IN CONCLUSION: Selective iN-OS inhibition might prove to have clinical application as it prevents the decrease in GFR following LPS, even after renal failure is established. Treatment with a non selective NOS inhibitor in septic patients should be reconsidered.
Assuntos
Lipopolissacarídeos/farmacologia , Óxido Nítrico Sintase/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/farmacologia , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/mortalidade , Análise de Variância , Animais , Modelos Animais de Doenças , Interações Medicamentosas , Masculino , Probabilidade , Ratos , Ratos Wistar , Valores de Referência , Análise de SobrevidaRESUMO
OBJECTIVES: This is a randomized controlled study of anemic patients with severe congestive heart failure (CHF) to assess the effect of correction of the anemia on cardiac and renal function and hospitalization. BACKGROUND: Although mild anemia occurs frequently in patients with CHF, there is very little information about the effect of correcting it with erythropoietin (EPO) and intravenous iron. METHODS: Thirty-two patients with moderate to severe CHF (New York Heart Association [NYHA] class III to IV) who had a left ventricular ejection fraction (LVEF) of < or =40% despite maximally tolerated doses of CHF medications and whose hemoglobin (Hb) levels were persistently between 10.0 and 11.5 g% were randomized into two groups. Group A (16 patients) received subcutaneous EPO and IV iron to increase the level of Hb to at least 12.5 g%. In Group B (16 patients) the anemia was not treated. The doses of all the CHF medications were maintained at the maximally tolerated levels except for oral and intravenous (IV) furosemide, whose doses were increased or decreased according to the clinical need. RESULTS: Over a mean of 8.2+/-2.6 months, four patients in Group B and none in Group A died of CHF-related illnesses. The mean NYHA class improved by 42.1% in A and worsened by 11.4% in B. The LVEF increased by 5.5% in A and decreased by 5.4% in B. The serum creatinine did not change in A and increased by 28.6% in B. The need for oral and IV furosemide decreased by 51.3% and 91.3% respectively in A and increased by 28.5% and 28.0% respectively in B. The number of days spent in hospital compared with the same period of time before entering the study decreased by 79.0% in A and increased by 57.6% in B. CONCLUSIONS: When anemia in CHF is treated with EPO and IV iron, a marked improvement in cardiac and patient function is seen, associated with less hospitalization and renal impairment and less need for diuretics.
Assuntos
Anemia/complicações , Anemia/tratamento farmacológico , Eritropoetina/administração & dosagem , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Ferro/administração & dosagem , Idoso , Feminino , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Masculino , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: The purpose of this study is to assess the role of the nitric oxide (NO) pathway in protamine-induced cardiotoxicity and to formulate a possible explanation for this adverse effect. METHODS: Isolated rat hearts were perfused by Krebs--Henseleit (KH) solution using a modified Langendorff model. They were randomized into three groups: A, 40 min perfusion with KH solution; B, 20 min perfusion with KH solution and 20 min with protamine; C, as B but Ng-monomethyl-L-arginine (L-NMMA), a non-selective inhibitor of the NO pathway, was added during 40 min of the perfusion period. Left ventricular (LV) function was measured every 10 min. NO and tumor necrosis factor-alpha (TNF) were detected in the effluent from the coronary sinus (CS) and in the supernatant of the cardiac myocytes culture. Nitric oxide synthases (NOS) mRNA levels were determined in groups A and B from LV samples at baseline and after 40 min of perfusion. RESULTS: We found that protamine at a dose of 12 microg/ml causes significant depression of LV function (decreased peak systolic pressure to 22.5+/-3.2% and dP/dt max to 22.9+/-3.1%). L-NMMA did not prevent protamine cardiotoxicity. NOS mRNA was not detected from LV samples in any group. The NO in the effluent from the CS and from the supernatant of the cardiomyocytes culture was below detectable levels. However, a significant amount of TNF was measured in the effluent from the CS (108+/-17 pg/min for group B and 117+/-13 pg/min for group C) and in the supernatant of the cardiomyocytes culture (65+/-21 pg/ml). CONCLUSIONS: This study suggests that direct protamine-induced cardiotoxicity does not depend on the NO pathway. Our finding that protamine induced TNF release by cardiomyocytes can shed new light on the understanding of protamine cardiotoxicity.
Assuntos
Coração/efeitos dos fármacos , Antagonistas de Heparina/toxicidade , Óxido Nítrico/metabolismo , Protaminas/toxicidade , Animais , Masculino , Miocárdio/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Perfusão , RNA Mensageiro/genética , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Many patients with chronic diseases such as chronic renal failure, chronic inflammatory bowel disease and rheumatoid arthritis are anaemic. Recently congestive heart failure (CHF) has also been found to be associated with anaemia. In all these diseases this anaemia or chronic disease is at least partially due to excessive production of cytokines and leukotrines that interfere both with the effect of erythropoietin (EPO) at the bone marrow and the release of stored iron in the reticuloendothelial system. Treating this anaemia with subcutaneous EPO and IV iron improves the weakness, fatigue, cachexia, nutritional state, mood, cognitive function and quality of life. In the case of CHF it also improves cardiac function and patient functional class, prevents deterioration of renal function and markedly reduces hospitalization. Very few agents in medicine improve so many aspects of the patient so well and so quickly. Unfortunately (for the suffering patient) this anaemia is often ignored and goes untreated.
Assuntos
Anemia/complicações , Anemia/tratamento farmacológico , Baixo Débito Cardíaco/sangue , Baixo Débito Cardíaco/tratamento farmacológico , Doença Crônica , Eritropoetina/uso terapêutico , Humanos , Ferro/administração & dosagem , Ferro/uso terapêutico , Falência Renal Crônica/sangue , Falência Renal Crônica/tratamento farmacológico , Proteínas RecombinantesRESUMO
BACKGROUND: Plasma nitric oxide (NO) levels have been found to be high in haemodialysis (HD) patients, especially in those prone to hypotension in dialysis. The aim of the study was to prevent dialysis hypotension episodes by i.v. administration of methylene blue (MB), an inhibitor of NO activity and/or production. METHODS: MB was given i.v. in 18 stable HD patients with hypotensive episodes during almost every dialysis, in 18 HD patients without hypotension during dialyses, and in five healthy controls. MB was given as a bolus of 1 mg/kg bodyweight followed by a constant infusion of 0.1 mg/kg bodyweight lasting 210 min until the end of the dialysis session and only as a bolus on a non-dialysis day. Systolic and diastolic blood pressures (BP) were measured at 10-min intervals during HD sessions with or without MB and on a non-dialysis day with MB. RESULTS: In hypotension-prone patients, MB completely prevented the hypotension during dialysis and increased both systolic and diastolic BP on non-dialysis days. In normotensive patients, MB increased BP during the first hour of dialysis and for 90 min on the non-dialysis day. The BP in the healthy controls remained unchanged. Plasma and platelet NO(2)+NO(3) (stable metabolites of NO) levels were determined. The NO(2)+NO(3) generation rate in the first post-dialysis day was calculated. The plasma and platelet NO(2)+NO(3) were higher in the hypotensive group than in the normotensive dialysis group. The generation rate of nitrates was higher (P<0.01) in the hypotensive group (1.21+/-0.13 micromol/min and 0.74+/-0.16 after MB) than in the normotensive patients (0.61+/-0.11 micromol/ min and 0.27+/-0.14 after MB). No side-effects were recorded. CONCLUSIONS: MB is an efficient therapy in the prevention of dialysis hypotension.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipotensão/etiologia , Hipotensão/prevenção & controle , Falência Renal Crônica/terapia , Azul de Metileno/uso terapêutico , Diálise Renal/efeitos adversos , Adulto , Idoso , Plaquetas/fisiologia , Diástole/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Azul de Metileno/farmacologia , Pessoa de Meia-Idade , Nitratos/sangue , Óxido Nítrico/antagonistas & inibidores , Nitritos/sangue , Sístole/efeitos dos fármacos , Fatores de TempoRESUMO
Tetrahydrobiopterin (BH4) has been shown to be required for dimerization and acquisition of nitric oxide (NO) generating capacity by nitric oxide synthase (NOS). In the present study we have investigated the hypothesis that BH4 may affect NOS activity through a novel mechanism-namely, modulating arginine transport in rat cardiac myocytes. Cardiac myocytes have been previously shown to express cationic amino acid transport proteins (y+ system) CAT-1 and CAT-2. Increasing extracellular BH4 concentrations up to 0.5 mmol/L augments arginine transport in 1 mmol/L arginine media (no BH4, 558 +/- 42 fmol arginine/microg protein/min; 0.1 mmol/L BH4, 580 +/- 11 fmol arginine/microg protein/min; 0.5 mmol/L BH4, 944 +/- 71* fmol arginine/microg protein/min; 1.0 mmol/L BH4, 983+/-84* fmol arginine/microg protein/min, n = 4; *: P <.05 vs no BH4). Treating the cells with lipopolysaccharide (LPS) (10 microg/mL) significantly augmented arginine transport only in the presence of BH4 (no BH4, 600 +/- 33 fmol arginine/microg protein/min; 0.1 mmol/L BH4, 691 +/- 29*dagger fmol arginine/microg protein/min; 0.5 mmol/L BH4, 1123 +/- 32*dagger fmol arginine/microg protein/min; 1.0 mmol/L BH4, 1296 +/- 42*dagger fmol arginine/microg protein/min, n = 4; *: P <.01 vs no BH4, dagger: P <.05 vs no LPS). The administration of biopterin, sodium nitroprusside (NO donor), 2,4-diamino-6-hydroxy-pyrimidine (inhibitor of BH4 synthesis), and sepiapterin (the precursor of de novo synthesis of BH4) to unstimulated cells had no effect on arginine uptake values. Using reverse trancriptase-polymerase chain reaction, we next studied the steady state levels for CAT-1 and CAT-2 mRNA. Incubation with BH4 significantly increased CAT-2 mRNA expression in a concentration-dependent manner in 0.1, 0.5, and 1 mmol/L BH4, respectively. Northern blotting analysis further confirmed this observation. We also found that in the presence of BH4 in these concentrations, CAT-1 mRNA expression was abolished. We suggest that BH4 augments intracellular arginine availability by modulating CAT-2 mRNA expression and suggest that its presence is required for the LPS effect on trans-membrane arginine traffic.
Assuntos
Arginina/metabolismo , Biopterinas/análogos & derivados , Biopterinas/farmacologia , Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Miocárdio/metabolismo , RNA Mensageiro/metabolismo , Sistemas de Transporte de Aminoácidos Básicos , Animais , Antioxidantes/farmacologia , Arginina/farmacocinética , Transporte Biológico/efeitos dos fármacos , Proteínas de Transporte/genética , Células Cultivadas , Relação Dose-Resposta a Droga , Espaço Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Proteínas de Membrana/genética , Miocárdio/citologia , Nitritos/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: It is now more and more evident that anemia of predialysis chronic renal failure (CRF) should be actively treated, since long-standing anemia may cause irremediable damage to the heart. The most common form of treatment of this anemia is subcutaneous erythropoietin (EPO). iron (Fe) deficiency can also contribute to anemia in predialysis CRF, and intravenous iron (i.v. Fe) can frequently improve it. It is possible, therefore, that the combination of EPO and i.v. Fe may have an additive effect, and cause a rapid improvement in anemia with relatively small doses of EPO. PURPOSE: The purpose of this study was an initial study: to assess the ability of a combination of low-dose EPO and i.v. Fe, given weekly for 5 doses, to correct the anemia of predialysis CRF patients compared to the use of i.v. Fe alone in a randomized study. In the follow-up study: to assess the ability of the maintenance of adequate iron stores for one year to achieve and maintain the target Hct of 35% with the minimum dose of EPO. Initial study: METHOD: Ninety predialysis CRF patients (creatinine clearance 10-40 ml/min/1.73 m2 received either: Group A (45 patients): 200 mg i.v. Fe as Fe sucrose (Venofer, Vifor Int.) once per week for 5 doses in combination with 2,000 international units (IU) EPO (Eprex, Cilag-Janssen), subcutaneously given simultaneously also for 5 doses. Group B (45 patients): the same dose of i.v. Fe as in Group A but without EPO. RESULTS: The mean increase in hematocrit (Hct) and hemoglobin (Hb) by one week after the last dose was greater in group A, 4.54 +/- 2.64% (p < 0.01) and 1.37 +/- 0.84 g% (p < 0.01), respectively, than in Group B, 2.74 +/- 2.72% (p < 0.05) and 0.91 +/- 0.78 g% (p < 0.05), respectively. 80% of those in Group A had an increase in Hct of 3 vol% or more compared to 48.9% in Group B (p < 0.01). 40% of those in Group A reached the target Hct of 35% compared to 28.9% in Group B (p > 0.05). Follow-up study: During a 12-month follow-up period, enough i.v. iron was given to maintain the Hct at 35%, while keeping the serum ferritin at < 400 ug/l and % Fe Sat at < 40%. If the i.v. Fe alone was not capable of maintaining the target Hct, EPO was given in increasing doses. Eighteen patients required dialysis. Of the 72 patients who did not require dialysis, 24 (33.3%) maintained the target Hct with i.v. Fe alone, without EPO. All the remaining 48 patients (66.7%) continued to receive EPO in addition to the i.v. Fe, and 47 achieved and maintained the target Hct with a mean EPO dose of 2,979 +/- 1,326 IU/week. CONCLUSION: The combination of low-dose EPO and i.v. Fe had a rapid and additive effect on the correction of anemia in CRF predialysis patients. Maintaining adequate iron stores with i.v. Fe during a subsequent maintenance phase allowed the target Hct of 35% to be reached and maintained with low-dose EPO in two-thirds of the predialysis patients and with no EPO at all in one-third.
Assuntos
Anemia/terapia , Eritropoetina/administração & dosagem , Compostos Férricos/administração & dosagem , Falência Renal Crônica/complicações , Diálise Renal , Sacarose/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/etiologia , Quimioterapia Combinada , Feminino , Óxido de Ferro Sacarado , Ferritinas/sangue , Ácido Glucárico , Hematócrito , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Proteínas RecombinantesRESUMO
OBJECTIVE: To evaluate the effect of aminoguanidine (AG) on de novo interleukin 1beta (IL1beta), nitric oxide (NO), and interleukin 1 receptor antagonist (IL1ra) production by osteoarthritic human synovial tissue and articular cartilage cultures. METHODS: Synovial tissue and cartilage, obtained during surgery from 29 patients undergoing total knee or hip replacement for osteoarthritis, were cut into small pieces and cultured in the presence or absence of lipopolysaccharide (LPS) and test materials. IL1beta, IL1ra, and NO were determined in culture media. The inducible nitric oxide synthase inhibitor, AG, was added to cultures in various concentrations (0.3-3 mmol/l). RESULTS: In synovial tissue cultures AG (0.3, 1, and 3 mmol/l) decreased LPS (1 microg/ml) stimulated IL1beta and NO release in the media in a dose dependent manner (p<0.05 at 1 mmol/l and p<0.05 at 0.3 mmol/l, respectively). In articular cartilage cultures AG (0.3, 1, and 3 mmol/l) decreased LPS (1 microg/ml) stimulated IL1beta and NO release in the media in a dose dependent manner (p<0.05 at 1 mmol/l and p<0.01 at 0.3 mmol/l, respectively). Hydrocortisone (5 microg/ml) also significantly decreased LPS stimulated IL1beta release in media of synovial tissue and cartilage cultures and NO in media of synovial cultures. AG (0.3, 1, and 3 mmol/l) decreased LPS (1 microg/ml) stimulated IL1ra levels in media of synovial tissue cultures in a dose dependent manner (p<0.05 at 1 mmol/l) but increased LPS (1 microg/ml) stimulated IL1ra release in media of cartilage cultures (p<0.01 at 3 mmol/l). The NO donor, nitroprusside (10, 30, 100, and 300 microg/ml) stimulated IL1beta release in media of synovial tissue cultures in a dose dependent manner (p<0.01 at 100 microg/ml). AG and nitroprusside at the concentrations used had no toxic effect on human synovial cells. CONCLUSIONS: NO synthase inhibitors may modulate osteoarthritis and articular inflammatory processes not only by decreasing NO synthesis but also by their effects on ILbeta and IL1ra production.
Assuntos
Regulação para Baixo , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Interleucina-1/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Osteoartrite/metabolismo , Idoso , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacologia , Nitroprussiato/farmacologia , Osteoartrite/patologia , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/efeitos dos fármacos , Receptores de Interleucina-1/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismoRESUMO
OBJECTIVES: The purpose of this study was to explore interactions between paracrine angiotensin II (Ang-II) and tumor necrosis factor-alpha (TNF-alpha) during myocardial ischemia. BACKGROUND: Ischemic myocardium releases significant amounts of TNF-alpha. This paracrine release correlated with postischemic myocardial injury. Other studies showed myocardial protection obtained by the use of angiotensin-converting enzyme inhibitors (i.e., captopril) and the Ang-II type 1 receptor antagonist losartan after ischemia. The possibility that these agents decrease TNF-alpha synthesis has not yet been investigated. METHODS: Using the modified Langendorff model, isolated rat hearts underwent either 90 min of nonischemic perfusion (control group) or 1 h of global cardioplegic ischemia. In both groups, either captopril (360 micromol/liter) or losartan (182.2 micromol/liter) was added before ischemia. The hearts were assayed for messenger ribonucleic acid (mRNA) expression and effluent TNF-alpha levels. In addition, cardiac myocytes were incubated in cell culture with Ang-II. RESULTS: After ischemia, TNF-alpha mRNA expression intensified from 0.63 +/- 0.06 (control group) to 0.92 +/- 0.12 (p < 0.03), and effluent TNF-alpha levels were 711 +/- 154 pg/ml. The TNF-alpha mRNA expression declined to 0.46 +/- 0.07 (p < 0.01) and 0.65 +/- 0.08 (p < 0.02) in captopril- and losartan-treated hearts, respectively. Effluent TNF-alpha was below detectable levels. Concentrations of TNF-alpha in supernatants of incubated cardiac myocytes treated with 10 and 50 nmol/liter of Ang-II were 206.0 +/- 47.0 pg/ml and 810 +/- 130 pg/ml, respectively (p < 0.004). When pretreated with 700 micromol/liter of losartan, TNF-alpha was below detectable levels. CONCLUSIONS: This study presents an original explanation for previously reported myocardial protection after ischemia, obtained by the use of captopril and losartan. These drugs reduce TNF-alpha synthesis, providing strong evidence of active interactions between paracrine TNF-alpha and Ang-II in the evolution of the ischemic cascade.
Assuntos
Angiotensina II/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Comunicação Parácrina/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Animais Recém-Nascidos , Captopril/farmacologia , Células Cultivadas , Losartan/farmacologia , Masculino , Ratos , Ratos WistarRESUMO
The prevalence of congestive heart failure (CHF) is increasing rapidly in the community. We and others have shown that the prevalence and severity of both anemia and chronic renal failure (CRF) increase steadily with increasing severity of CHF. We have also shown that CHF patients may be resistant to standard drug therapy for CHF as long as the associated anemia is not corrected, and that correction of the anemia with subcutaneous erythropoietin and intravenous iron sucrose (Venofer: Vifor International, St. Gallen, Switzerland) may improve both the CHF and CRF and markedly reduce hospitalizations without causing side effects. We report here our experience with correcting anemia in this manner in 126 cases of anemic-resistant CHF patients. As in our previous studies, correction of the anemia improved both CHF and CRF, and reduced hospitalizations. Our studies suggest that correction of even mild anemia in CHF may be an important addition to the treatment of patients with the combination of CHF and CRF.
Assuntos
Anemia/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Falência Renal Crônica/fisiopatologia , Idoso , Anemia/sangue , Anemia/etiologia , Progressão da Doença , Quimioterapia Combinada , Eritropoetina/administração & dosagem , Feminino , Compostos Férricos/administração & dosagem , Óxido de Ferro Sacarado , Taxa de Filtração Glomerular , Ácido Glucárico , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/terapia , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Masculino , Proteínas Recombinantes , Volume Sistólico , Sacarose/administração & dosagemRESUMO
BACKGROUND: Excess cardiovascular mortality has been documented in chronic haemodialysis patients. Oxidative stress is greater in haemodialysis patients with prevalent cardiovascular disease than in those without, suggesting a role for oxidative stress in excess cardiovascular disease in haemodialysis. We investigated the effect of high-dose vitamin E supplementation on cardiovascular disease outcomes in haemodialysis patients with pre-existing cardiovascular disease. METHODS: Haemodialysis patients with pre-existing cardiovascular disease (n=196) aged 40-75 years at baseline from six dialysis centres were enrolled and randomised to receive 800 IU/day vitamin E or matching placebo. Patients were followed for a median 519 days. The primary endpoint was a composite variable consisting of: myocardial infarction (fatal and non-fatal), ischaemic stroke, peripheral vascular disease (excluding the arteriovenous fistula), and unstable angina. Secondary outcomes included each of the component outcomes, total mortality, and cardiovascular-disease mortality. FINDINGS: A total of 15 (16%) of the 97 patients assigned to vitamin E and 33 (33%) of the 99 patients assigned to placebo had a primary endpoint (relative risk 0.46 [95% CI 0.27-0.78], p=0.014). Five (5.1%) patients assigned to vitamin E and 17 (17.2%) patients assigned to placebo had myocardial infarction (0.3 [0.11-0.78], p=0.016). No significant differences in other secondary endpoints, cardiovascular disease, or total mortality were detected. INTERPRETATION: In haemodialysis patients with prevalent cardiovascular disease, supplementation with 800 IU/day vitamin E reduces composite cardiovascular disease endpoints and myocardial infarction.