RESUMEN
The decrease in tight junction proteins and their adapter proteins in the hypertensive brain is remarkable. Here, we aimed to investigate tight junction proteins and peroxisome proliferator-activated receptor (PPARγ) activation as well as inflammation factors and cell death proteins in the brainstem of hypertension models, namely spontaneously hypertensive rats (SHR) and borderline hypertensive rats (BHR). At first, SHR and BHR groups were treated with PPARγ agonist, pioglitazone. Then, occludin, claudin-1, claudin-2, claudin-12, ZO-1, and NF-κB p65 gene expression levels; pIKKß, NF-κB p65, TNF, IL-1ß, caspase-3, caspase-9 levels, and PARP-1 cleavage were evaluated. Significantly lower pIKKß, NF-κB p65, TNF, and IL-1ß levels were measured in pioglitazone-treated SHR. Results from this study confirm higher occludin (1.35-fold), claudin-2 (7.45-fold), claudin-12 (1.12-fold), and NF-κB p65 subunit (4.76-fold) expressions in the BHR group when compared to the SHR group. Pioglitazone was found effective in terms of regulating gene expression in SHR. Pioglitazone significantly increased occludin (8.17-fold), claudin-2 (2.41-fold), and claudin-12 (1.85-fold) mRNA levels, which were accompanied by decreased cleaved caspase-3, caspase-9 levels, PARP-1 activation, and proinflammatory factor levels in SHR (p Ë 0.05). Our work has led us to conclude that alterations in tight junction proteins, particularly occludin, and cell death parameters in the brainstem following PPARγ activation may contribute to neuroprotection in essential hypertension.
Asunto(s)
Hipertensión , PPAR gamma , Ratas , Animales , Pioglitazona/farmacología , PPAR gamma/metabolismo , FN-kappa B/metabolismo , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Agonistas de PPAR-gamma , Proteínas de Uniones Estrechas/genética , Proteínas de Uniones Estrechas/metabolismo , Ocludina/genética , Ocludina/metabolismo , Claudina-2/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Hipertensión/tratamiento farmacológico , Ratas Endogámicas SHR , Muerte Celular , Tronco Encefálico/metabolismoRESUMEN
Reactive oxygen and nitrogen species produced at low levels under normal cellular metabolism act as important signal molecules. However, at increased production, they cause damage associated with oxidative stress, which can lead to the development of many diseases, such as cardiovascular, metabolic, neurodegenerative, diabetes, and cancer. The defense systems used to maintain normal redox homeostasis plays an important role in cellular responses to oxidative stress. The key players here are Nrf2-regulated redox signaling and autophagy. A tight interface has been described between these two processes under stress conditions and their role in oxidative stress-induced diseases progression. In this review, we focus on the role of Nrf2 as a key player in redox regulation in cell response to oxidative stress. We also summarize the current knowledge about the autophagy regulation and the role of redox signaling in this process. In line with the focus of our review, we describe in more detail information about the interplay between Nrf2 and autophagy pathways in myocardium and the role of these processes in cardiovascular disease development.
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Enfermedades Cardiovasculares , Factor 2 Relacionado con NF-E2 , Autofagia , Enfermedades Cardiovasculares/metabolismo , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Background: Large epidemiological studies point towards a link between the incidence of arterial hypertension, ischaemic heart disease, metabolic disease and exposure to traffic noise, supporting the role of noise exposure as an independent cardiovascular risk factor. We characterised the underlying molecular mechanisms leading to noise-dependent adverse effects on the vasculature and myocardium in an animal model of aircraft noise exposure and identified oxidative stress and inflammation as central players in mediating vascular and cardiac dysfunction. Here, we studied the impact of noise-induced oxidative DNA damage on vascular function in DNA-repair deficient 8-oxoguanine glycosylase knockout (Ogg1-/-) mice.Methods and results: Noise exposure (peak sound levels of 85 and mean sound level of 72 dB(A) applied for 4d) caused oxidative DNA damage (8-oxoguanine) and enhanced NOX-2 expression in C57BL/6 mice with synergistic increases in Ogg1-/- mice (shown by immunohistochemistry). A similar pattern was found for oxidative burst of blood leukocytes and other markers of oxidative stress (4-hydroxynonenal, 3-nitrotyrosine) and inflammation (cyclooxygenase-2). We observed additive impairment of noise exposure and genetic Ogg1 deficiency on endothelium-independent relaxation (nitroglycerine), which may be due to exacerbated oxidative DNA damage leading to leukocyte activation and oxidative aldehyde dehydrogenase inhibition.Conclusions: The finding that chronic noise exposure causes oxidative DNA damage in mice is worrisome since these potential mutagenic lesions could contribute to cancer progression. Human field studies have to demonstrate whether oxidative DNA damage is also found in urban populations with high levels of noise exposure as recently shown for workers with high occupational noise exposure.
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Aeronaves , Daño del ADN , ADN Glicosilasas/deficiencia , Exposición a Riesgos Ambientales/efectos adversos , Nitratos/metabolismo , Ruido/efectos adversos , Estallido Respiratorio/fisiología , Animales , ADN Glicosilasas/genética , Ratones , Ratones Noqueados , Estrés Oxidativo/fisiologíaRESUMEN
The peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor and nutrition factor which takes part in the cellular signaling by several agonists such as pioglitazone. PPARγ can serve as potential target in treatments of metabolic syndrome diseases and/or hypertension. In the present study we investigated the effects of pioglitazone, a PPARγ agonist, on hypertension development in young and adult borderline hypertensive rats (BHR). In renal signaling we observed connections between PPARγ and Nrf2, antioxidant in adult animals and differences between young and adult BHR in Nrf2-activated detoxificant outputs (NQO1, HO-1) and NO-synthases. Blood pressure in animals had been detected by cuff plethysmography, cell signaling in the kidney was studied by gene expression determination using qPCR, and nitric oxide synthase (NOS) activity was measured by radioactive detection. Pioglitazone treatment in adult BHR caused no detectable changes in antioxidant and detoxificant responses. The main effects were observed in blood pressure improvement, endothelial NOS expression and NOS activities in both young and adult BHR.
Asunto(s)
Envejecimiento/fisiología , Hipertensión , Riñón/efectos de los fármacos , Riñón/metabolismo , PPAR gamma/agonistas , Pioglitazona/farmacología , Envejecimiento/efectos de los fármacos , Animales , Hipertensión/fisiopatología , RatasRESUMEN
Inhibition of nitric oxide (NO) production can influence blood pressure regulation and increase hypertension. Asymmetric dimethylarginine, ADMA, an analogue of L-arginine, can inhibit NO synthesis, impair endothelial function, and is a risk marker of cardiovascular diseases. Homocysteine (Hcy) level affects oxidative stress production of reactive oxygen species (ROS) in hypertension and also influences changes in signaling and cell damage. The present study was focused on experimental effects of exogenous NOS inhibitors and their effect on ADMA, an endogenous NOS inhibitor, homocysteine and ROS production measured as reactive oxidative metabolites (ROM). We compared effects of the two potential exogenous NO-inhibitors: NG-nitro L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI). Levels of ADMA, Hcy, ROM and total thiols (TTL) were not changed in the L-NAME group. With 7-NI administration, we observed unchanged NOS activity in the left ventricle and a pronounced decrease of ADMA and Hcy levels, accompanied by ROM over-production in plasma. TTL/ROM ratio was more favorable than in the L-NAME group. We observed that 7-NI, an exogenous NOinhibitor, can decrease and improve the levels of ADMA, Hcy, and ROM, and increase TTL/ROM ratio in the plasma of spontaneously hypertensive rats.
Asunto(s)
Arginina/análogos & derivados , Inhibidores Enzimáticos/farmacología , Homocisteína/sangre , Hipertensión/enzimología , Indazoles/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Aorta/efectos de los fármacos , Aorta/enzimología , Aorta/fisiopatología , Arginina/sangre , Biomarcadores/sangre , Modelos Animales de Enfermedad , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/enzimología , Ventrículos Cardíacos/fisiopatología , Hipertensión/sangre , Hipertensión/fisiopatología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/metabolismo , Oxidación-Reducción , Ratas Endogámicas SHRRESUMEN
Although the role of nitric oxide (NO) in essential hypertension is still unclear, the effects of long-term NO deficiency have not yet been investigated during the critical juvenile period in spontaneously hypertensive rats (SHR). We aimed to analyze the effects of chronic NO synthase (NOS) inhibition on systolic blood pressure (sBP), vasoactivity, morphological changes and superoxide level in the thoracic aorta (TA), NOS activity in different tissues, and general biomarkers of oxidative stress in plasma of young SHR. Four-week-old SHR were treated with NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, p.o.) for 4-5 weeks. L-NAME treatment induced a transient sBP increase only, and surprisingly, slightly inhibited endothelium-dependent relaxation of TA. Hereby, the inhibition of NOS activity varied from tissue to tissue, ranging from the lowest in the TA and the kidney to the highest in the brain stem. In spite of an increased sensitivity of adrenergic receptors, the maximal adrenergic contraction of TA was unchanged, which was associated with changes in elastin arrangement and an increase in wall thickness. The production of reactive oxygen species in the TA was increased; however, the level of selected biomarkers of oxidative stress did not change. Our findings proved that the TA of young SHR responded to chronic NO deficiency by the development of adaptive mechanisms on the functional (preserved NO-derived vasorelaxation, unincreased contraction) and molecular (preserved NOS activity) level.
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Aorta Torácica/metabolismo , Hipertensión/metabolismo , Óxido Nítrico Sintasa/metabolismo , Ratas Endogámicas SHR/metabolismo , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/patología , Biomarcadores/metabolismo , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Hipertensión/tratamiento farmacológico , Masculino , NG-Nitroarginina Metil Éster/uso terapéutico , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Especies Reactivas de Oxígeno/metabolismo , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
BACKGROUND: The brain stem contains important nuclei that control cardiovascular function via the sympathetic nervous system (SNS), which is strongly influenced by nitric oxide. Its biological activity is also largely determined by oxygen free radicals. Despite many experimental studies, the role of AT1R-NAD(P)H oxidase-superoxide pathway in NO-deficiency is not yet sufficiently clarified. We determined changes in free radical signaling and antioxidant and detoxification response in the brain stem of young and adult Wistar rats during chronic administration of exogenous NO inhibitors. METHODS: Young (4 weeks) and adult (10 weeks) Wistar rats were treated with 7-nitroindazole (7-NI group, 10 mg/kg/day), a specific nNOS inhibitor, with NG-nitro-L-arginine-methyl ester (L-NAME group, 50 mg/kg/day), a nonspecific NOS inhibitor, and with drinking water (Control group) during 6 weeks. Systolic blood pressure was measured by non-invasive plethysmography. Expression of genes (AT1R, AT2R, p22phox, SOD and NOS isoforms, HO-1, MDR1a, housekeeper GAPDH) was identified by real-time PCR. NOS activity was detected by conversion of [3H]-L-arginine to [3H]-L-citrulline and SOD activity was measured using UV VIS spectroscopy. RESULTS: We observed a blood pressure elevation and decrease in NOS activity only after L-NAME application in both age groups. Gene expression of nNOS (youngs) and eNOS (adults) in the brain stem decreased after both inhibitors. The radical signaling pathway triggered by AT1R and p22phox was elevated in L-NAME adults, but not in young rats. Moreover, L-NAME-induced NOS inhibition increased antioxidant response, as indicated by the observed elevation of mRNA SOD3, HO-1, AT2R and MDR1a in adult rats. 7-NI did not have a significant effect on AT1R-NADPH oxidase-superoxide pathway, yet it affected antioxidant response of mRNA expression of SOD1 and stimulated total activity of SOD in young rats and mRNA expression of AT2R in adult rats. CONCLUSION: Our results show that chronic NOS inhibition by two different NOS inhibitors has age-dependent effect on radical signaling and antioxidant/detoxificant response in Wistar rats. While 7-NI had neuroprotective effect in the brain stem of young Wistar rats, L-NAME- induced NOS inhibition evoked activation of AT1R-NAD(P)H oxidase pathway in adult Wistar rats. Triggering of the radical pathway was followed by activation of protective compensation mechanism at the gene expression level.
Asunto(s)
Antioxidantes/metabolismo , Tronco Encefálico/metabolismo , Inhibidores Enzimáticos/farmacología , Radicales Libres/metabolismo , Inactivación Metabólica , Óxido Nítrico Sintasa/antagonistas & inhibidores , Factores de Edad , Animales , Tronco Encefálico/efectos de los fármacos , Indazoles/farmacología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/deficiencia , Ratas , Ratas WistarRESUMEN
Activation of nuclear factor-κB (NF-κB) by increased production of reactive oxygen species (ROS) might induce transcription and expression of different antioxidant enzymes and also of nitric oxide synthase (NOS) isoforms. Thus, we aimed at studying the effect of NF-κB inhibition, caused by JSH-23 (4-methyl-N (1)-(3-phenyl-propyl)-benzene-1,2-diamine) injection, on ROS and NO generation in hereditary hypertriglyceridemic (HTG) rats. 12-week-old, male Wistar and HTG rats were treated with JSH-23 (bolus, 10 µmol, i.v.). After one week, blood pressure (BP), superoxide dismutase (SOD) activity, SOD1, endothelial NOS (eNOS), and NF-κB (p65) protein expressions were higher in the heart of HTG rats compared to control rats. On the other hand, NOS activity was decreased. In HTG rats, JSH-23 treatment increased BP and heart conjugated dienes (CD) concentration (measured as the marker of tissue oxidative damage). Concomitantly, SOD activity together with SOD1 expression was decreased, while NOS activity and eNOS protein expression were increased significantly. In conclusion, NF-κB inhibition in HTG rats led to decreased ROS degradation by SOD followed by increased oxidative damage in the heart and BP elevation. In these conditions, increased NO generation may represent rather a counterregulatory mechanism activated by ROS. Nevertheless, this mechanism was not sufficient enough to compensate BP increase in HTG rats.
Asunto(s)
Miocardio/metabolismo , Factor de Transcripción ReIA/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Glutatión/análisis , Ventrículos Cardíacos/metabolismo , Hiperlipoproteinemia Tipo IV/patología , Hiperlipoproteinemia Tipo IV/veterinaria , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fenilendiaminas/farmacología , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Factor de Transcripción ReIA/genéticaRESUMEN
Quercetin (QCT) is flavonoid that possesses various biological functions including anti-oxidative and radical-scavenging activities. Moreover, QCT exerts some preventive actions in treatment of cardiovascular diseases. The aim of present study was to explore effects of prolonged administration of QCT on changes induced by repeated application of doxorubicin (DOX) in rat hearts. We focused on the ultrastructure of myocardium, matrix metalloproteinases (MMPs), biometric parameters, and apoptosis induction. Our aim was also to examine effects of QCT on ischemic tolerance in hearts exposed to chronic effects of DOX, and to determine possible mechanisms underlying effects of QCT. Our results showed that QCT prevented several negative chronic effects of DOX: (I) reversed DOX-induced blood pressure increase; (II) mediated improvement of deleterious effects of DOX on ultrastructure of left ventricle; (III) prevented DOX-induced effects on tissue MMP-2 activation; and (iv) reversed effects of DOX on apoptosis induction and superoxide dismutase inhibition. Moreover, we showed that rat hearts exposed to effects of QCT were more resistant to ischemia/reperfusion injury. Effects of QCT on modulation of ischemic tolerance were linked to Akt kinase activation and connexin-43 up-regulation. Taken together, these results demonstrate that prolonged treatment with QCT prevented negative chronic effects of DOX on blood pressure, cellular damage, MMP-2 activation, and apoptosis induction. Moreover, QCT influenced myocardial responses to acute ischemic stress. These facts bring new insights into mechanisms of QCT action on rat hearts exposed to the chronic effects of DOX.
Asunto(s)
Apoptosis/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Ventrículos Cardíacos/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Quercetina/farmacología , Daño por Reperfusión/tratamiento farmacológico , Animales , Presión Sanguínea/efectos de los fármacos , Conexina 43/metabolismo , Ventrículos Cardíacos/metabolismo , Masculino , Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Daño por Reperfusión/metabolismo , Superóxido Dismutasa/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
While the unequivocal pattern of endothelial nitric oxide synthase (eNOS) inhibition in cardiovascular control is recognized, the role of NO produced by neuronal NOS (nNOS) remains unclear. The aim of this study was to compare the effects of chronic treatment with 7-nitroindazole (7-NI, nNOS inhibitor) and NG-nitro-l-arginine methylester (l-NAME, general and predominantly eNOS inhibitor) on cardiovascular system of young normotensive rats. Wistar rats (4 weeks old) were used: controls and rats administered either 7-NI (10 mg/kg bw/day) or l-NAME (50 mg/kg bw/day) in drinking water for 6 weeks. The systolic blood pressure (sBP) was measured by plethysmographic method, and the vasoactivity of isolated arteries was recorded. 7-NI-treatment did not affect sBP; however, the sBP was increased after l-NAME-treatment. l-NAME inhibited acetylcholine-induced relaxation of thoracic aorta (TA), whereas it remained unchanged after 7-NI-treatment. The response of TA to sodium nitroprusside was increased in both experimental groups. The expression of eNOS and nNOS in TA was unchanged in both experimental groups, whereas the activity of NOS was decreased in l-NAME-treated group. Noradrenaline- and angiotensin II-induced contractions of TA were reduced in l-NAME-treated group; however, the contractions remained unchanged in 7-NI-treated group. In all groups, the endogenous angiotensin II participated in adrenergic contraction of TA; this contribution was significantly increased in l-NAME-treated group. Neurogenic contractions in mesenteric artery (MA) remained unchanged after 7-NI-treatment, but increased after l-NAME-treatment. Results show that NO deficiency induced by administration of 7-NI and l-NAME had different cardiovascular effects: eNOS and nNOS triggered distinct signaling pathways in young normotensive rats
Asunto(s)
Animales , Ratas , Vasodilatadores/farmacocinética , Ligasas/farmacocinética , Ácido Nítrico/farmacocinética , Fenómenos Fisiológicos Cardiovasculares , Indazoles/farmacocinética , NG-Nitroarginina Metil Éster/farmacocinética , Nitroprusiato/farmacocinéticaRESUMEN
Metabolic syndrome (MetS), which is rapidly becoming prevalent worldwide, is long known to be associated with hypertension and recently with oxidative stress. Of note is that oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, contributes to sympathoexcitation and hypertension. This study sought to identify the source of tissue oxidative stress in RVLM and their roles in neural mechanism of hypertension associated with MetS. Adult normotensive rats subjected to a high-fructose diet for 8 weeks developed metabolic traits of MetS, alongside increases in sympathetic vasomotor activity and blood pressure. In RVLM of these MetS rats, the tissue level of reactive oxygen species was increased, nitric oxide (NO) was decreased, and mitochondrial electron transport capacity was reduced. Whereas the protein expression of neuronal NO synthase (nNOS) or protein inhibitor of nNOS was increased, the ratio of nNOS dimer/monomer was significantly decreased. Oral intake of pioglitazone or intracisternal infusion of tempol or coenzyme Q10 significantly abrogated all those molecular events in high-fructose diet-fed rats and ameliorated sympathoexcitation and hypertension. Gene silencing of protein inhibitor of nNOS mRNA in RVLM using lentivirus carrying small hairpin RNA inhibited protein inhibitor of nNOS expression, increased the ratio of nNOS dimer/monomer, restored NO content, and alleviated oxidative stress in RVLM of high-fructose diet-fed rats, alongside significantly reduced sympathoexcitation and hypertension. These results suggest that redox-sensitive and protein inhibitor of nNOS-mediated nNOS uncoupling is engaged in a vicious cycle that sustains the production of reactive oxygen species in RVLM, resulting in sympathoexcitation and hypertension associated with MetS.
Asunto(s)
Dineínas Citoplasmáticas/metabolismo , Hipertensión/metabolismo , Bulbo Raquídeo/metabolismo , Síndrome Metabólico/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Western Blotting , Dineínas Citoplasmáticas/genética , Dieta Alta en Grasa/efectos adversos , Hipertensión/etiología , Hipertensión/fisiopatología , Hipoglucemiantes/farmacología , Masculino , Síndrome Metabólico/etiología , Microscopía Confocal , NADPH Oxidasas/metabolismo , Oxidación-Reducción , Pioglitazona , Interferencia de ARN , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Tiazolidinedionas/farmacología , Sistema Vasomotor/efectos de los fármacos , Sistema Vasomotor/fisiologíaRESUMEN
While the unequivocal pattern of endothelial nitric oxide synthase (eNOS) inhibition in cardiovascular control is recognized, the role of NO produced by neuronal NOS (nNOS) remains unclear. The aim of this study was to compare the effects of chronic treatment with 7-nitroindazole (7-NI, nNOS inhibitor) and N(G)-nitro-L-arginine methylester (L-NAME, general and predominantly eNOS inhibitor) on cardiovascular system of young normotensive rats. Wistar rats (4 weeks old) were used: controls and rats administered either 7-NI (10 mg/kg bw/day) or L-NAME (50 mg/kg bw/day) in drinking water for 6 weeks. The systolic blood pressure (sBP) was measured by plethysmographic method, and the vasoactivity of isolated arteries was recorded. 7-NI-treatment did not affect sBP; however, the sBP was increased after L-NAME-treatment. L-NAME inhibited acetylcholine-induced relaxation of thoracic aorta (TA), whereas it remained unchanged after 7-NI-treatment. The response of TA to sodium nitroprusside was increased in both experimental groups. The expression of eNOS and nNOS in TA was unchanged in both experimental groups, whereas the activity of NOS was decreased in L-NAME-treated group. Noradrenaline- and angiotensin II-induced contractions of TA were reduced in L-NAME-treated group; however, the contractions remained unchanged in 7-NI-treated group. In all groups, the endogenous angiotensin II participated in adrenergic contraction of TA; this contribution was significantly increased in L-NAME-treated group. Neurogenic contractions in mesenteric artery (MA) remained unchanged after 7-NI-treatment, but increased after L-NAME-treatment. Results show that NO deficiency induced by administration of 7-NI and L-NAME had different cardiovascular effects: eNOS and nNOS triggered distinct signaling pathways in young normotensive rats.
Asunto(s)
Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Vasoconstrictores/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Presión Sanguínea/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , Indazoles/farmacología , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo III/genética , Nitroprusiato/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Vasoconstricción/efectos de los fármacosRESUMEN
This study investigated the influence of chronic crowding stress on nitric oxide (NO) production, vascular function and oxidative status in young Wistar-Kyoto (WKY), borderline hypertensive (BHR) and spontaneously hypertensive (SHR) female rats. Five-week old rats were exposed to crowding for two weeks. Crowding elevated plasma corticosterone (P<0.05) and accelerated BP (P<0.01 versus basal) only in BHR. NO production and superoxide concentration were significantly higher in the aortas of control BHR and SHR versus WKY. Total acetylcholine (ACh)-induced relaxation in the femoral artery was reduced in control SHR versus WKY and BHR, and stress did not affect it significantly in any genotype. The attenuation of ACh-induced relaxation in SHR versus WKY was associated with reduction of its NO-independent component. Crowding elevated NO production in all strains investigated but superoxide concentration was increased only in WKY, which resulted in reduced NO-dependent relaxation in WKY. In crowded BHR and SHR, superoxide concentration was either unchanged or reduced, respectively, but NO-dependent relaxation was unchanged in both BHR and SHR versus their respective control group. This study points to genotype-related differences in stress vulnerability in young female rats. The most pronounced negative influence of stress was observed in BHR despite preserved endothelial function.
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Presión Sanguínea , Aglomeración , Arteria Femoral/fisiopatología , Óxido Nítrico/metabolismo , Estrés Psicológico/fisiopatología , Vasoconstricción , Sistema Vasomotor/fisiopatología , Animales , Femenino , Genética de Población , Genotipo , Hipertensión , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especificidad de la EspecieRESUMEN
Reactive oxygen species (ROS) are products of normal cellular metabolism and derive from various sources in different cellular compartments. Oxidative stress resultant from imbalance between ROS generation and antioxidant defense mechanisms is important in pathogenesis of cardiovascular diseases, such as hypertension, heart failure, atherosclerosis, diabetes, and cardiac hypertrophy. In this review we focus on hypertension and address sources of cellular ROS generation, mechanisms involved in regulation of radical homeostasis, superoxide dismutase isoforms in pathophysiology of hypertension; as well as radical intracellular signaling and phosphorylation processes in proteins of the affected cardiovascular tissues. Finally, we discuss the transcriptional factors involved in redox-sensitive gene transcription and antioxidant response, as well as their roles in hypertension.
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Sistema Cardiovascular/fisiopatología , Hipertensión/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , Animales , Sistema Cardiovascular/metabolismo , Humanos , Hipertensión/etiología , Ratones , Oxidación-Reducción , Ratas , Transducción de SeñalRESUMEN
PPAR γ receptor plays an important role in oxidative stress response. Its agonists can influence vascular contractility in experimental hypertension. Our study was focused on the effects of a PPAR γ agonist pioglitazone (PIO) on blood pressure regulation, vasoactivity of vessels, and redox-sensitive signaling at the central (brainstem, BS) and peripheral (left ventricle, LV) levels in young prehypertensive rats. 5-week-old SHR were treated either with PIO (10 mg/kg/day, 2 weeks) or with saline using gastric gavage. Administration of PIO significantly slowed down blood pressure increase and improved lipid profile and aortic relaxation after insulin stimulation. A significant increase in PPAR γ expression was found only in BS, not in LV. PIO treatment did not influence NOS changes, but had tissue-dependent effect on SOD regulation and increased SOD activity, observed in LV. The treatment with PIO differentially affected also the levels of other intracellular signaling components: Akt kinase increased in the the BS, while ß -catenin level was down-regulated in the BS and up-regulated in the LV. We found that the lowering of blood pressure in young SHR can be connected with insulin sensitivity of vessels and that ß -catenin and SOD levels are important agents mediating PIO effects in the BS and LV.
RESUMEN
We aimed to perform a chemical analysis of both Alibernet red wine and an alcohol-free Alibernet red wine extract (AWE) and to investigate the effects of AWE on nitric oxide and reactive oxygen species production as well as blood pressure development in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHRs). Total antioxidant capacity together with total phenolic and selected mineral content was measured in wine and AWE. Young 6-week-old male WKY and SHR were treated with AWE (24,2 mg/kg/day) for 3 weeks. Total NOS and SOD activities, eNOS and SOD1 protein expressions, and superoxide production were determined in the tissues. Both antioxidant capacity and phenolic content were significantly higher in AWE compared to wine. The AWE increased NOS activity in the left ventricle, aorta, and kidney of SHR, while it did not change NOS activity in WKY rats. Similarly, increased SOD activity in the plasma and left ventricle was observed in SHR only. There were no changes in eNOS and SOD1 expressions. In conclusion, phenolics and minerals included in AWE may contribute directly to increased NOS and SOD activities of SHR. Nevertheless, 3 weeks of AWE treatment failed to affect blood pressure of SHR.
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Hipertensión/metabolismo , Óxido Nítrico/metabolismo , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno/metabolismo , Vino/análisis , Animales , Antioxidantes/química , Antioxidantes/farmacología , Aorta/efectos de los fármacos , Aorta/enzimología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/enzimología , Hipertensión/patología , Riñón/efectos de los fármacos , Riñón/enzimología , Masculino , Minerales/análisis , Minerales/farmacología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Extractos Vegetales/química , Polifenoles/análisis , Polifenoles/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Vitis/químicaRESUMEN
AIM: To investigate the role of matrix metalloproteinases (MMPs) in the responses of rats to a prolonged doxorubicin (DOX) treatment. METHODS: Male Wistar rats were used. DOX was administered by intraperitoneal injections of seven doses (cumulative dose was 15 mg/kg). Control animals were treated with saline. Tissue or plasma samples were collected at four and eight weeks after the application of the last dose. Protein levels were determined by immunoblot assay, and MMP activities were measured by gelatin zymography. Superoxide content was analyzed using a lucigenin chemiluminescence assay and superoxide dismutase (SOD) activities with a SOD assay kit. Qualitative structural alterations of the heart were characterized by transmission electron microscopy. RESULTS: Systolic blood pressure was higher in DOX-treated rats as compared with the control rats at 8 weeks after treatment. In contrast, there were no differences in the heart rate between the control and DOX-treated rats. DOX treatment caused marked heterogeneous subcellular alterations of cardiomyocytes and structural disorganizations of the cardiac extracellular space. The effects of DOX were linked to a stimulation of plasma MMP-2 and MMP-9 activities that had already increased by 4 weeks after the end of the treatment. In the left ventricle, however, DOX only led to increased MMP-2 activation at 8 weeks after the end of treatment. These changes in tissue MMP-2 were connected with stimulation of Akt kinase activation, inhibition of SOD, an increase in superoxide levels, induction of iNOS protein expression and caspase-3 activation. CONCLUSION: Our results show that MMPs are involved in the chronic cardiotoxicity of DOX in rats. The data also suggest that reactive oxygen species (superoxide), NO production (iNOS) and the Akt kinase pathway can modulate MMP-2 activities in rat hearts influenced by DOX.
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Antibióticos Antineoplásicos/toxicidad , Doxorrubicina/toxicidad , Corazón/efectos de los fármacos , Metaloproteinasas de la Matriz/metabolismo , Animales , Caspasa 3/metabolismo , Activación Enzimática/efectos de los fármacos , Masculino , Metaloproteinasas de la Matriz/sangre , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Superóxidos/metabolismoRESUMEN
OBJECTIVES: This paper reviews and compares major approaches and strategies to modulation of antioxidative response in the therapy of hypertension and cardiovascular diseases. DESIGN: There are two major strategies of modulation of antioxidative response in hypertension and cardiovascular diseases: (i) modulation of NO levels by NOS stimulation, increase of NO bioavailability, administration of NO, and NOS gene incorporation; (ii) scavenging of superoxide and suppression of oxidative stress by activation of antioxidant gene expression or by suppression of selected genes by RNA silencing. These strategies are accomplished by several concepts, including (1) delivery of external agents, (2) antioxidant gene therapy and RNA silencing, and (3) combined therapies and approaches. CONCLUSION: Combined therapies and approches often achieve multiplicative effects and are the most promising attitude in antioxidant-oriented therapy of hypertension and cardiovascular diseases.
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Antioxidantes/metabolismo , Antioxidantes/farmacología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/terapia , Hipertensión/metabolismo , Hipertensión/terapia , HumanosRESUMEN
The status of nitric oxide (NO) in spontaneously hypertensive rats (SHR) is unclear and its bioavailability may be affected by imbalance with reactive oxygen species. We studied cardiovascular effects of an NO donor, pentaerythrityl tetranitrate (PETN) in SHR. We used Wistar rats, SHR and SHR treated with PETN (200 mg/kg/day). After six weeks, myocardium and aorta from each group were taken for biochemical and iliac artery for functional and morphological study. Long-term administration of PETN to SHR increased cGMP level in platelets and did not affect blood pressure. In myocardium, the therapy resulted in a decrease in cardiac hypertrophy and MDA level, and the increased antioxidant enzyme activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx). In aorta, PETN decreased the NO-synthase activity and had no affect on the enzyme activities of SOD and GPx or on MDA level. In the iliac artery, the endothelium-dependent relaxation to acetylcholine was slightly improved and the maximum vasoconstriction to noradrenaline was decreased. Wall thickness, cross-sectional area, inner diameter, and wall thickness/ inner diameter measured after perfusion fixation (120 mmHg) were not affected. The small effect of PETN on cardiovascular system suggests that NO deficiency is probably not the main cause of pathological alterations in SHR.
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Aorta/efectos de los fármacos , Corazón/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Arteria Ilíaca/efectos de los fármacos , Donantes de Óxido Nítrico/uso terapéutico , Tetranitrato de Pentaeritritol/uso terapéutico , Acetilcolina/farmacología , Animales , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , GMP Cíclico/sangre , Glutatión Peroxidasa/metabolismo , Hipertensión/patología , Hipertensión/fisiopatología , Arteria Ilíaca/patología , Arteria Ilíaca/fisiopatología , Masculino , Miocardio/metabolismo , Óxido Nítrico Sintasa/metabolismo , Norepinefrina/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Superóxido Dismutasa/metabolismo , Vasoconstrictores/farmacología , Vasodilatadores/farmacologíaRESUMEN
The attenuated nitric oxide (NO) formation and/or elevated production of reactive oxygen species are often found in experimental and human hypertension. We aimed to determine possible effects of N-acetylcysteine (1.5 g/kg/day) and N-acetyl-5-methoxytryptamine (melatonin, 10 mg/kg/day) in adult spontaneously hypertensive rats (SHR) with established hypertension. After a six-week-treatment, blood pressure was measured and NO synthase (NOS) activity, concentration of conjugated dienes, protein expression of endothelial NOS, inducible NOS and nuclear factor-kappaB (NF-kappaB) in the left ventricle were determined. Both treatments improved the NO pathway by means of enhanced NOS activity and reduced reactive oxygen species level as indicated by decreased conjugated diene concentrations and lowered NF-kappaB expression. N-acetylcysteine (but not melatonin) also increased the endothelial NOS protein expression. However, only melatonin was able to reduce blood pressure significantly. Subsequent in vitro study revealed that both N-acetylcysteine and melatonin lowered the tone of phenylephrine-precontracted femoral artery via NO-dependent relaxation. Nevertheless, melatonin-induced relaxation also involved NO-independent component which was preserved even after the blockade of soluble guanylate cyclase by oxadiazolo[4,3-a]quinoxalin-1-one. In conclusion, both N-acetylcysteine and melatonin were able to improve the NO/reactive oxygen species balance in adult SHR, but blood pressure was significantly lowered by melatonin only. This implies that a partial restoration of NO/reactive oxygen species balance achieved by the antioxidants such as N-acetylcysteine has no therapeutic effect in adult rats with established hypertension. The observed antihypertensive effect of melatonin is thus mediated by additional mechanisms independent of NO pathway.