RESUMEN
BACKGROUND: Resveratrol has been shown to have protective effects for patients in shock-like states, and Akt (protein kinase B) is known to play a role in pro-inflammatory events in response to injury. The aim of this study is to determine whether resveratrol provides cardioprotection mediated via an Akt-dependent pathway in trauma-hemorrhaged animals. METHODS: Male Sprague-Dawley rats underwent trauma-hemorrhage and resuscitation. A single dose of resveratrol (30 mg/kg body weight) with or without a PI3K inhibitor (wortmannin) or vehicle was administered intravenously during the resuscitation. Two hours after either the trauma-hemorrhage or sham operation, the cardiac output, the positive maximal pressure increase of the left ventricle (+dP/dt(max)), and the negative maximal pressure decrease of the left ventricle (-dP/dt(max)) were measured. Cardiac myeloperoxidase (MPO) activity, interleukin (IL)-6, and intercellular adhesion molecule (ICAM)-1 levels, Akt activity, and apoptosis were measured. One-way ANOVA and Tukey's test were used for statistical analysis. RESULTS: Cardiac output and ± dP/dt(max) decreased significantly after trauma-hemorrhage. Administration of resveratrol significantly improved these cardiac function parameters. Trauma-hemorrhage increased cardiac MPO activity, IL-6 levels, and ICAM-1 levels, and these parameters were significantly improved in the resveratrol-treated rats subjected to trauma-hemorrhage. Although trauma-hemorrhage decreased cardiac Akt phosphorylation (p-Akt), resveratrol treatment following trauma-hemorrhage prevented the same decrease in cardiac p-Akt. The increase in cardiac apoptosis was attenuated in rats that received resveratrol. Co-administration of wortmannin prevented the beneficial effects of resveratrol on the attenuation of pro-inflammatory responses and cardiac injury after trauma-hemorrhage. CONCLUSION: Resveratrol attenuates cardiac injury following trauma-hemorrhage, which is, at least in part, due to its anti-inflammatory effects via Akt-dependent pathways.
Asunto(s)
Cardiotónicos/uso terapéutico , Corazón/fisiopatología , Hemorragia/complicaciones , Proteínas Proto-Oncogénicas c-akt/fisiología , Transducción de Señal/fisiología , Estilbenos/uso terapéutico , Heridas y Lesiones/complicaciones , Androstadienos/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Gasto Cardíaco/efectos de los fármacos , Gasto Cardíaco/fisiología , Cardiotónicos/farmacología , Corazón/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-6/metabolismo , Masculino , Modelos Animales , Miocardio/metabolismo , Miocardio/patología , Peroxidasa/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Ratas , Ratas Sprague-Dawley , Resveratrol , Estilbenos/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiología , WortmaninaRESUMEN
Although astringinin administration under adverse circulatory conditions is known to be protective, the mechanism by which astringinin produces the salutary effects remains unknown. We hypothesize that astringinin administration in males following trauma-hemorrhage decreases cytokine production and protects against hepatic injury. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure: 40 mmHg for 90 min, then resuscitation). Different doses of astringinin (0.01, 0.03, 0.1, 0.3 mg/kg of body weight) or vehicle were administered intravenously during resuscitation. Concentrations of plasma aspartate aminotransferase (AST) with alanine aminotransferase (ALT) and various hepatic parameters were measured (n = 8 rats/group) at 24 h after resuscitation. One-way ANOVA and Tukey testing were used for statistical analysis. Trauma-hemorrhage significantly increased plasma AST and ALT levels at 24 h postresuscitation; there was a dose-related benefit when astringinin was administered at doses of 0.01 to 0.3 mg/kg. In astringinin-treated (0.3 mg/kg) rats subjected to trauma-hemorrhage, there were significant improvements in liver myeloperoxidase (MPO) activity (237.80 +/- 45.89 vs. 495.95 +/- 70.64 U/mg protein, P < 0.05), interleukin-6 (IL-6) levels (218.54 +/- 34.52 vs. 478.60 +/- 76.21 pg/mg protein, P < 0.05), cytokine-induced neutrophil chemoattractant (CINC)-1 (88.32 +/- 20.33 vs. 200.70 +/- 32.68 pg/mg protein, P < 0.05), CINC-3 (110.83 +/- 26.63 vs. 290.14 +/- 76.82 pg/mg protein, P < 0.05) and intercellular adhesion molecule (ICAM)-1 concentrations (1,868.5 +/- 211.5 vs. 3,645.0 +/- 709.2 pg/mg protein, P < 0.05), as well as in histology. Results show that astringinin significantly attenuates proinflammatory responses and hepatic injury after trauma-hemorrhage. In conclusion, the salutary effects of astringinin administration on attenuation of hepatic injury following trauma-hemorrhage are likely due to reduction of pro-inflammatory mediator levels.
Asunto(s)
Hepatopatías/tratamiento farmacológico , Choque Hemorrágico/metabolismo , Estilbenos/farmacología , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Quimiocina CXCL1/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-6/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Hepatopatías/enzimología , Hepatopatías/inmunología , Hepatopatías/metabolismo , Masculino , Peroxidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Resucitación/métodos , Choque Hemorrágico/enzimología , Choque Hemorrágico/inmunologíaRESUMEN
OBJECTIVE: To determine whether resveratrol provides vasculoprotection in trauma-hemorrhaged animals and whether the effects are mediated via estrogen receptor-dependent hemeoxygenase-1. DESIGN: Prospective, multiexperimental, randomized, controlled studies. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 300-350 g. INTERVENTIONS: Male Sprague-Dawley rats underwent trauma hemorrhage (mean arterial pressure 40 mm Hg for 90 min, then resuscitation). Resveratrol (30 mg/kg) with or without an estrogen receptor antagonist (ICI 182,780), a hemeoxygenase enzyme inhibitor (chromium-mesoporphyrin), or vehicle was injected during resuscitation. At 24 hrs after trauma hemorrhage with resuscitation or sham operation, the animals were euthanized for further evaluation. MEASUREMENTS AND MAIN RESULTS: Acetylcholine-induced endothelium-dependent relaxation decreased, whereas nicotinamide adenine dinucleotide-stimulated superoxide radical production in the aorta and aortic p22phox, p47phox, gp91phox, NOX1, and NOX4 mRNA concentrations increased in trauma-hemorrhaged rats vs. sham rats. All altered parameters were normalized in resveratrol-treated trauma-hemorrhaged rats. Furthermore, there was a significant increase in hemeoxygenase-1 after trauma hemorrhage, and resveratrol treatment further increased hemeoxygenase-1 expression in trauma-hemorrhaged rats. However, administration of ICI 182,780 or chromium-mesoporphyrin abolished the resveratrol-induced prevention of shock-induced oxidative stress and endothelial damage. In the resveratrol-treated rats subjected to trauma hemorrhage, there were significant improvements in plasma aspartate aminotransferase and alanine aminotransferase levels, and mortality rate, and there was lesser damage in histology. CONCLUSIONS: Resveratrol treatment prevented the overproduction of superoxide radical/NADPH oxidase expression and restored the trauma-hemorrhage-impaired endothelium-dependent relaxation via estrogen receptor-dependent stimulation of hemeoxygenase-1 expression.
Asunto(s)
Endotelio Vascular/efectos de los fármacos , Hemo-Oxigenasa 1/fisiología , Hemorragia/fisiopatología , Receptores de Estrógenos/fisiología , Estilbenos/farmacología , Superóxidos/metabolismo , Animales , Antioxidantes/farmacología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatología , Endotelio Vascular/fisiopatología , Estradiol/análogos & derivados , Estradiol/farmacología , Fulvestrant , Hemo-Oxigenasa 1/antagonistas & inhibidores , Luminiscencia , Masculino , Mesoporfirinas/farmacología , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Receptores de Estrógenos/antagonistas & inhibidores , Resveratrol , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Nitric oxide (NO) deficiency is associated with development of hypertension. We examined whether melatonin protects against the blood pressure increase is because of the restoration of the NO pathway. Spontaneous hypertensive rats (SHR) and control normotensive Wistar Kyoto (WKY) rats aged 4 weeks were assigned to four groups (N=6 for each group): untreated SHR and WKY, melatonin-treated SHR and WKY. Melatonin-treated rats received 0.01% melatonin in drinking water for 8 wks. All rats were sacrificed at 12 wk of age. SHR had higher blood pressure than WKY, which melatonin prevented. Plasma asymmetric dimethylarginine (ADMA) levels were elevated in SHR, combined with a reduction in plasma L-arginine to ADMA ratio (AAR). In the kidney, L-arginine, ADMA, and AAR were not different between SHR and WKY rats, whereas L-citrulline level was increased in SHR. Melatonin decreased plasma ADMA level and restored plasma AAR. Renal dimethylarginine dimethylaminohydrolase (DDAH, ADMA-metabolizing enzyme) activity was lower in SHR than WKY rats, which melatonin therapy prevented. Also, melatonin elevated both L-arginine and ADMA but reduced L-citrulline level in the kidney in SHR, which was associated with the prevention of reduced renal argininosuccinate lyase (ASL) expression in SHR. Moreover, melatonin reduced the degree of oxidative damaged DNA product, 8- hydroxydeoxyguanosine (8-OHdG) immunostaining in SHR. The observed antihypertensive effects of melatonin in young SHR are because of the restoration of the NO pathway by reduction of plasma ADMA, restoration of plasma AAR, preservation of renal L-Arg availability, and attenuation of oxidative stress.
Asunto(s)
Arginina/análogos & derivados , Hipertensión/metabolismo , Hipertensión/prevención & control , Melatonina/farmacología , Análisis de Varianza , Animales , Arginina/metabolismo , Presión Sanguínea/efectos de los fármacos , Western Blotting , Peso Corporal , Citrulina/metabolismo , Histocitoquímica , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Tamaño de los Órganos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
Hyperhomocysteinemia (HHcy) has been shown to be an independent risk factor for cardiovascular diseases, superior mesenteric thrombosis and inflammatory bowel disease. Superior mesenteric artery (SMA) supplies the intestine and reduced SMA blood flow results in intestinal ischemia. Although in vitro studies have shown that endothelium-dependent vasorelaxation of SMA is reduced in the presence of homocysteine incubation, it is not confirmed with in vivo studies. In this work, we evaluated responsiveness of SMA to endothelium-dependent or -independent vasodilators and a vasoconstrictor in the absence and presence of acute HHcy in vivo to clarify effect of HHcy on superior mesenteric vascular function. Sodium nitroprusside (SNP), bradykinin (BK), and [Sar1,Thr8]angiotensin II ([Sar1,Thr8]-ANG II) were intravenously administrated in sequence in male Sprague-Dawley rats with or without D,L-homocysteine infusion (6 mg/kg/min) through femoral vein. Agonists-induced changes in carotid artery blood pressure, superior mesenteric blood flow and vascular resistance were measured in the present study. We found that acute HHcy infusion had little effects on SNP-induced hemodynamic changes; however, BK-induced changes in blood pressure, blood flow and vascular resistance were significantly reduced in the presence of HHcy infusion. Additionally, HHcy also markedly decreased [Sar1,Thr8]-ANG II-induced superior mesenteric hemodynamic changes. These results demonstrated that responsiveness of SMA to vasoconstrictor, endothelium-dependent, but not endothelium-independent vasodilator, was inhibited in the presence of Hcy infusion. This HHcy-associated vascular hyporesponsiveness to vasoconstrictors and endothelium-dependent vasodilators may partially contribute to circulatory dysfunctions.
Asunto(s)
Angiotensina II/farmacología , Bradiquinina/farmacología , Hemodinámica/efectos de los fármacos , Homocisteína/farmacología , Arteria Mesentérica Superior/fisiología , Nitroprusiato/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Hemodinámica/fisiología , Homocisteína/administración & dosificación , Hiperhomocisteinemia/fisiopatología , Infusiones Intravenosas , Masculino , Arteria Mesentérica Superior/efectos de los fármacos , Modelos Animales , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiologíaRESUMEN
Although reduced vascular reactivity to vasoconstrictors has been well documented, it is not clear whether renal blood flow (RBF) and renal vascular response exhibit the same pattern following sepsis. We examined RBF and renal vascular response during early sepsis. Male Sprague-Dawley rats underwent cecal ligation and puncture (CLP)-induced sepsis. At 5 h after CLP or sham operation, RBF and plasma nitric oxide (NO) concentration were measured. Moreover, angiotensin II (50 ng/kg body weight) was employed to evaluate the renal vascular response (n = 12 rats/group). The results showed that CLP caused higher heart rate (HR), RBF and lower renal vascular resistance (RVR). In addition, plasma nitrite-nitrate (NOx) increased significantly after CLP. After angiotensin II infusion, maximal response in mean blood pressure (MBP), RBF and RVR were less in CLP rats. Thus, we found that CLP induced hyporeactivity of renal artery together with overproduction of NO during an early stage of sepsis.
Asunto(s)
Angiotensina II/farmacología , Arteria Renal/efectos de los fármacos , Sepsis/fisiopatología , Animales , Presión Sanguínea/efectos de los fármacos , Ciego/cirugía , Ligadura , Masculino , Óxido Nítrico/sangre , Ratas , Ratas Sprague-Dawley , Circulación Renal/efectos de los fármacos , Resistencia Vascular/efectos de los fármacosRESUMEN
Although studies have demonstrated that resveratrol administration following adverse circulatory conditions is known to be protective, the mechanism by which resveratrol produces the salutary effects remains unknown. We hypothesized that resveratrol administration in males following trauma-hemorrhage decreases cytokine production and protects against lung injury. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure 40 mmHg for 90 min, then resuscitation). A single dose of resveratrol (30 mg/kg of body weight) or vehicle was administered intravenously during resuscitation. Twenty-four hours thereafter, tissue myeloperoxidase activity (a marker of neutrophil sequestration), cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-3, intercellular adhesion molecule (ICAM)-1, and interleukin (IL)-6 levels in the lung and protein concentrations in bronchoalveolar lavage fluid were measured (n = 6 rats/group). One-way ANOVA and Tukey's test were used for statistical analysis. Trauma-hemorrhage increased lung myeloperoxidase activity, CINC-1, CINC-3, ICAM-1, and IL-6 levels and protein concentrations in bronchoalveolar lavage fluid. These parameters were significantly improved in the resveratrol-treated rats subjected to trauma-hemorrhage. The salutary effects of resveratrol administration on attenuation of lung injury following trauma-hemorrhage are likely due to reduction of pro-inflammatory mediators.
Asunto(s)
Citocinas/biosíntesis , Hemorragia/tratamiento farmacológico , Hemorragia/metabolismo , Neumonía/tratamiento farmacológico , Neumonía/metabolismo , Estilbenos/uso terapéutico , Heridas y Lesiones/tratamiento farmacológico , Animales , Hemorragia/complicaciones , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Peroxidasa/metabolismo , Neumonía/complicaciones , Ratas , Ratas Sprague-Dawley , Resveratrol , Heridas y Lesiones/complicaciones , Heridas y Lesiones/metabolismoRESUMEN
Estrogen protects females against cardiovascular diseases in both receptor-dependent, genomic or non-genomic manner. Although part of the protective effects is attributed to its enhancement of nitric oxide (NO) production and antioxidant properties, in vivo evidence is difficult to establish. We thus employed paraquat (PQ)-treated rats as a model for oxidative stress and to compare oxidative damage determined by malondialdehyde (MDA) contents as index for lipid peroxidation of various tissues. Samples from aorta, lung, and liver exhibited low but detectable MDA level in intact control rats; sham operation did not but PQ-treatment significantly enhanced the MDA levels of all tissues. Different hormonal status were achieved by comparing sham-operated (sham), sham treated with estrogen receptor antagonist ICI182,780 (ICI), and ovariectomized (OVX) rats. OVX significantly reduced plasma estrogen level, ICI effectively blocked estrous cycle without reducing estrogen level. Derived from rats subjected to identical PQ treatment, MDA level was significantly higher in OVX rats than that of sham in isolated aortic rings. In lung tissues, MDA level were similar in all groups. In liver tissues, ICI rats exhibited higher level of MDA than both sham and OVX rats. These data indicated that hormonal status could affect the degree of lipid peroxidation under similar oxidative stress induced by PQ, and that not all tissues responded identically.
Asunto(s)
Estrógenos/fisiología , Peroxidación de Lípido/fisiología , Receptores de Estrógenos/fisiología , Animales , Antioxidantes/fisiología , Femenino , Ovariectomía , Paraquat , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/antagonistas & inhibidoresRESUMEN
Resveratrol (RSV) has been shown to inhibit the inflammatory reaction and ameliorate the organ damage resulting from trauma-hemorrhage (TH). However, the effects of RSV on the metabolomic profiles under these conditions remain unclear. The aim of this study was to determine the metabolomic profiles of plasma in TH rats and to evaluate the therapeutic effects of RSV using high-performance liquid chromatography-mass spectrometry. Thirty male Sprague-Dawley rats were divided into sham operation (n = 10), sham-operation plus RSV treatment (n = 10), TH (n = 10), and TH plus RSV treatment (n = 10) groups. Plasma samples were obtained at 24 h after surgery. Electrospray ionization-tandem mass spectrometry was used to characterize the plasma metabolomes. The systemic analyses of plasma metabolomes and their targets were determined using a number of computational approaches, including principal component analysis, partial least squares discriminant analysis, and heat map analysis. Using these methods, the effects of RSV on the metabolomic profiles in animals that underwent trauma-hemorrhagic injury were determined. These approaches allowed a clear discrimination of the pathophysiological characteristics among the groups. The results demonstrate RSV treatment significantly reduced the metabolic derangements caused by TH. Compared with the sham-operated rats, the plasma levels of carnitine in the TH rats were relatively lower, but the levels of acetylcarnitine and butyrylcarnitine were higher, suggesting that RSV ameliorated the deranged carnitine metabolism in TH rats. There was a statistically significant increase in carnitine. In addition, RSV treatment reduced ketoacidosis and protein degradation, as evidenced by the attenuation of the elevated plasma branched-chain amino acid levels in the TH rats. Our study showed that the alterations of the metabolomic profiles in the rats subjected to trauma-hemorrhagic shock were attenuated by RSV treatment. In view of the metabolomic evidence, we conclude that RSV exerts beneficial effects in trauma-hemorrhagic shock injury and that these effects are partially mediated by improving energy metabolism and reducing protein degradation.
Asunto(s)
Choque Hemorrágico/tratamiento farmacológico , Estilbenos/uso terapéutico , Vasodilatadores/uso terapéutico , Heridas y Lesiones/complicaciones , Animales , Carnitina/sangre , Evaluación Preclínica de Medicamentos/métodos , Masculino , Metaboloma/efectos de los fármacos , Metabolómica/métodos , Ratas Sprague-Dawley , Resveratrol , Choque Hemorrágico/sangre , Choque Hemorrágico/etiología , Heridas y Lesiones/sangreAsunto(s)
Permeabilidad Capilar/efectos de los fármacos , Carboxipeptidasa B2/farmacología , Sepsis/tratamiento farmacológico , Adenosina Monofosfato/metabolismo , Animales , Permeabilidad Capilar/fisiología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Humanos , Lipopolisacáridos/farmacología , Sensibilidad y Especificidad , Sepsis/enzimología , Sepsis/fisiopatología , Quinasas Asociadas a rho/metabolismoRESUMEN
Mild hyperhomocysteinemia (HHcy) is a risk factor for vascular disease and is closely associated with endothelial dysfunction. Oxidative stress and decreased nitric oxide (NO) bioavailability were reported in HHcy-induced vascular injury; however, the exact relationship is not understood. We thus directly determine the production of reactive oxygen species (ROS) and NO in cultured endothelial cells (HUVECs) to demonstrate the correlated variation between ROS and NO induced by Hcy (homocysteine), Cys (cysteine), another thiol compound, and Met (methionine), precursor of HHcy in animal study. HUVECs were treated with Hcy, Cys, or Met for 0.5 or 22-24 h; ROS generation was detected by DCF fluorescence with flow cytometry and NO by chemiluminescence. In non-cytotoxic (<1.0 mM) concentration ranges, Met exerted no effects on either ROS production or NO concentration, Cys decreased ROS production and increased NO in both short-term (0.5 h) and long-term (22-24 h) treatments; Hcy, however, induced a biphasic effect on ROS production, i.e., inhibitory at 0.5 h but stimulatory at 24 h. The maximal stimulation by Hcy (0.25 mM) was significantly reduced by co-incubation (12 h) with estrogen (1 microM). Hcy caused an early (0.5 h) increase of medium NO which was absent in long-term Hcy treatment. The oxidative stress caused by long-term Hcy incubation could be ameliorated by estrogen, consistent with earlier in vivo observations that estrogen prevents HHcy-induced injury.
Asunto(s)
Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Homocisteína/farmacología , Óxido Nítrico/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cisteína/farmacología , Endotelio Vascular/citología , Humanos , Metionina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Venas Umbilicales/citologíaRESUMEN
Estrogen (17beta-estradiol, or E2) reduces systolic blood pressure (SBP) increment and increases aortic cyclic guanosine monophosphate (cGMP) in male spontaneously hypertensive rats (SHRs). It is unknown, however, whether the E2-enhanced aortic cGMP is essential for the BP-lowering effect or not. Nomega-nitro-L-arginine-methyl ester (L-NAME), an L-arginine analogue and nitric oxide (NO) synthase inhibitor, significantly increases SBP and decreases aortic cGMP in male SHRs. We thus treated male SHRs with vehicle (corn oil) or E2 (s.c, 2 mg/kg/week) with or without L-NAME (20 mg/dl in the drinking water). SBP was measured weekly. Plasma nitrate/nitrite (NOx) concentrations and aortic cGMP levels were all measured at the end of the study. We found that SBP increment was significantly higher in L-NAME group, compared with the controls, and that E2 treatment reduced this L-NAME effect. Plasma 4NOx concentrations were not significantly different among different groups. Basal and acetylcholine-induced aortic cGMP, but not sodium nitroprusside-induced cGMP, were significantly lower in L-NAME group, compared with the controls. E2 co-administration did not modify L-NAME-induced aortic cGMP decrease. These data indicate that E2-induced BP-lowering effect in L-NAME treated male SHRs is not closely associated with the enhancement of vascular cGMP.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , GMP Cíclico/fisiología , Inhibidores Enzimáticos/farmacología , Estradiol/farmacología , NG-Nitroarginina Metil Éster/antagonistas & inhibidores , Óxido Nítrico Sintasa/antagonistas & inhibidores , Acetilcolina/farmacología , Animales , Aorta Torácica/metabolismo , Masculino , NG-Nitroarginina Metil Éster/farmacología , Nitratos/sangre , Donantes de Óxido Nítrico/farmacología , Nitritos/sangre , Nitroprusiato/farmacología , Ratas , Ratas Endogámicas SHR , Vasodilatadores/farmacologíaRESUMEN
Both NADPH oxidase-derived reactive oxygen species (ROS) and asymmetric dimethylarginine (ADMA) are increased in hypertension. Apocynin, an NADPH oxidase inhibitor, could inhibit ROS, thus we tested whether apocynin can block NADPH oxidase and prevent increases of ADMA and blood pressure (BP) in spontaneously hypertensive rats (SHRs). SHRs and Wistar Kyoto (WKY) rats, aged 4 weeks, were assigned to four groups: untreated SHRs and WKY rats, SHRs and WKY rats that received 2.5 mM apocynin for 8 weeks. BP was significantly higher in SHRs compared to WKY rats, which was attenuated by apocynin. Apocynin prevented p47phox translocation in SHR kidneys, but not the increase of superoxide and H(2)O(2). Additionally, apocynin did not protect SHRs against increased ADMA. Apocynin blocks NADPH oxidase to attenuate hypertension, but has little effect on the ADMA/nitric oxide (NO) pathway in young SHRs. The reduction of ROS and the preservation of NO simultaneously might be a better approach to restoring ROS-NO balance to prevent hypertension.
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Acetofenonas/farmacología , Antioxidantes/farmacología , Arginina/análogos & derivados , Hipertensión/tratamiento farmacológico , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Arginina/metabolismo , Hipertensión/metabolismo , Masculino , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Hypertension and hypertensive end-organ damage have been associated with decreased nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) both can inhibit NO availability by competition with L-arginine (L-Arg). However, whether a combined analysis of these 3 parameters can serve as an ideal biomarker of hypertension remains unclear. We measured the plasma and renal levels of L-Arg, ADMA, and SDMA in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) control rats at 3 stages: 4 weeks old (prehypertensive), 12 weeks old (hypertensive), and 24 weeks old (end-organ damage). The plasma and renal L-Arg/ADMA ratio (AAR) and the ADMA/SDMA ratio (ASR) were computed for all 3 age stages. Our results revealed an ADMA level increase, and an AAR decrease in plasma and kidneys may develop early on, even before the onset of hypertension in 4-week-old SHRs. The renal ADMA level and AAR were restored in SHRs at 24 weeks of age, which might protect SHRs against kidney injury. We found that the plasma AAR is superior to the levels of L-Arg and ADMA in plasma, and it predicted blood pressure and urinary NOx levels. Renal AAR is a strong independent marker of renal dimethylarginine dimethylaminohydrolase (DDAH) activity. The plasma ASR was correlated strongly to blood pressure. However, renal DDAH activity was related to the renal ASR but not the plasma ASR. In conclusion, the AAR and ASR may serve as better markers for disease activity and progression than each individual parameter. Clinical use of these ratios to elucidate the role of ADMA in hypertension awaits further validation.
Asunto(s)
Arginina/análogos & derivados , Biomarcadores/metabolismo , Óxido Nítrico/deficiencia , Ratas Endogámicas SHR/metabolismo , Amidohidrolasas/análisis , Amidohidrolasas/metabolismo , Animales , Arginina/sangre , Arginina/metabolismo , Arginina/orina , Presión Sanguínea , Hipertensión/sangre , Hipertensión/fisiopatología , Masculino , Modelos Animales , Óxido Nítrico/orina , Ratas , Ratas Endogámicas WKYRESUMEN
Resveratrol protects against organ injury caused by trauma-hemorrhage, although the mechanism remains unknown. We have previously shown that it exerts protective effects in the liver via estrogen receptors and their signaling. Thus, we set out to determine whether resveratrol-mediated estrogen receptor-dependent p38 mitogen-activated protein kinase (MAPK)/heme oxygenase 1 activation protects the intestine after trauma-hemorrhage. To study this, male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure, ~ 40 mmHg for 90 min) followed by fluid resuscitation. Animals were pretreated with an estrogen receptor antagonist (ICI 182,780), a specific p38 MAPK inhibitor (SB-203580), or a heme oxygenase enzyme antagonist (chromium-mesoporphyrin) 30 min before vehicle or resveratrol (30 mg/kg) administration, followed by resuscitation, and were killed 2 h thereafter. Intestinal water content, myeloperoxidase activity, and TNF-α, IL-6, intercellular adhesion molecule 1, cytokine-induced neutrophil chemoattractant (CINC) 1, and CINC-3 levels and edema of the lung were measured. Mean arterial blood pressure, cardiac output, positive maximal pressure of left ventricular increase (+dP/dtmax), and negative maximal pressure of left ventricular decrease (-dP/dtmax) were also determined. Intestinal p38 MAPK activity and heme oxygenase 1 expression were also determined. Trauma-hemorrhage led to an increase in intestinal water content, myeloperoxidase activity, and TNF-α, IL-6, intercellular adhesion molecule 1, CINC-1, and CINC-3 levels. This was accompanied by a decrease in intestinal p38 MAPK activity. Administration of resveratrol improved all of the above parameters. Resveratrol treatment also increased intestinal heme oxygenase 1 expression as compared with vehicle-treated trauma-hemorrhaged rats. Administration of ICI 182,780, SB-203850, or chromium-mesoporphyrin with resveratrol abolished the resveratrol-mediated improvement of the above parameters. Resveratrol administration also attenuated trauma-hemorrhage-induced cardiac dysfunction and edema of the lung. These results suggest that estrogen receptor-dependent upregulation of the p38 MAPK/heme oxygenase 1 pathway plays a critical role in mediating the salutary effects of resveratrol on shock-induced intestinal injury.
Asunto(s)
Hemo-Oxigenasa 1/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Choque Hemorrágico/metabolismo , Estilbenos/uso terapéutico , Heridas y Lesiones/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-6/metabolismo , Intestinos/lesiones , Masculino , Peroxidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/genética , Resveratrol , Choque Hemorrágico/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismo , Heridas y Lesiones/tratamiento farmacológicoRESUMEN
Astringinin can attenuate organ injury following trauma-hemorrhage, the mechanism remains unknown. Protein kinase B/hemeoxygenase-1 (Akt/HO-1) pathway exerts potent anti-inflammatory effects in various tissues. The aim of this study is to elucidate whether Akt/HO-1 plays any role in astringinin-mediated attenuation of hepatic injury following trauma-hemorrhage. For study this, male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure 35-40 mmHg for 90 min) followed by fluid resuscitation. A single dose of astringinin (0.3 mg/kg body weight) with or without a PI3K inhibitor (wortmannin) or a HO antagonist (chromium-mesoporphyrin) was administered during resuscitation. Various parameters were measured at 24 h post-resuscitation. Results showed that trauma-hemorrhage increased plasma aspartate and alanine aminotransferases (AST and ALT) concentrations and hepatic myeloperoxidase activity, cytokine induced neutrophil chemoattractant (CINC)-1, CINC-3, intercellular adhesion molecule-1, and interleukin-6 levels. These parameters were significantly improved in the astringinin-treated rats subjected to trauma-hemorrhage. Astringinin treatment also increased hepatic Akt activation and HO-1 expression as compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of wortmannin or chromium-mesoporphyrin abolished the astringinin-induced beneficial effects on post-resuscitation pro-inflammatory responses and hepatic injury. These findings collectively suggest that the salutary effects of astringinin administration on attenuation of hepatic injury after trauma-hemorrhage are likely mediated via Akt dependent HO-1 up-regulation.
Asunto(s)
Hemo-Oxigenasa 1/metabolismo , Hemorragia/tratamiento farmacológico , Hígado/lesiones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Estilbenos/uso terapéutico , Heridas y Lesiones/tratamiento farmacológico , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Hemorragia/sangre , Hemorragia/complicaciones , Hemorragia/enzimología , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-6/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Peroxidasa/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Estilbenos/farmacología , Heridas y Lesiones/sangre , Heridas y Lesiones/complicaciones , Heridas y Lesiones/enzimologíaRESUMEN
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, decreases NO synthesis. Plasma ADMA concentrations increase markedly in hypertension. We tested whether the development of hypertension and the increases in ADMA in spontaneously hypertensive rats (SHR) are prevented by aliskiren, a renin inhibitor. Male SHRs and normotensive Wistar Kyoto (WKY) control rats, aged 4 weeks (pre-hypertensive stage), were assigned to 4 groups: untreated SHRs and WKY rats, and SHRs that received oral aliskiren 10 and 30 mg/kg/day for 6 weeks. All rats were sacrificed at age 10 weeks. Blood pressure decreased at age 6, 8, and 10 weeks in SHRs that received high-dose aliskiren. Aliskiren mitigated the increases in plasma ADMA in SHRs. Renal ADMA levels were lower in SHRs that received high-dose aliskiren versus SHRs. SHRs experienced decreased plasma and kidney l-Arg-to-ADMA ratios versus control rats, which were reverted by 30 mg/kg aliskiren. Renal cortical neuronal NOS-α and -ß levels increased in SHRs fed with high-dose aliskiren. Early aliskiren treatment mitigates increases in ADMA, restores l-Arg-to-ADMA ratios, enhances neuronal NOS-α, prevents decreased nNOS-ß levels in the kidney-which might restore NO bioavailability and contribute to the decrease of blood pressure in young SHRs. Our findings suggest that aliskiren is a therapeutic agent for prehypertension that regulates the ADMA/NO pathway.
Asunto(s)
Amidas/farmacología , Antihipertensivos/farmacología , Arginina/análogos & derivados , Fumaratos/farmacología , Hipertensión/prevención & control , Animales , Arginina/metabolismo , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipertensión/enzimología , Hipertensión/metabolismo , Hipertensión/fisiopatología , Corteza Renal/efectos de los fármacos , Corteza Renal/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas , Ratas Endogámicas SHR , Renina/metabolismoRESUMEN
BACKGROUND: Protein kinase B (Akt) is known to be involved in pro-inflammatory and chemotactic events in response to injury. Akt activation also leads to the induction of hemeoxygenase (HO)-1, which exerts potent anti-inflammatory effects. The aim of this study is to elucidate whether Akt/HO-1 plays any role in resveratrol-mediated attenuation of hepatic injury after trauma hemorrhage. METHODS: Male Sprague-Dawley rats were subjected to trauma hemorrhage. A single dose of resveratrol (30-mg/kg body weight) with or without a PI3 K inhibitor (wortmannin) or an HO antagonist (chromium-mesoporphyrin) was administered intravenously during resuscitation. Various parameters were measured at 24 hours postresuscitation. RESULTS: Results showed that trauma hemorrhage increased hepatic myeloperoxidase activity, cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-3, intercellular adhesion molecule-1, and interleukin-6 levels and plasma aspartate and alanine aminotransferases concentrations. These parameters were significantly improved in the resveratrol-treated rats subjected to trauma hemorrhage. Resveratrol treatment also increased hepatic Akt activation and HO-1 expression as compared with vehicle-treated trauma hemorrhaged rats. Coadministration of wortmannin or chromium-mesoporphyrin prevented the beneficial effects of resveratrol administration on postresuscitation proinflammatory responses and hepatic injury. CONCLUSION: These findings collectively suggest that the salutary effects of resveratrol administration on attenuation of hepatic injury after trauma hemorrhage are likely mediated via up-regulation of Akt-dependent HO-1 expression.