RESUMO
Uric acid has promoted renal fibrosis and inflammation in experimental studies, but some studies have shown nephroprotective effects due to alleviated oxidative stress. We studied the influence of experimental hyperuricaemia in surgically 5/6 nephrectomized rats. Three weeks after subtotal nephrectomy or sham operation, the rats were allocated to control diet or 2.0% oxonic acid (uricase inhibitor) diet for 9 weeks. Then blood, urine and tissue samples were taken, and renal morphology and oxidative stress were examined. Inflammation and fibrosis were evaluated using immunohistochemistry and real-time PCR (RT-PCR). Remnant kidney rats ingesting normal or oxonic acid diet presented with ~60% reduction of creatinine clearance and suppressed plasma renin activity. Oxonic acid diet increased plasma uric acid levels by >80 µmol/L. In remnant kidney rats, moderate hyperuricaemia decreased glomerulosclerosis, tubulointerstitial damage and kidney mast cell count, without influencing the fibrosis marker collagen I messenger RNA (mRNA) content. In both sham-operated and 5/6 nephrectomized rats, the mast cell product 11-epi-prostaglandin-F2α excretion to the urine and kidney tissue cyclooxygenase-2 (COX-2) levels were decreased. To conclude, hyperuricaemic remnant kidney rats displayed improved kidney morphology and reduced markers of oxidative stress and inflammation. Thus, moderately elevated plasma uric acid had beneficial effects on the kidney in this low-renin model of experimental renal insufficiency.
Assuntos
Hiperuricemia , Nefropatias , Insuficiência Renal , Animais , Ratos , Fibrose , Hiperuricemia/patologia , Inflamação/patologia , Rim , Nefrectomia , Ácido Oxônico/farmacologia , Insuficiência Renal/patologia , Renina/genética , Ácido ÚricoRESUMO
Obstructive sleep apnoea (OSA) carries an increased risk of ischaemic stroke, but the underlying mechanism is not clear. As right-to-left shunting can occur through a patent foramen ovale (PFO) during periods of apnoea, we investigated nocturnal changes in fibrinolytic activity and platelet function in subjects who had OSA with or without PFO and in controls. We determined plasminogen activator inhibitor 1 (PAI-1) activity and antigen and platelet activation parameters. The severity of OSA was verified by polygraphy and PFO was detected by ear oximetry. We found a higher PAI-1 activity and antigen and a lower ratio of 2,3-dinor-PGF(1α) to 2,3-dinor-TXB(2) in the subjects with OSA than in the controls. Linear regression analysis showed the apnoea-hypopnoea index (ß-coefficient, 0.499; P = 0.032) and PFO (ß-coefficient, 0.594; P = 0.015) to be associated independently with PAI-1 activity in the morning, while the increment in PAI-1:Ag from evening to morning was significantly associated with the presence of PFO (r(s) = 0.563, P = 0.002). Both OSA and PFO reduce fibrinolytic activity during nocturnal sleep. We hypothesize that subjects having both OSA and PFO may develop a more severe prothrombotic state during sleep than those having either OSA or PFO alone.
RESUMO
In this study we investigated the relationship between melatonin pathway and multiple sclerosis (MS) in a high-risk Finnish population by studying the single nucleotide polymorphisms (SNPs) in the genes coding for critical enzymes and receptors involved in the melatonin pathway. A total of 590 subjects (193 MS patients and 397 healthy controls) were genotyped for seven SNPs in four genes including tryptophan hydroxylases (TPH)1 and 2, arylalkylamine N-acetyltransferase (AANAT) and melatonin receptor 1B (MTNR1B). An overrepresentation of T allele carriers of a functional polymorphism (G-703T, rs4570625) in the promoter region of TPH2 gene was observed in the progressive MS subtypes. The haplotype rs4570625-rs10506645TT of TPH2 gene was associated with the risk of severe disability in primary progressive MS (PPMS), while haplotype rs4570625-rs10506645TC appeared to be protective against disability in secondary progressive MS (SPMS). In the MTNR1B gene, the haplotype rs10830963-rs4753426GC was associated with the risk of SPMS, whereas another haplotype rs10830963-rs4753426GT showed an association with the risk of PPMS. These data showing the association of polymorphisms in the TPH2 and MTNR1B genes with the progressive subtypes of MS and disability suggest dysregulation in melatonin pathway. Melatonin pathway seems to be involved in disease progression, and therefore its potential effects in overcoming MS-related neurodegeneration may be worth evaluating in future clinical trials.
Assuntos
Predisposição Genética para Doença , Melatonina/genética , Esclerose Múltipla/genética , Receptor MT1 de Melatonina/genética , Triptofano Hidroxilase/genética , Estudos de Casos e Controles , Avaliação da Deficiência , Feminino , Finlândia , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Receptor MT2 de Melatonina , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Vitamin D receptor activation with paricalcitol can modulate the transcription of renin-angiotensin system components in the surgical 5/6 nephrectomy rat model (5/6 NX) of chronic renal insufficiency. We tested the hypothesis whether dietary modification of phosphate influences kidney renin-angiotensin system gene expression at the mRNA level in 5/6 NX rats. METHODS: Fifteen weeks after surgery, rats were given control diet (0.3% calcium, 0.5% phosphate), phosphate-lowering diet (3% calcium as carbonate) or high-phosphate diet (1.5%) for 12 weeks. Sham-operated rats were on control diet. RESULTS: Blood pressure, plasma phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were increased in remnant kidney rats, whereas creatinine clearance was decreased. Phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were further elevated by the high-phosphate diet, but were reduced by the phosphate-lowering diet. Plasma calcium was increased with the phosphate-lowering diet and decreased with the high-phosphate diet. Remnant kidney rats on control diet showed upregulated kidney angiotensin-converting enzyme (ACE) and angiotensin (Ang) IV receptor (AT(4)) transcription, while ACE2, Ang II type 2 receptor and renin receptor transcription were downregulated in comparison with sham rats. Phosphate-lowering diet reduced whereas high-phosphate diet increased kidney ACE, and these effects were observed at both mRNA and protein levels. Dietary phosphate loading also resulted in lower AT(1a) gene transcription. CONCLUSION: Dietary phosphate loading was associated with elevated kidney ACE expression, increased tissue damage and lower AT(1a) transcription in 5/6 NX rats. Phosphate binding with 3% calcium carbonate had opposite effects on ACE and kidney damage.
Assuntos
Rim/metabolismo , Peptidil Dipeptidase A/metabolismo , Fosfatos/farmacologia , RNA Mensageiro/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Autorradiografia , Western Blotting , Rim/efeitos dos fármacos , Masculino , Nefrectomia , Peptidil Dipeptidase A/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo RealRESUMO
OBJECTIVE: To study the diurnal variation of melatonin and cortisol in critically ill patients and to assess whether the severity of organ dysfunction, sedation and sympathetic activity correlate with the production of these hormones. DESIGN: Prospective clinical study. SETTING: Surgical intensive care unit in a university hospital. PATIENTS: Forty non-septic patients without brain injury and treatment with adrenergic agonists or corticosteroids. Twenty-five of the patients were sedated with benzodiazepines. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The pattern of melatonin production was monitored by the determination of 6-sulphatoxymelatonin (aMT6s) in urine. The 12-h aMT6s excretions at nights (11.8 +/- 8.9 microg, mean +/- SD) were higher than in the daytime (6.8 +/- 7.5 microg; P < 0.0001), and benzodiazepine treatment did not abolish the diurnal periodicity of aMT6s excretion during the entire 3-day study period. Serum cortisol concentrations at noon (524 +/- 276 nmol/l, mean +/- SD) were higher than at midnight (415 +/- 172 nmol/l; P < 0.0001), and the decrease at midnight was significant also in the patients treated with benzodiazepines. Sympathetic activity was monitored with urine vanillylmandelic acid (VMA). The 12-h VMA excretions did not show a diurnal variation, but a significant positive relationship between the 12-h VMA and aMT6s excretions was observed. The severity of organ dysfunction did not correlate either with the aMT6s and VMA excretion or with serum cortisol concentration. CONCLUSIONS: The diurnal variation of melatonin and cortisol is maintained in non-septic intensive care unit patients. Benzodiazepines do not impair the diurnal variation of melatonin and cortisol.
Assuntos
Ritmo Circadiano , Cuidados Críticos , Hidrocortisona/sangue , Melatonina/análogos & derivados , Melatonina/metabolismo , Feminino , Humanos , Masculino , Melatonina/urina , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Hyperuricemia may play a role in the pathogenesis of cardiovascular disease, but uric acid is also a significant antioxidant. We investigated the effects of oxonic acid-induced hyperuricemia on carotid artery tone in experimental renal insufficiency. METHODS: Three weeks after 5/6 nephrectomy (NX) or Sham operation, male Sprague-Dawley rats were allocated to 2.0% oxonic acid or control diet for 9 weeks. Blood pressure was monitored using tail cuff, isolated arterial rings were examined using myographs, and blood and urine samples were taken, as appropriate. Oxidative stress and antioxidant status were evaluated by measuring urinary 8-isoprostaglandin F(2 alpha) (8-iso-PGF(2 alpha)) excretion and plasma total peroxyl radical-trapping capacity (TRAP), respectively. RESULTS: Plasma creatinine was elevated twofold in NX rats, but neither NX nor oxonic acid diet influenced blood pressure. Urinary 8-iso-PGF(2 alpha) excretion was increased over 2.5-fold in NX rats on control diet. Oxonic acid diet increased plasma uric acid 2-3-fold, TRAP 1.5-fold, and reduced urinary 8-iso-PGF(2 alpha) excretion by 60-90%. Carotid vasorelaxation to acetylcholine in vitro, which could be abolished by nitric oxide (NO) synthase inhibition, was reduced following NX, whereas maximal response to acetylcholine was augmented in hyperuricemic NX rats. Vasorelaxation to nitroprusside was impaired in NX rats, whereas oxonic acid diet increased sensitivity also to nitroprusside in NX rats. CONCLUSIONS: Oxonic acid-induced hyperuricemia reduced oxidative stress in vivo, as evaluated using urinary 8-iso-PGF(2 alpha) excretion, increased plasma TRAP, and improved NO-mediated vasorelaxation in the carotid artery in experimental renal insufficiency.
Assuntos
Hiperuricemia/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal/fisiopatologia , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiologia , Creatinina/sangue , Dinoprosta/análogos & derivados , Dinoprosta/urina , Hiperuricemia/induzido quimicamente , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Nefrectomia , Ácido Oxônico , Peróxidos/metabolismo , Ratos , Ratos Sprague-Dawley , Ácido Úrico/sangue , Vasodilatação/efeitos dos fármacosRESUMO
Cyclooxygenase-2 (COX-2) is expressed in rheumatoid and osteoarthritic cartilage and produces pro-inflammatory prostanoids in the joint. In the present study, we investigated the effects of disease modifying anti-rheumatic drugs on COX-2 expression in chondrocytes. Unlike the other tested drugs, aurothiomalate was found to inhibit COX-2 expression in chondrocytes. In the further studies, effects and mechanisms of action of aurothiomalate were investigated in more detail. Aurothiomalate inhibited IL-1beta-induced COX-2 protein expression and PGE(2) production in chondrocytes in a dose-dependent manner. Because aurothiomalate did not alter IL-1beta-induced mRNA levels when measured 0-3 h after addition of IL-1beta, its effects on COX-2 mRNA degradation were tested by Actinomycin D assay. The half-life of COX-2 mRNA was reduced from 3 h to less than 1.5 h in aurothiomalate-treated cells. The 3'-untranslated region (3'-UTR) of COX-2 mRNA contains an ARE element which has been shown to bind mRNA stabilizing factor HuR. Interestingly, aurothiomalate inhibited HuR expression which may explain its destabilizing effect on COX-2 mRNA. Aurothiomalate reduced COX-2 expression and PGE(2) production also in human cartilage at drug concentrations which have been measured in serum and synovial fluid during treatment with aurothiomalate. The results show that aurothiomalate reduces COX-2 expression and PGE(2) production in chondrocyte cultures and in human cartilage. The action is likely mediated by enhanced COX-2 mRNA degradation possibly through a mechanism related to reduced expression of HuR. The results provide a novel mechanism of action for aurothiomalate which may be important in the treatment of arthritis.
Assuntos
Antirreumáticos/farmacologia , Cartilagem/enzimologia , Condrócitos/enzimologia , Inibidores de Ciclo-Oxigenase 2 , Ciclo-Oxigenase 2/biossíntese , Tiomalato Sódico de Ouro/farmacologia , Western Blotting , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Condrócitos/efeitos dos fármacos , Dinoprostona/biossíntese , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sais de TetrazólioRESUMO
OBJECTIVE: Elevated levels of 11-dehydrothromboxane B2 (11-dehydro-TXB2) excreted in urine have been observed in acute ischemic stroke. This marker of platelet activation has not been investigated in patients with acute spontaneous intracerebral hemorrhage (ICH). METHODS: We examined 43 patients with spontaneous ICH and 23 controls. Urinary excretion rates of 11-dehydro-TXB2, 2,3-dinor-thromboxane B2 (2,3 dinor-TXB2) and 2,3-dinor-6-ketoprostaglandin F(1alpha) (2,3-dinor-PGF(1alpha)) during the first week and at 3 months after ICH were compared between patients who had or had not used aspirin and controls. RESULTS: On admission, ICH patients without aspirin use had significantly higher urinary levels of 11-dehydro-TXB2 (p<0.001), 2,3-dinor-TXB2 (p<0.001) and 2,3-dinor-PGF(1alpha) (p=0.019) than controls. Aspirin users had significantly lower urinary levels of these metabolites than nonusers. The metabolite levels of aspirin users on admission did not significantly differ from those of controls. The differences between aspirin users and nonusers leveled off during the following 3-5 days, however, as the blocking effect of aspirin on the production of TXA2 and PGI2 ceased. Three months after ICH, the metabolite excretion levels in all the patients were similar to those in nonusers of aspirin on admission. On admission, aspirin users had longer bleeding times (p=0.032) than nonusers, but aspirin use did not associate with impaired recovery or hematoma enlargement. CONCLUSIONS: Urinary excretion levels of 11-dehydro-TXB2, 2,3-dinor-TXB2 and 2,3-dinor-PGF1alpha were higher in patients with acute ICH than in controls. The levels in aspirin users were equally low as in controls but rose to the levels of the other patients within a few days. The metabolite levels remained high 3 months after ICH in all patients. Prior use of aspirin did not seem to cause hematoma enlargement.
Assuntos
Hemorragia Cerebral/metabolismo , Epoprostenol/biossíntese , Tromboxano A2/biossíntese , 6-Cetoprostaglandina F1 alfa/análogos & derivados , 6-Cetoprostaglandina F1 alfa/urina , Doença Aguda , Idoso , Aspirina/farmacologia , Tempo de Sangramento , Coagulação Sanguínea/efeitos dos fármacos , Hemorragia Cerebral/sangue , Hemorragia Cerebral/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Regressão , Tromboxano B2/análogos & derivados , Tromboxano B2/urinaRESUMO
BACKGROUND: The aim of this study was to investigate the prostanoid production in pregnancies at high risk for hypertensive disorders, and the effect of low-dose acetylsalicylic acid (ASA) on prostanoids. MATERIAL AND METHODS: Ninety women with a bilateral notching in uterine arteries screened by Doppler ultrasound at 12-14 gestational weeks were randomized to the ASA (0.5 mg/kg/day) or placebo group. Forty-three women in both groups were followed up throughout the pregnancy. Urine samples were taken at baseline, and at 24-26 and 32-34 weeks of gestation to determine the urinary 11-dehydrothromboxane B(2) (u-11-dehydro-TxB(2)) and 2,3-dinor-6-keto-prostaglandin F(1alpha) (u-2,3-dinor-6-keto-PGF(1alpha)), the metabolites of thromboxane A(2) and prostacyclin, respectively. RESULTS: In the pregnancies with pregnancy-induced hypertension (PIH) before 37 gestational weeks, the 2,3-dinor-6-keto-PGF(1alpha)/11-dehydro-TxB(2) ratio did not increase as much as in other pregnancies (P = 0.028). In the placebo group pregnancies with preeclampsia had significantly lower 2,3-dinor-6-keto-PGF(1alpha) (P = 0.019) at 12-14 weeks of gestation compared to other pregnancies. In the placebo group the 2,3-dinor-6-keto-PGF(1alpha)/11-dehydroTxB(2) ratio remained unchanged throughout the pregnancy, with no significant difference between pregnancies with a normal or an adverse outcome. In the ASA group the 2,3-dinor-6-keto-PGF(1alpha)/11-dehydro-TxB(2) ratio increased (P < 0.001, early vs. midpregnancy). Again, the changes were similar in pregnancies with a normal or an adverse outcome. CONCLUSION: The balance of prostacyclin and thromboxane A(2) shifted in an unfavorable direction in pregnancies complicated by PIH. ASA had a favorable effect on the prostanoids.
Assuntos
6-Cetoprostaglandina F1 alfa/análogos & derivados , Aspirina/administração & dosagem , Inibidores de Ciclo-Oxigenase/administração & dosagem , Epoprostenol/metabolismo , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Tromboxano A2/metabolismo , Tromboxano B2/análogos & derivados , 6-Cetoprostaglandina F1 alfa/urina , Epoprostenol/análogos & derivados , Epoprostenol/urina , Feminino , Humanos , Hipertensão Induzida pela Gravidez/urina , Estudos Longitudinais , Gravidez , Complicações Cardiovasculares na Gravidez/urina , Resultado da Gravidez , Gravidez de Alto Risco , Prostaglandinas/metabolismo , Tromboxano A2/análogos & derivados , Tromboxano A2/urina , Tromboxano B2/urinaRESUMO
The effects of chronic nitric oxide deficiency on prostacyclin and thromboxane A(2) production in vivo are unknown. Therefore, we treated rats with N(G)-nitro-L-arginine methyl ester (L-NAME), and used losartan and high calcium diet as antihypertensive treatments. Forty eight Wistar rats were divided into six groups: control; losartan (20mgkg(-1)day(-1)); high calcium diet (dietary calcium elevated from 1.1% to 3%); L-NAME (20mgkg(-1)day(-1)); losartan+L-NAME and high calcium diet+L-NAME. Prostacyclin and thromboxane A(2) production were measured after eight weeks as urinary 2,3-dinor-6-keto-PGF(1alpha) and 11-dehydro-TXB(2), respectively. Both the high calcium diet and losartan reduced blood pressure in L-NAME hypertension. Chronic nitric oxide deficiency did not modulate prostacyclin production but it nearly doubled thromboxane A(2) production in vivo. This effect was not influenced by lowering of blood pressure by blockade of angiotensin II type 1 receptors. Independent of the level of blood pressure and blockade of nitric oxide synthesis the high calcium diet decreased prostacyclin production by one third and increased thromboxane A(2) production almost two-fold in vivo.
Assuntos
Cálcio da Dieta/metabolismo , Epoprostenol/metabolismo , Hipertensão/metabolismo , Óxido Nítrico/metabolismo , Receptores de Angiotensina/metabolismo , Tromboxano A2/metabolismo , Antagonistas de Receptores de Angiotensina , Animais , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/uso terapêutico , Inibidores Enzimáticos/metabolismo , Hipertensão/tratamento farmacológico , Losartan/metabolismo , Losartan/uso terapêutico , Masculino , NG-Nitroarginina Metil Éster/metabolismo , Ratos , Ratos WistarRESUMO
Our purpose was to determine urinary 9 alpha,11 beta-prostaglandin F2, the primary metabolite of prostaglandin D2, in pregnancies at high risk for hypertensive disorders and the effect of acetylsalicylic acid on 9 alpha,11 beta-prostaglandin F2. Ninety high risk women were randomised to acetylsalicylic acid and placebo groups at 12-14 weeks of gestation, with 43 women in both groups followed up successfully. 9 alpha,11 beta-prostaglandin F2 was determined at baseline, at 24-26, and at 32-34 weeks of gestation. Fifteen normotensive non-pregnant women, 17 normotensive pregnant women at 12-14, and 15 at 30-34 weeks of gestation served as controls. Urinary 9 alpha,11 beta-prostaglandin F2 was significantly higher in pregnant women at 12-14 weeks of gestation as compared to non-pregnant women. High risk pregnancies had higher 9 alpha,11 beta-prostaglandin F2 as compared to normotensive pregnancies at 12-14, and at 30-34 weeks of gestation. Urinary 9 alpha,11 beta-prostaglandin F2 increased throughout pregnancy unrelated to the outcome of the pregnancy or to the treatment.
Assuntos
Aspirina/uso terapêutico , Dinoprosta/urina , Hipertensão/urina , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/urina , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Complicações Cardiovasculares na Gravidez/urina , Feminino , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Pré-Eclâmpsia/complicações , Gravidez , Prognóstico , Fatores de TempoRESUMO
The effects of nicotinic acid (2500 mg orally during 12 hr) and pyridoxine (300 mg orally twice daily for seven days) on the excretion of urinary 2,3-dinor-6-ketoprostaglandin F1alpha, 11-dehydrothromboxane B2 and leukotriene E4, the markers of systemic prostacyclin, thromboxane A2 and cysteinyl leukotriene production, respectively, were investigated in healthy male volunteers (n=6-8). Nicotinic acid increased 11-dehydrothromboxane B2 and leukotriene E4 excretions to 2.6- and 2.0 times the initial values (P<0.05), respectively. In the volunteers treated with pyridoxine, 11-dehydrothromboxane B2 and leukotriene E4 excretions were decreased to 70% (P<0.05) and 65% (P<0.01) of the initial values, respectively, but the excretion of 2,3-dinor-6-ketoprostaglandin F1alpha was increased 1.7 times (P<0.01). The results suggest that nicotinic acid increases thromboxane and leukotriene synthesis which may not be beneficial for patients with cardiovascular diseases or asthma. In contrast, the increase in prostacyclin production and the inhibition in thromboxane and leukotriene synthesis by pyridoxine might be beneficial in disorders where the production of prostacyclin is decreased and the formation of thromboxane and cysteinyl leukotrienes is enhanced.