Effects of L-Arginine and α / 中国医学科学院学报

Kidney is one of the important organs of the body.With both excretory and endocrine functions,it plays a vital role in regulating the normal physiological state.As a precursor of the nitric oxide(NO)synthesis

Efeito agudo do exercício de força com restrição do fluxo sanguíneo sobre parâmetros antioxidantes em indivíduos jovens saudáveis / Acute effects of strength exercise with blood flow restriction on vascular function of young healthy males

O treinamento de força com restrição do fluxo sanguíneo (TFRFS) promove adaptações neuromusculares semelhantes às do treinamento de força tradicional utilizando pequenas cargas de treinamento. No entanto, sua repercussão sobre parâmetros antioxidantes e sobre a função vascular precisa ser mais bem compreendida. Objetivos: O objetivo do presente estudo foi investigar o efeito de uma sessão de exercício de força de baixa intensidade com restrição do fluxo sanguíneo, em comparação ao exercício de força de alta intensidade e de baixa intensidade sem restrição do fluxo sanguíneo, sobre os níveis de subprodutos do oxido nítrico e a atividade de enzimas antioxidantes em jovens saudáveis. Métodos: Onze indivíduos jovens realizaram três sessões de exercício de força: baixa intensidade com restrição do fluxo sanguíneo (BIRFS), alta intensidade (AI) ou baixa intensidade (BI). Foram avaliadas a atividade das enzimas antioxidantes catalase (CAT), superóxido dismutase (SOD) e dos metabólitos do óxido nítrico (NOx). Resultados: Não houve modificações nos níveis plasmáticos de NOx nas diferentes condições de exercício (p > 0,05). A atividade da SOD apresentou uma diminuição significativa na condição BIRFS (p < 0,05). A atividade da CAT diminuiu significativamente na condição BI (p < 0.05). Conclusões: A partir do presente estudo sugere-se que uma sessão de treinamento de força de baixa intensidade com restrição do fluxo sanguíneo não reduz a biodisponibilidade do óxido nítrico, bem como não induz desequilíbrio redox em indivíduos jovens saudáveis.

Strength training with blood flow restriction (STBFR) provokes similar neuromuscular adaptations to traditional strength training using low training loads. However, there is a need for better understanding of the repercussions for antioxidant parameters and vascular function. Objectives: The objective of the present study was to investigate the effects of a session of low intensity strength training with blood flow restriction, compared with high intensity and low intensity strength training without blood flow restriction, on the levels of nitric oxide products and antioxidant enzyme activity in healthy young men. Methods: Eleven young men performed three strength exercise sessions: low intensity with blood flow restriction (LIBFR), high intensity (HI), and low intensity (LI). Activity of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) was assessed and metabolites of nitric oxide (NOx) were assayed before and after each session. Results: There were no changes to NOx plasma levels under the different exercise conditions (p > 0.05). However, SOD activity exhibited a significant reduction after the LIBFR condition (p < 0.05), while CAT activity reduced significantly after the LI condition (p < 0.05). Conclusions: The results of this study suggest that one session of low intensity strength training with blood flow restriction does not reduce bioavailability of nitric oxide or induce redox imbalance in healthy young men.

Nitric oxide modulates ATP-evoked currents in mouse Leydig cells

Testosterone synthesis within Leydig cells is a calcium-dependent process. Intracellular calcium levels are regulated by different processes including ATP-activated P2X purinergic receptors, T-type Ca2+ channels modulated by the luteinizing hormone, and intracellular calcium storages recruited by a calcium-induced calcium release mechanism. On the other hand, nitric oxide (NO) is reported to have an inhibitory role in testosterone production. Based on these observations, we investigated the interaction between the purinergic and nitrergic systems in Leydig cells of adult mice. For this purpose, we recorded ATP-evoked currents in isolated Leydig cells using the whole cell patch clamp technique after treatment with L-NAME (300 μM and 1 mM), L-arginine (10, 100, 300, and 500 μM), ODQ (300 μM), and 8-Br-cGMP (100 μM). Our results show that NO produced by Leydig cells in basal conditions is insufficient to change the ATP-evoked currents and that extra NO provided by adding 300 μM L-arginine positively modulates the current through a mechanism involving the NO/cGMP signaling pathway. Thus, we report an interaction between the nitrergic and purinergic systems in Leydig cells and suggest that Ca2+ entry via the purinergic receptors can be regulated by NO.

Effects of a Single Bout of Resistance Exercise in Different Volumes on Endothelium Adaptations in Healthy Animals / Efeitos de uma Sessão de Exercício Resistido em Diferentes Volumes sobre Adaptações Endoteliais em Animais Saudáveis

Abstract Background: Resistance exercise (RE) has been recommended for patients with cardiovascular diseases. Recently, a few studies have demonstrated that the intensity of a single bout of RE has an effect on endothelial adaptations to exercise. However, there is no data about the effects of different volumes of RE on endothelium function. Objective: The aim of the study was to evaluate the effects of different volumes of RE in a single bout on endothelium-dependent vasodilatation and nitric oxide (NO) synthesis in the mesenteric artery of healthy animals. Methods: Male Wistar rats were divided into three groups: Control (Ct); low-volume RE (LV, 5 sets x 10 repetitions) and high-volume RE (HV, 15 sets x 10 repetitions). The established intensity was 70% of the maximal repetition test. After the exercise protocol, rings of mesenteric artery were used for assessment of vascular reactivity, and other mesenteric arteries were prepared for detection of measure NO production by DAF-FM fluorescence. Insulin responsiveness on NO synthesis was evaluated by stimulating the vascular rings with insulin (10 nM). Results: The maximal relaxation response to insulin increased in the HV group only as compared with the Ct group. Moreover, the inhibition of nitric oxide synthesis (L-NAME) completely abolished the insulin-induced vasorelaxation in exercised rats. NO production showed a volume-dependent increase in the endothelial and smooth muscle layer. In endothelial layer, only Ct and LV groups showed a significant increase in NO synthesis when compared to their respective group under basal condition. On the other hand, in smooth muscle layer, NO fluorescence increased in all groups when compared to their respective group under basal condition. Conclusions: Our results suggest that a single bout of RE promotes vascular endothelium changes in a volume-dependent manner. The 15 sets x 10 repetitions exercise plan induced the greatest levels of NO synthesis.

Resumo Fundamentos: O exercício resistido (ER) tem sido recomendado para pacientes com doenças cardiovasculares. Recentemente, alguns estudos demonstraram que a intensidade de uma sessão de ER exerce um efeito sobre a disfunção endotelial. No entanto, não há dados sobre os efeitos de diferentes volumes de ER sobre a função endotelial. Objetivo: O objetivo deste estudo foi avaliar os efeitos de diferentes volumes de ER, realizados em uma única sessão, sobre a vasodilatação dependente do endotélio e síntese de óxido nítrico (NO) em artéria mesentérica de animais saudáveis. Métodos: Ratos Wistar machos foram divididos em três grupos: Controle (Ct); baixo volume (BV, 5 séries x 10 repetições) e alto volume de ER (AV, 15 séries x 10 repetições). Foi estabelecida a intensidade de 70% do teste de repetição máxima. Após o protocolo de exercício, anéis de artéria mesentérica foram utilizados na avaliação da reatividade vascular, e outras artérias mesentéricas foram preparadas para a detecção da produção de NO por fluorescência com para do DAF-FM. A resposta à insulina pela síntese de NO foi avaliada estimulando-se os anéis vasculares com insulina (10nM). Resultados: A resposta máxima do relaxamento induzido por insulina foi aumentada somente no grupo AV em comparação ao grupo Ct. Além disso, a inibição da síntese do NO (L-NAME), aboliu completamente o relaxamento vascular induzido por insulina em ratos exercitados. A produção de NO mostrou um aumento dependente do volume no endotélio e no músculo liso. No endotélio, apenas os grupos Ct e BV mostraram aumento significativo na síntese de NO quando comparado aos seus respectivos grupos sob condição basal. No entanto, no músculo liso, a fluorescência foi aumentada em todos os grupos quando comparados aos seus respectivos grupos sob a condição basal. Conclusões: Nossos resultados sugerem que uma única sessão de ER foi capaz de promover adaptações no endotélio vascular. Além disso, nós observamos que este efeito é volume-dependente e o volume de 15 séries x10 repetições induziu o maior aumento na síntese de NO.

Effects of exercise training on stress-induced vascular reactivity alterations: role of nitric oxide and prostanoids

Background: Physical exercise may modify biologic stress responses. Objective: To investigate the impact of exercise training on vascular alterations induced by acute stress, focusing on nitric oxide and cyclooxygenase pathways. Method: Wistar rats were separated into: sedentary, trained (60-min swimming, 5 days/week during 8 weeks, carrying a 5% body-weight load), stressed (2 h-immobilization), and trained/stressed. Response curves for noradrenaline, in the absence and presence of L-NAME or indomethacin, were obtained in intact and denuded aortas (n=7-10). Results: None of the procedures altered the denuded aorta reactivity. Intact aortas from stressed, trained, and trained/stressed rats showed similar reduction in noradrenaline maximal responses (sedentary 3.54±0.15, stressed 2.80±0.10*, trained 2.82±0.11*, trained/stressed 2.97± 0.21*, *P<0.05 relate to sedentary). Endothelium removal and L-NAME abolished this hyporeactivity in all experimental groups, except in trained/stressed rats that showed a partial aorta reactivity recovery in L-NAME presence (L-NAME: sedentary 5.23±0,26#, stressed 5.55±0.38#, trained 5.28±0.30#, trained/stressed 4.42±0.41, #P<0.05 related to trained/stressed). Indomethacin determined a decrease in sensitivity (EC50) in intact aortas of trained rats without abolishing the aortal hyporeactivity in trained, stressed, and trained/stressed rats. Conclusions: Exercise-induced vascular adaptive response involved an increase in endothelial vasodilator prostaglandins and nitric oxide. Stress-induced vascular adaptive response involved an increase in endothelial nitric oxide. Beside the involvement of the endothelial nitric oxide pathway, the vascular response of trained/stressed rats involved an additional mechanism yet to be elucidated. These findings advance on the understanding of the vascular processes after exercise and stress alone and in combination. .

Effects of nitric oxide on magnocellular neurons of the supraoptic nucleus involve multiple mechanisms

Physiological evidence indicates that the supraoptic nucleus (SON) is an important region for integrating information related to homeostasis of body fluids. Located bilaterally to the optic chiasm, this nucleus is composed of magnocellular neurosecretory cells (MNCs) responsible for the synthesis and release of vasopressin and oxytocin to the neurohypophysis. At the cellular level, the control of vasopressin and oxytocin release is directly linked to the firing frequency of MNCs. In general, we can say that the excitability of these cells can be controlled via two distinct mechanisms: 1) the intrinsic membrane properties of the MNCs themselves and 2) synaptic input from circumventricular organs that contain osmosensitive neurons. It has also been demonstrated that MNCs are sensitive to osmotic stimuli in the physiological range. Therefore, the study of their intrinsic membrane properties became imperative to explain the osmosensitivity of MNCs. In addition to this, the discovery that several neurotransmitters and neuropeptides can modulate their electrical activity greatly increased our knowledge about the role played by the MNCs in fluid homeostasis. In particular, nitric oxide (NO) may be an important player in fluid balance homeostasis, because it has been demonstrated that the enzyme responsible for its production has an increased activity following a hypertonic stimulation of the system. At the cellular level, NO has been shown to change the electrical excitability of MNCs. Therefore, in this review, we focus on some important points concerning nitrergic modulation of the neuroendocrine system, particularly the effects of NO on the SON.

Nitric oxide mediated TNF-α, IL-1β gene expression in liver induced by crush injury of rat's soft tissues / 法医学杂志

OBJECTIVE@#To explore the effect of nitric oxide (NO) on the gene expression of hepatic TNF-α and IL-1β by crush injury of rat's soft tissues.@*METHODS@#Rats were randomly divided into sham group, crush group, crush+aminoguanidine (AG) group, and crush+L-arginine (L-Arg) group. Activities of ALT and AST as well as NO level in serum were measured. Gene expressions of TNF-α and IL-1β were detected with RT-PCR.@*RESULTS@#Obvious increase in TNF-α and IL-1β mRNA expression was detected in the crush group compared with the sham group (P<0.05). After pretreated L-Arg, expressions of TNF-α and IL-1β mRNA were markedly increased (P<0.05). After pretreated AG, those indices obviously decreased (P<0.05). Activities of ALT and AST enhanced and NO level increased in the crush group compared with the sham group (P<0.05). Pretreatment with L-Arg or AG led to substantial increased or reduced activities of ALT and AST as well as NO levels, respectively.@*CONCLUSION@#Endogenous NO mediated TNF-α, IL-1β mRNA up expression in liver induced by increased production of NO after crush injury of rat's soft tissues.

Instalación del equipo para terapia con óxido nítrico inhalado en paciente con asistencia mecánica ventilatoria / Equipment installation for inhaled nitric oxide therapy in required mechanical ventilation patients", "_i": "

La instalación del equipo para terapia con óxido nítrico inhalado en paciente con asistencia mecánica ventilatoria es un conjunto de actividades que pretenden garantizar la administración segura y continua del óxido nítrico inhalado, con la finalidad de evitar o limitar los efectos secundarios derivados de esta terapia. Este procedimiento se encuentra dividido en tres etapas: la preparación del sistema de suministro del óxido nítrico, la conexión del sistema de inyección del gas y la instalación del monitoreo del suministro de gas; además es imprescindible tener presente las indicaciones, contraindicaciones, complicaciones y puntos importantes en todo el proceso de instalación del sistema.

Equipment installation for inhaled nitric oxide therapy in required mechanical ventilation patients is a set of activities that pretend to assure the safe and continual administration of inhaled nitric oxide in order to avoid or limit the secondary effects resulting from this therapy. This procedure is divided in three stages: the supply system preparation of the nitric oxide, the connection of the gas injection system and the monitoring gas supply installation; is essential, as well, keep in mind the indications, contraindications, complications and main points in all the system installation process

Fine-tuning of defensive behaviors in the dorsal periaqueductal gray by atypical neurotransmitters

This paper presents an up-to-date review of the evidence indicating that atypical neurotransmitters such as nitric oxide (NO) and endocannabinoids (eCBs) play an important role in the regulation of aversive responses in the periaqueductal gray (PAG). Among the results supporting this role, several studies have shown that inhibitors of neuronal NO synthase or cannabinoid receptor type 1 (CB1) receptor agonists cause clear anxiolytic responses when injected into this region. The nitrergic and eCB systems can regulate the activity of classical neurotransmitters such as glutamate and γ-aminobutyric acid (GABA) that control PAG activity. We propose that they exert a ‘fine-tuning’ regulatory control of defensive responses in this area. This control, however, is probably complex, which may explain the usually bell-shaped dose-response curves observed with drugs that act on NO- or CB1-mediated neurotransmission. Even if the mechanisms responsible for this complex interaction are still poorly understood, they are beginning to be recognized. For example, activation of transient receptor potential vanilloid type-1 channel (TRPV1) receptors by anandamide seems to counteract the anxiolytic effects induced by CB1 receptor activation caused by this compound. Further studies, however, are needed to identify other mechanisms responsible for this fine-tuning effect.

Pharmacodynamic study on acute hypotensive activities of Carissa carandas extract in normal rats

This study aims to evaluate the effect of Carissa carandas extract on cardiovascular function of normal rats. Intravenous bolus injection of this extract in the doses of 5 mg kg[-1]-45 mg kg[-1], produced dose dependent reduction in arterial blood pressure [p<0.001]. The 45mg/kg dose caused a 50.75% +/- 2.71 decrease in MABP which was highly significant with P value< 0.0005 when compared with its controls. Significant reduction in heart rate frequency was observed after CC injection at a dose of 45 mg kg[-1] [p<0.001]. The results were comparable with Acetylcholine 10[-4] M. The receptor activity performed for which Atropine 10[-4]M was administered I.V. and then the extract [45mg/kg] was administered. A highly Non Significant fall in Mean Arterial Blood pressure was observed 1.51% +/- 0.22 [P>0.05].It was concluded that the Carissa carandas Ethanol extract possess potent acute hypotensive effect in normal rats. It stimulates the muscarinic receptors located on the endothelial cells of the vasculature. This stimulation results in the release of endothelial-derived relaxing factors [EDRFs] or nitric oxide that diffuses to vasculature smooth muscles and causes their relaxation

The effect of cardiopulmonary bypass in coronary artery bypass surgeries (on-pump versus off-pump) on erectile function and endothelium-derived nitric oxide levels

PURPOSE: To investigate the effects of on-pump and off-pump coronary artery bypass grafting (CABG) on the erectile function and endothelium-derived nitric oxide (eNO) levels. MATERIALS AND METHODS: Twenty-eight consecutive patients were randomized into two groups depending on use of cardiopulmonary bypass in CABG surgery. The erectile function was evaluated by using the IIEF-5 questionnaire. The plasma eNO levels were determined at baseline and after reactive hyperemia before and after surgery. Blood was collected in one minute after cuff deflation from the radial artery on the same side. RESULTS: After CABG surgery the mean IIEF-5 score increased insignificantly over baseline from 14.8 to 15.8 (p = 0.29) and 12.4 to 14.3 (p = 0.11) after on-pump and off-pump CABG surgeries, respectively. The baseline plasma NO levels before surgery were 18.16 ± 7.63 nmol/L in on-pump and 21.76 ± 11.08 nmol/L in off-pump CABG. After reactive hyperemia the plasma NO levels were 22.14 ± 10.52 nmol/L in on-pump and 21.49 ± 9.13 nmol/L in off-pump CABG before the surgery. The difference in the plasma NO levels before surgery was not significant (p = 0.51). Two hours after surgery, the difference of the plasma NO levels at baseline (24.44 ± 12.31on-pump and 20.58 ± 6.74 nmol/L off-pump CABG) and after reactive hyperemia (35.55 ± 23.54 nmol/L on-pump and 23.00 ± 15.40 nmol/L off-pump CABG) were not significantly different from each other (p = 0.11). CONCLUSIONS: Patients who had on-pump or off-pump CABG surgeries had higher IIEF-5 scores. Nevertheless, the improvement was insignificant in both groups. Meanwhile, on-pump or off-pump CABG surgeries did not have significant effect on plasma eNO levels.

Disfunção endotelial e hipertensão pulmonar / Endothelial dysfunction and pulmonary hypertension

Alterações no endotélio vascular pulmonar podem cursar mudanças abruptas no funcionamento harmônico do leito vascular pulmonar. Essas mudanças podem causar situações de aumento de resistência e de pressão da artéria pulmonar levando a uma condição de hipertensão pulmonar. Dessa forma, dosagens dos níveis de óxido nítrico pulmonar por meio do condensado do exalado pulmonar podem ser interessantes por contribuir para o ajuste da melhor terapêutica a ser empregada, e auxiliar no diagnóstico de hipertensão pulmonar. Algumas terapêuticas inalatórias podem auxiliar no tratamento da hipertensão pulmonar, destacando-se, entre elas, o óxido nítrico inalado, nitroprussiato de sódio, nitroglicerina e milrinone inalados na tentativa de reduzir a pressão elevada da artéria pulmonar. Cabe às equipes especializadas determinar qual o melhor tratamento a ser empregado para cada paciente, diante das diversas opções disponíveis. A presente revisão tem a finalidade de atualizar aspectos da disfunção endotelial na hipertensão pulmonar embasada em cinco tópicos: 1) O papel do óxido nítrico no sistema respiratório; 2) Alguns aspectos fisiopatológicos da hipertensão pulmonar; 3) O papel do óxido nítrico na hipertensão pulmonar; 4) O recurso da dosagem de nitrito no condensado pulmonar como expressão da microcirculação pulmonar e; 5) As opções terapêuticas inalatórias para o tratamento da hipertensão pulmonar.

Changes in pulmonary vascular endothelium may cause abrupt changes in the harmonious functioning of the pulmonary vascular circulation. These changes can lead to situations of increased resistance and pulmonary artery pressure leading to pulmonary hypertension condition. Thus, measurements of pulmonary nitric oxide levels by exhaled breath condensate may be an interesting contribution to the adjustment of treatment to be employed, and assist in the diagnosis of pulmonary hypertension. Some inhalation therapies can assist in the treatment of pulmonary hypertension, such as: inhaled nitric oxide, sodium nitroprusside, nitroglycerin and inhaled milrinone in an attempt to reduce the increased pulmonary artery pressure. This review aims to update aspects of endothelial dysfunction in pulmonary hypertension based on five topics: 1) The role of nitric oxide in the respiratory system; 2) Some pathophysiological aspects of pulmonary hypertension, 3) The role of nitric oxide in pulmonary hypertension and 4) The appeal of the determination of nitrite in the condensate and pulmonary expression of pulmonary microcirculation and 5) The inhalation therapeutic options for the pulmonary hypertension treatment.

Via nitrato-nitrito-óxido-nítrico: aspectos fisiológicos e terapêuticos / Nitrate-nitrite nitric oxide pathway: physiological and therapeutical aspects

A formação de NO nitrito-dependente é uma via que complementa a via enzimática, pois atuam em paralelo, porém, quando a suplementação de oxigênio está comprometida, há redução na expressão das enzimas NOS, comprometendo a formação de NO a partir desta via. Então, entra em ação a via nitrito-dependente, a qual desempenha funções favoráveis em condições de déficit de oxigênio. Assim sendo, esta é uma via de papel importantíssimo em condições patológicas que cursam com isquemia, tornando necessário garantir o armazenamento deste substrato, seja via farmacológica ou pela dieta alimentar. O papel na fisiologia, fisiopatologia, nutrição e terapêutica do nitrito e nitrato podem gerar frutos promissores para o desenvolvimento de novos caminhos na abordagem de algumas doenças e mudar a visão atual sobre os constituintes alimentares, no âmbito da saúde e doença. O presente texto tem como objetivo revisar e discutir as funções biológicas e o metabolismo do NO independente da via enzimática no organismo, além de abordar o uso terapêutico de nitrato ou nitrito em condições de doença.

The nitrite-dependent NO pathway is one that complements the enzymatic pathway of NO release, because they act in parallel, but when oxygen supplementation is compromised there is a reduction in the expression of NOS enzymes affecting the formation of NO from this pathway. Thus, the nitrite-dependent pathway swings into action, which plays favorableroles under oxygen deficit conditions. Therefore this is a very important role in pathological conditions that occurs with ischemia, making it necessary to ensure the storage of this substrate, either through a pharmacological or nutritional diet. The role in physiology, pathophysiology, nutrition and treatment of nitrite and nitrate can bear fruit for the development of promising new grounds in addressing some diseases and to change the current view on foods, health and diseases. The aim of this paper is to review and discuss the biological functions and metabolism of NO enzymatic-independent pathway in the body and to discuss the therapeutic use of nitrate or nitrite in disease conditions.

Involvement of nitric oxide in learning & memory processes.

Nitric oxide (NO), synthesized from the amino acid, L-arginine by nitric oxide synthase (NOS) has received attention as a neurotransmitter in the brain. NO has been found to induce cognitive behaviour in experimental animals. In order to show evidence for the involvement of NO in learning and memory processes, the reports indicating the effects of its precursor, donors, and inhibitors of its synthesis in mammals, birds, fishes and invertebrates have been reviewed. Further, learning and memory impairment occurring in man and animals due to defective NO activity in the brain due to pathological conditions such as epilepsy, stress, diabetes and side effects of therapeutic agents and reversal of this condition by L-arginine and NO donors have been included. In addition, the reports that indicate ageing-induced impairment of cognition that is known to occur in Alzheimer's disease due to deposition of the toxic protein, beta amyloid and the effect of L-arginine and NO donors in preventing dementia in these patients have been reviewed.

Implicações farmacogenéticas de polimorfismos da eNOS para drogas de ação cardiovascular / Pharmacogenetic implications of the eNOS polymorphisms for cardiovascular action drugs / Implicaciones farmacogenéticas de polimorfismos de la eNOS para drogas de acción cardiovascular

A farmacogenética é um dos campos mais promissores da medicina. A conclusão do Projeto Genoma permitiu que esse campo começasse a descobrir fatores complexos modulando a resposta às drogas, e novas tecnologias estão a poucos passos de permitir uma grande expansão da área. As doenças cardiovasculares estão atualmente entre as maiores causas de internações hospitalares e morte, e têm sido alvo de grande parte dos estudos genéticos de doenças complexas. Paralelamente à identificação de marcadores de suscetibilidade à doença, é necessária a investigação de como perfis genéticos diferentes podem alterar respostas aos fármacos atualmente empregados. O sistema biológico que controla a produção endotelial do óxido nítrico tem sido um dos grandes alvos nas respostas farmacológicas aos fármacos usados na terapia de doenças cardiovasculares. Esta revisão tem como objetivo abordar os conhecimentos correntes da interação entre as variações genéticas da eNOS e as respostas farmacológicas aos fármacos empregados no sistema cardiovascular.

The pharmacogenetics is one of the most promising fields of medicine. The conclusion of the Genome Project allowed this field to start discovering complex factors modulating the response to drugs, and new technologies are close a great expansion of the area. The cardiovascular diseases are currently among the major causes of hospitalizations and death, and have been the target of a large part of genetic studies of complex diseases. Parallel to the susceptibility to disease markers identification, it is necessary to investigate how different genetic profiles can change the responses to the currently used drugs. The biological system that controls the endothelial production of the nitric oxide has been one of the greatest targets in the pharmacological responses to the drugs used in the cardiovascular diseases therapy. This review aims at approaching the current knowledge on interaction among the genetic variations of eNOS and the pharmacological responses to the drugs used in the cardiovascular system.

La farmacogenética es uno de los campos más promisorios de la medicina. La conclusión del Proyecto Genoma permitió que ese campo comenzase a descubrir factores complejos modulando la respuesta a las drogas, y nuevas tecnologías están a pocos pasos de permitir una gran expansión del área. Las enfermedades cardiovasculares están actualmente entre las mayores causas de internaciones hospitalarias y muerte, y han sido objeto de gran parte de los estudios genéticos de enfermedades complejas. Paralelamente a la identificación de marcadores de susceptibilidad a la enfermedad, es necesaria la investigación sobre como perfiles genéticos diferentes pueden alterar respuestas a los fármacos actualmente empleados. El sistema biológico que controla la producción endotelial del óxido nítrico ha sido un de los grandes blancos en las respuestas farmacológicas a los fármacos usados en la terapia de enfermedades cardiovasculares. Esta revisión tiene como objetivo abordar los conocimientos corrientes de la interacción entre las variaciones genéticas de la eNOS y las respuestas farmacológicas a los fármacos empleados en el sistema cardiovascular.

Role of nitric oxide in the diuresis and natriuresis occurring in patients with obstructive sleep apnoea syndrome.

Objective. To determine whether nitric oxide (NO) has any role in the diuresis and natriuresis observed in patients with obstructive sleep apnoea syndrome (OSAS). Methods. We measured 12-hour urine volume in the day and in the night in patients with OSAS (n=20) and determined the concentrations of urinary sodium and nitrate. The frequency of urination in the night was also noted. The measurements were done again after two nights of continuous positive airway pressure (CPAP) therapy and after putting the patients on oral anti-oxidant treatment (vitamin C–100mg BD and vitamin E–400IU BD) for 45 days. Ten healthy normal subjects underwent the same protocol except the CPAP therapy. Results. In patients with OSAS, the night urine volume and sodium concentration were similar and the nitrate levels were higher compared to those in the day. After CPAP therapy, while the urine volume and sodium concentration decreased, the nitrate level became similar to that in the day. Such effects were not observed after anti-oxidant treatment. The frequency of urination was decreased in both the instances. The effects observed after CPAP therapy were similar to those observed in control subjects with or without anti-oxidant treatment. Conclusion. Renal NO promotes diuresis and natriuresis in patients with OSAS.

Óxido nítrico e sistema cardiovascular: ativação celular, reatividade vascular e variante genética / Nitric oxide and the cardiovascular system: cell activation, vascular reactivity and genetic variant / Óxido nítrico y sistema cardiovascular: activación celular, reactividad vascular y variante genética

O óxido nítrico (NO), primariamente identificado como um fator relaxante derivado do endotélio, é um radical livre atuante na sinalização de diferentes processos biológicos. A identificação das isoformas das sintases do NO (NOS) e a subsequente caracterização dos mecanismos de ativação celulares das enzimas possibilitaram tanto a compreensão de parte das interações fisiológicas como a compreensão de parte dos mecanismos de doença, na qual o NO está envolvido. A isoforma endotelial da NOS (eNOS), expressa principalmente no endotélio vascular, desempenha importante papel na regulação da reatividade vascular e no desenvolvimento e na progressão da aterosclerose. Esta revisão tem o propósito de contextualizar o leitor sobre a estrutura da eNOS e seus mecanismos de ativação celular. Tendo em vista os avanços da biologia molecular, trataremos ainda dos conhecidos mecanismos de regulação da expressão gênica e do papel de variantes no código genético da eNOS associados a fenótipos cardiovasculares. Embora se reconheça a importância do NO como molécula ateroprotetora, nossa atenção estará voltada à revisão de literatura envolvendo NO e sua participação na modulação do fenótipo de vasodilatação muscular.

Nitric oxide (NO), primarily identified as an endothelium-derived relaxing factor, is a free radical that signals different biological processes. The identification of NO synthase (NOS) isoforms and the subsequent characterization of the mechanisms of cell activation of the enzymes permitted the partial understanding of both the physiological interactions and of the mechanisms of the diseases in which NO is involved. Mainly expressed in the vascular endothelium, the endothelial NOS isoform (eNOS) plays an important role in the regulation of vascular reactivity and in the development and progression of atherosclerosis. The purpose of this review is to contextualize the reader about the eNOS structure and its mechanisms of cell activation. In view of the advances in molecular biology, we will also address the known mechanisms of gene expression regulation and the role of variants on the genetic code of eNOS associated with cardiovascular phenotypes. Although the importance of NO as an atheroprotective molecule is recognized, our focus will be the review of the literature on NO and its participation in the modulation of the muscle vasodilatation phenotype.

El óxido nítrico (NO), primariamente identificado como un factor relajante derivado del endotelio, es un radical libre actuante en la señalización de diferentes procesos biológicos. La identificación de las isoformas de las sintasas del NO (NOS) y la subsecuente caracterización de los mecanismos de activación celulares de las enzimas posibilitaron tanto la comprensión de parte de las interacciones fisiológicas como la comprensión de parte de los mecanismos de enfermedad, en la cual el NO está envuelto. La isoforma endotelial de la NOS (eNOS), expresada principalmente en el endotelio vascular, desempeña importante papel en la regulación de la reactividad vascular y en el desarrollo y en la progresión de la aterosclerosis. Esta revisión tiene el propósito de contextualizar al lector sobre la estructura de la eNOS y sus mecanismos de activación celular. Teniendo en vista los avances de la biología molecular, trataremos aun de los conocidos mecanismos de regulación de la expresión génica y del papel de variantes en el código genético de la eNOS asociados a fenotipos cardiovasculares. Aunque se reconozca la importancia del NO como molécula ateroprotectora, nuestra atención estará volcada a la revisión de literatura envolviendo NO y su participación en la modulación del fenotipo de vasodilatación muscular.

Efecto vasodilatador mediado por óxido nítrico del extracto hidroalcohólico de Zea mays L. (maíz morado) en anillos aórticos de rata / Vasodilator effect mediated by nitric oxide of the Zea mays L (andean purple corn) hydroalcoholic extract in aortic rings of rat

Objetivo. Evaluar la respuesta vasodilatadora e inhibidora de la vasoconstricción del extracto hidroalcohólico de Zea mays L. (maíz morado) y determinar si esta respuesta es mediada por óxido nítrico (NO). Materiales y métodos. Se obtuvo un extracto de las corontas de maíz morado maceradas durante ocho días en etanol al 70 por ciento, y posterior concentración del producto. Se trabajó con anillos aórticos de rata en cámara de órganos aislados, bañada con solución Krebs-Hensleit (K-H) y se registró la actividad vasomotora con un transductor de tensión isométrica. Se produjo una contracción basal con KCl 120 mM sobre la cual determinó el efecto vasodilatador de tres dosis del extracto: 0,1; 0,5 y 1,0 mg/mL. Se utilizó L-NG-Nitroarginina metil ester (L-NAME) para comprobar que la vasodilatación depende de la óxido nítrico sinteasa (NOs). Luego se comparó la inhibición de la contracción vascular tras la incubación durante 30 minutos, con extracto de maíz morado y captopril 10-5 M. Resultados. Se observó una reducción de la contracción máxima (100 por ciento) a 85,25 ± 2,60 por ciento, 77,76 ± 3,23 por ciento y 73,3 ± 4,87 por ciento, para las dosis de 0,1; 0,5 y 1,0 mg/mL, respectivamente. La vasodilatación fue inhibida por la incubación previa con L-NAME. El extracto de maíz morado no inhibió la contracción vascular, a diferencia del captopril (reducción a 75,27 ± 8,61 por ciento). Conclusión. El extracto hidroalcohólico de Zea mays L produce vasodilatación dependiente de la síntesis de NO.

Objective: To evaluate the vasodilator response of the hydroalcoholic extract of Zea mays L. (Andean purple corn) and to determine if this response is mediated by nitric oxide (NO). Material and methods: We obtained an extract by maceration for eight days of Andean purple corn cobs in 70 percent ethanol and subsequent concentration of the product. Thoracic aortic rings were evaluated in an isolated organ chamber, bathed with Krebs-Hensleit solution (KH), and vasomotor activity was recorded with an isometric tension transducer. Basal contraction was produced with 120 mM KCl and then, we proceeded to determinate the vasodilator effect of 3 doses of the extract: 0.1, 0.5, and 1.0 mg/mL. We used L-NG-Nitroarginin methyl ester (L-NAME) to verify that the vasodilation depends on nitric oxide sinteasa (NOs). Then we compared the inhibition of vascular contraction after incubation for 30 minutes, with purple corn extract and captopril 10-5 M. Results: We observed a reduction in maximum contraction (100 percent) to 85.25 ± 2.60 percent, 77.76 ± 3.23 percent, and 73.3 ± 4.87 percent for doses of 0.1, 0.5 and 1,0 mg/mL respectively. The vasodilation was inhibited by prior incubation with L-NAME. Andean purple corn extract did not inhibit vascular contraction as captopril did (reduction to 75.27 ± 8.61 percent). Conclusion. The hydroalcoholic extract of Zea mays L produces NO dependent vasodilation.

VEGF en capa muscular de vasos placentarios: expresión en preeclampsia y asociación con status antioxidante / VEGF in muscular layer of placental vessels: expression in preeclampsia and its association with the antioxidant status

Introducción: La preeclampsia es una enfermedad gestacional de origen placentario, de alta prevalencia y morbi-mortalidad materna y fetal. Su patogenia es desconocida, aunque sabemos que en ella ocurre placentación anómala e isquemia placentaria, que conlleva desarrollo de estrés oxidativo (EO) y disfunción endotelial. En condiciones normales la perfusión placentaria es regulada fundamentalmente por óxido nítrico (NO). El factor de crecimiento vascular endotelial (VEGF) es clave en su modulación, aumentando la actividad de enzimas productoras de NO, manteniendo una perfusión placentaria y gestación normales. Objetivo: Caracterizar el perfil de parámetros oxidativos en preeclampsia, asociado con expresión de VEGF en capa muscular de vasos placentarios (CMVP). Metodología: Estudio analítico, observacional, transversal. Se tomaron muestras placentarias y plasmáticas de embarazadas con preeclampsia (n=12) y embarazos normales (n=15). En placenta se determinó: expresión de VEGF en CMVP, malondialdehído y actividad enzimática antioxidante–superóxido dismutasa, glutatión peroxidasa y catalasa. En plasma materno se determinó: F2-isoprostanos y capacidad plasmática antioxidante total (FRAP). Resultados: Pacientes con preeclampsia mostraron mayor expresión de VEGF en CMVP y reducción del FRAP, incremento de F2-isoprostanos y malondialdehído, y menor actividad de superóxido dismutasa (p<0.05). Discusión: Expresión de VEGF en CMVPy parámetros de EO aumentan en preeclampsia. En condiciones normoxémicas, VEGF en CMVP estimula la producción de NO, manteniendo una perfusión placentaria y gestación normales. En condiciones de hipoxia, EO y bajas defensas antioxidantes, como la preeclampsia, VEGF en CMVP favorecería la producción de pro-oxidantes en desmedro de la de NO, lo que contribuiría a explicar la fisiopatología de esta enfermedad.

Introduction: Preeclampsia is a systemic pregnancy disorder, which has high prevalence and high maternal and fetal mortality associated. Its pathogenesis is unknown, but is thought to occur in three phases: abnormal placentation, placental ischemia, which involves development of oxidative stress (OS), and endothelial dysfunction. During normal placental perfusion is regulated primarily by nitric oxide (NO). The vascular endothelial growth factor (VEGF) is a key modulator, increasing the activity of enzymes producing NO, maintaining placental perfusion and normal pregnancy. Objective: To characterize the profile of oxidative parameters in Preeclampsia, associated with VEGF expression in muscular layer of placental vessels (MLPV).Methodology: Analytical, observational, transversal study. Placental and blood plasma samples were taken of pregnant women with preeclampsia (n=12) and normal pregnancies (n=15). In placenta was determined: expression of VEGF in MLPV, malondialdehyde and antioxidant enzyme activity - superoxide dismutase, glutathione peroxidase and catalase. Was determined in maternal plasma F2-isoprostanes and plasma total antioxidant capacity (FRAP). Results: Patients with preeclampsia showed higher expression of VEGF in MLPV and reduced FRAP, increased F2-isoprostanes and malondialdehyde, and decreased activity of superoxide dismutase (p <0.05). Discussion: VEGF expression in MLPV and parameters of OS are both increased in preeclampsia. In normal, VEGF in MLPV stimulates NO production, maintaining a normal pregnancy and placental perfusion. Under hypoxic conditions, OS and low antioxidant defenses, as in preeclampsia, VEGF in MLPV favors the production of pro oxidant agents, at the expense of NO, which would help explain the pathophysiology of this disease.