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Therapeutic use of alternative nitric oxide (NO) sources, such as nitrite and nitrate may be a protective influence on pulmonary vasculature abnormalities. Aim: To evaluate whether the maternal administration of nitrite prevents the morphological and molecular changes that affect the pulmonary arterioles of congenital diaphragmatic hernia (CDH) neonates. Methods: CEUA #88/2017. Sprague-Dawley neonate rats were divided into 6 groups: 1. control; 2. control + nitrite; 3. nitrofen exposed; 4. nitrofen exposed + nitrite; 5. CDH and 6. CDH + nitrite. The pregnant rats from nitrofen exposed and CDH groups were exposed to nitrofen on gestational day (GD) 9.5. The treatment with nitrite was made by gavage (15 mg/kg/day), on the last five gestational days. On GD 21.5 the fetuses were harvested. The following parameters were analyzed: lung and plasma nitrite concentration; media wall thickness (MWT) and endothelial NO synthase eNOS and inducible NO synthase iNOS immunohistochemistry of pulmonary arterioles. Results: Nitrite treatment increased the maternal plasma concentration of nitrite in control and nitrofen-exposed rats. All neonates exposed to nitrofen showed an increase of nitrofen in the lung and plasma. Nitrite treatment decreased the MWT of pulmonary arterioles of CDH neonates. Nitrite treatment increased eNOS marker and attenuated iNOS marker in neonates with CDH. Conclusions: Nitrite maternal treatment rescued the morphometry and recovered eNOS expression of CDH pulmonary arterioles during CDH. Nitrite is a potential prenatally therapeutic approach to vascular alterations present in CDH neonates.

Introduction:Variations in blood pressure (BP) are, in part, genetically determined and some polymorphisms of renin-angiotensin- aldosterone system (RAAS) and synthase of endothelial nitric oxide (eNOS) have been related to hypertension (HT). Conversely, physical exercise is considered a non-pharmacological tool for HT control, treatment, and prevention. Objective: The purpose of this study is to investigate the relationship between eNOS and RAAS polymorphisms, their epistatic interaction, and the respective humoral factors in the BP control in normotensive/pre-hypertension and hypertensive older adults and how this relationship can be modulated by training status (TS) level. Methods:A total of 155 older adults (66.94 ± 6.83 years old) performed the following evaluations: AAHPERD battery test to determine the general functional fitness index (GFFI), systolic and diastolic blood pressure (SBP and DBP), blood collection for DNA extraction, analysis of eNOS gene polymorphisms rs2070744; rs61722009 and rs1799983 and RAAS polymorphisms rs699; rs1799752 and rs5186, and quantification of ACE activity (Fluorimetric Assay) and nitrite concentration (Chemiluminescence Method). Results and Conclusion:Good TS level appears to exert greater influence on SBP for G2 and G3 (G1: 125.79 ± 14.03/ G2: 119.91 ± 11.72/G3: 119.71 ± 10.85) and on NO2 for G3 (G1: 0.42 ± 0.25/ G2: 0.54 ± 0.45/ G3: 0.71 ± 0.52). No associations were observed between eNOS and RAAS polymorphisms, but the epistasis was identified between eNOS polymorphism, rs2070744, and RAAS polymorphism, rs699, revealing a statistically significant interaction (p = .0235) with training score of 0.63, a training test accuracy of 0.61 and a cross-validation consistency of 10/10. This result suggests an increased risk of hypertension.

Abstract Background Matrix metalloproteinase-9 (MMP-9) participates in the degradation of components of the extracellular matrix and it is involved in vascular remodeling and vasomotor changes. The aim of this study was to investigate the plasma levels of MMP-9 in acute vascular alterations due to hypertensive crisis. Methods This cross-sectional study was performed in 40 normotensive (NT) and 58 controlled hypertensive subjects (CHyp) followed up in outpatient clinic. Moreover, 57 patients with hypertensive emergency (HypEmerg) and 43 in hypertensive urgency (HypUrg), seen in emergency department, were also included. Hypertensive crisis was divided into HypEmerg, which was characterized by levels of systolic blood pressure (BP) ≥ 180 mmHg and/or diastolic BP ≥ 120 mmHg complicated with target-organ damage (TOD), and HypUrg, defined by BP elevation without TOD. Univariate and multivariate regression analysis was performed to identify the influence of independent variables on MMP-9 levels. A p-value

VEGF is an important neurotrophic and vascular factor involved in mental disorders. The objective of this study was to verify the effect of genetic polymorphisms in the VEGF pathway on the risk for depression, symptom intensity, and suicide attempts. To examine the association between the VEGF pathway and depression, we genotyped polymorphisms and measured the plasma concentrations of VEGF, KDR, and FLT1 proteins. The participants were 160 patients with depression and 114 healthy controls. The questionnaires that assessed the clinical profile of the patients were the MINI-International Neuropsychiatric Interview, GRID-HAMD21, CTQ, BSI, and the number of suicide attempts. Genotyping of participants was performed using the real-time PCR and protein measurements were performed using the enzyme-linked immunosorbent assay (ELISA). VEGF and its inhibitors were reduced in depression. Individuals with depression and displaying the homozygous AA of the rs699947 polymorphism had higher plasma concentrations of VEGF (p-value = 0.006) and were associated with a greater number of suicide attempts (p-value = 0.041). Individuals with depression that were homozygous for the G allele of the FLT1 polymorphism rs7993418 were associated with lower symptom severity (p-value = 0.040). Our results suggest that VEGF pathway polymorphisms are associated with the number of suicide attempts and the severity of depressive symptoms.

Objective: Obesity is a chronic disease caused by both environmental and genetic factors. Epidemiological studies have documented that increased energy intake and sedentary lifestyle, as well as a genetic contribution, are forces behind the obesity epidemic. Knowledge about the interaction between genetic and environmental components can facilitate the choice of the most effective and specific measures for the prevention of obesity. The aim of this study was to assess the association between the FTO, AKT1, and AKTIP genes and childhood obesity and insulin resistance. Methods: This was a case–control study in which SNPs in the FTO (rs99396096), AKT1, and AKTIP genes were genotyped in groups of controls and obese/overweight children. The study included 195 obese/overweight children and 153 control subjects. Results: As expected, the obese/overweight group subjects had higher body mass index, higher fasting glucose, HOMA‐IR index, total cholesterol, low‐density lipoprotein, and triglycerides. However, no significant differences were observed in genes polymorphisms genotype or allele frequencies. Conclusion: The present results suggest that AKT1, FTO, and AKTIP polymorphisms were not associated with obesity/overweight in Brazilians children. Future studies on the genetics of obesity in Brazilian children and their environment interactions are needed.

Endothelial nitric oxide synthase (eNOS) gene polymorphisms are associated with reduced eNOS activity and nitric oxide (NO) production leading to an increase in blood pressure (BP). Regular exercise is the main strategy to minimize the deleterious effects of polymorphisms. However, due to the differences that physical exercise can be performed, some controversial results are found. Therefore it seems reasonable to evaluate the training status (TS). Thus, this study aimed to investigate the association of eNOS gene haplotypes and different levels of TS on nitrite concentrations (NO2-) and BP values in older adult. 424 elderly performed the following assessments: General Functional Fitness Index (GFFI) to estimate TS, systolic and diastolic blood pressure (SBP and DBP), blood collection for analysis of NO2- and g.-786T>C, intron 4b/a (VNTR) and 894G>T polymorphisms. Multivariate logistic regression showed that NO2- was influenced by GFFI and 4b/4a Intron 4. Regarding BP, GFFI influenced SBP and DBP, and just intron 4 was associated with variations in DBP. It can be observed that GFFI affected the NO2-, SBP and DBP independently of haplotypes. Therefore, maintenance of good level of TS can overcome the negative influence of genetics factors (intron 4) by increasing NO2- concentration and decreasing BP values.

O nitric oxide (NO, óxido nítrico) é um mediador endógeno vasoativo que contribui para a homeostase vascular pulmonar. O NO é produzido por três isoformas das nitric oxide synthases (NOS, óxido nítrico sintases)-NOS neuronial (nNOS); NOS induzida (iNOS); e NOS endotelial (eNOS)-estando as três presentes no pulmão. Estudos que utilizaram inibidores farmacológicos ou camundongos knockout têm demonstrado que o NO derivado da eNOS desempenha importantes papéis ao modular o tônus vascular pulmonar e atenuar a hipertensão pulmonar. Por outro lado, estudos focados no papel da iNOS têm mostrado que essa isoforma contribui para a fisiopatologia da lesão pulmonar aguda e da síndrome do desconforto respiratório agudo. Esta revisão objetivou delinear o papel desempenhado pelo NO no controle da circulação pulmonar, tanto em condições fisiológicas como fisiopatológicas. Além disso, revisamos as evidências de que a via L-arginina-NO-guanosina monofosfato cíclico seja um importante alvo farmacológico para a terapia de doenças vasculares pulmonares.Nitric oxide (NO) is an endogenous vasoactive compound that contributes to pulmonary vascular homeostasis and is produced by three nitric oxide synthase (NOS) isoforms-neuronal NOS (nNOS); inducible NOS (iNOS); and endothelial NOS (eNOS)-all three of which are present in the lung. Studies using pharmacological inhibitors or knockout mice have shown that eNOS-derived NO plays an important role in modulating pulmonary vascular tone and attenuating pulmonary hypertension. However, studies focusing on the role of iNOS have shown that this isoform contributes to the pathophysiology of acute lung injury and acute respiratory distress syndrome. This review aimed at outlining the role played by NO in the control of pulmonary circulation, both under physiological and pathophysiological conditions. In addition, we review the evidence that the L-arginine-NO-cyclic guanosine monophosphate pathway is a major pharmacological target in the treatment of pulmonary vascular diseases.

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.

O chumbo (Pb) é um metal pesado muito tóxico, mesmo em baixas concentrações. Ainda não foi possível estabelecer uma concentração considerada "segura" para exposições. A toxicidade ao metal é atribuída principalmente a alterações enzimáticas, como a inibição da enzima delta aminolevulínico desidratase (ALAD) e à habilidade de competir com o cálcio. A absorção do chumbo se dá prinicpalmente através das vias respiratórias e gastrointestinal. Uma vez absorvido, o metal é encontrado no sangue, tecidos moles e mineralizados. Cerca de 99% do conteúdo absorvido é encontrado nos ossos, principal reservatório de chumbo. Aproximadamente 1% encontrase livre no plasma e disponível para atravessar membranas biológicas e promover os efeitos tóxicos. Apesar das medidas tomadas no sentido de diminuir as concentrações do metal na natureza, alguns indivíduos podem ser mais susceptíveis aos efeitos prejudiciais causados pela exposição ao chumbo. Fatores genéticos vem sendo estudados e associados a diferentes concentrações sanguíneas e plasmáticas do metal em indivíduos expostos. Portadores de diferentes genótipos podem experimentar maiores ou menores concentrações sanguíneas e plasmáticas de Pb. Reconhecer o indivíduo, ou grupo de indivíduos mais susceptíveis às altas concentrações de chumbo pode ser uma ferramenta útil na prevenção dos efeitos tóxicos do metal. O gene que codifica a ALAD e gene do Receptor da Vitamina D (VDR), os quais estão relacionados a toxicocinética do chumbo foram focos dessa revisão.

As respostas às drogas são influenciadas por múltiplos fatores, incluindo-se estado de saúde, influências ambientais e características genéticas. A farmacogenética é uma área da farmacologia clínica que estuda como diferenças genéticas entre indivíduos podem afetar as respostas às drogas. Neste sentido, polimorfismos genéticos em enzimas metabolizadoras, transportadores ou receptores contribuem para as variações nas respostas a medicamentos. Esta revisão objetiva introduzir alguns princípios, aplicações clínicas e perspectivas da farmacogenética, enfatizando alguns importantes achados clínicos e aplicações que podem contribuir para a melhoria da terapêutica.

A variabilidade de resposta à droga entre pacientes é parcialmente devida à composição genética única que cada indivíduos apresenta. O ramo da Farmacologia Clínica que estuda tais variabilidades é chamado de farmacogenética. Variações genéticas (chamadas de polimorfismos) podem modificar tanto parâmetros farmacocinéticos (por alterarem a atividade de enzimas importantes no metabolismo de fármacos) quanto parâmetros farmacodinâmicos (por modificar a afinidade de um receptor pelos agonistas ou antagonistas). Atualmente, a farmacogenética vem sendo valorizada como uma ferramenta útil na busca de terapêuticas melhores. Esta revisão enfoca a farmacogenética de drogas de ação cardiovascular. Especificamente, alguns casos clínicos ilustrativos de doenças cardiovasculares serão apresentados e comentados quanto às suas possíveis bases farmacogenéticas.

Abstract Objective: Obesity is a chronic disease caused by both environmental and genetic factors. Epidemiological studies have documented that increased energy intake and sedentary lifestyle, as well as a genetic contribution, are forces behind the obesity epidemic. Knowledge about the interaction between genetic and environmental components can facilitate the choice of the most effective and specific measures for the prevention of obesity. The aim of this study was to assess the association between the FTO, AKT1, and AKTIP genes and childhood obesity and insulin resistance. Methods: This was a case-control study in which SNPs in the FTO (rs99396096), AKT1, and AKTIP genes were genotyped in groups of controls and obese/overweight children. The study included 195 obese/overweight children and 153 control subjects. Results: As expected, the obese/overweight group subjects had higher body mass index, higher fasting glucose, HOMA-IR index, total cholesterol, low-density lipoprotein, and triglycerides. However, no significant differences were observed in genes polymorphisms genotype or allele frequencies. Conclusion: The present results suggest that AKT1, FTO, and AKTIP polymorphisms were not associated with obesity/overweight in Brazilians children. Future studies on the genetics of obesity in Brazilian children and their environment interactions are needed.

Erectile dysfunction (ED) is a common male disorder, often associated with cardiovascular disease and ageing. The Sildenafil, a PDE5 inhibitor, can improve the erectile function by prolonging the nitric oxide (NO) downstream effect. NO is a molecule of pivotal importance in erection physiology and is mainly produced by neuronal nitric oxide synthase (nNOS) and endothelial NO synthase (eNOS). While it has been shown that eNOS and nNOS genetic polymorphisms could be associated with Sildenafil responsiveness in ED, no study so far has assessed whether nNOS polymorphisms and PDE5A polymorphism could be associated with increased risk to ED or with intensity of symptoms. A total of 119 ED patients and 114 controls were studied, with evaluation of the clinical disability by the International Index for Erectile Function instrument, plasma assessment of nitrite levels and genomic DNA analysis regarding the rs41279104 and rs2682826 polymorphisms of the NOS1 gene and the rs2389866, rs3733526 and rs13124532 polymorphisms of the PDE5A gene. We have found a significant association of the rs2682826 with lower IIEF scores in the clinical ED group. While this result should be confirmed in other populations, it may be helpful in establishing a genetic panel to better assess disease risk and prognosis on ED therapy.

Objectives: We aimed to assess the plasma HO-1 level and its interrelationship with the plasma sFLT-1 level in preeclamptic and healthy pregnant women with different variants of microsatellite polymorphism (GTn) located in the promoter region of the HMOX-1 gene. Methods: HO-1 and sFLT-1 were measured by ELISA. HMOX1 genotyping was performed using fragment analysis. Results: We found similar and higher levels of plasma HO-1 and sFLT-1, respectively, in preeclampsia. Similar genotypes and alleles frequencies were found in both groups and the absence of modulation of HO-1 levels by genotypes were observed. Conclusion: The plasma HO-1 levels are not increased in preeclampsia women and neither related to sFLT-1 levels and GTn polymorphism.

Bupropion has been used to treat psychic depression and as a therapy for smoking cessation, the latter mainly in association with nicotine. However, there have been no detailed studies of the hemodynamic effects of the association of bupropion with nicotine during replacement therapy. In this study, we evaluated the effects of such an association on the cardiovascular parameters in anesthetized dogs. Bupropion, either alone or together with nicotine, had no significant effect on the cardiac index (CI; 4.7 ± 0.2 vs 4.3 ± 0.1 and 3.5 ± 0.3 vs 3.4 ± 0.3 L.min-1.m2, respectively; mean ± SEM) and meanarterial pressure (MAP; 134 ± 5.0 vs 145 ± 11.0 and 118 ± 5.0 vs 133 ± 10.5 mmHg, respectively). There was a slight but significant increase in the systemic vascular resistance index (SVRI; 2165 ± 93 vs 2645 ± 126 and 2335 ± 100 vs 2737 ± 200 dyn.cm-5m-2, respectively). However, there was a significant increase in the mean pulmonary artery pressure (MPAP; 20 ± 0.8 vs 25 ± 1.6 and 18 ± 1.3 vs 25 ± 1.6 mmHg, respectively; p < 0.05) and pulmonary vascular resistance index (IRVP; 194 ± 11 vs 272 ± 21 and 206 ± 32 vs 307 ± 42 dyn.cm-5m-2, respectively; p < 0.05). These results show that bupropion alone or in association with nicotine does not markedly affect most hemodynamic parameters of the systemic circulation, although the significant increase in MPAP and IRVP can elevate the pulmonary pressure. [ABSTRACT FROM AUTHOR]