Nitric oxide (NO) is a mediator of vascular smooth muscle tension that metabolises rapidly in blood. NO delivered by inhalation can therefore be used as a selective pulmonary vasodilator to relieve pulmonary hypertension or to improve oxygenation with no systemic effects. In artificial ventilation nitric oxide has been administered in inspiration gas as a continuous gas flow or to form constant inspired concentration. Homogeneous inspired gas mixture has been regarded essential for successful therapy and the therapy has been characterized by the mixture NO concentration. The response in oxygenation on NO therapy has, however, been variable. Administration of NO as a short pulse synchronously with inspiration has been suggested to improve the response. In this study the NO administration was examined theoretically and experimentally with the aim to relieve pulmonary hypertension and improve oxygenation during artificial ventilation. For the experimental study a system for the synchronized administration was developed. The effect on oxygenation was studied during equine anaesthesia where hypoxemia develops regularly secondary to left-to-right shunt caused by atelectasis. By administering the NO as a short pulse in early inspiration to well ventilated lung areas the oxygenation could be effectively improved. Delayed administration to low ventilated lung areas was found possible for a negative contribution on oxygenation, which reduces the improvement gained in the well-ventilated lung areas. When NO is delivered into the whole inspiration, the net effect on oxygenation is the sum of these negative and positive contributions, whereas with pulsed delivery to the early inspiration the negative contribution can be avoided. This finding may be the main explanation for the varying response in oxygenation detected in patients as a response to NO inhalation. When the NO therapy aimed for the relief of induced pulmonary hypertension in pigs, no difference was observed between NO delivery as a short pulse or given to the whole inspiration. Maximum vasodilatation was observed with 105 nmol/min delivery rate. A larger delivery rate only contributed to an abrupt increase in pulmonary pressure at cessation of the delivery. The NO uptake from alveoli to tissue depends on the alveolar NO partial pressure. In a simulation this partial pressure was shown to be independent of the administration mode. Also the relationship between the NO uptake and delivery setting was not explicit. With pulsed delivery, expired NO can be reduced which was confirmed by the experimental results. This is important when the NO therapy is given in rebreathing circuit.

Pulmonary hypertension syndrome (PHS) in broiler chickens adequately represents idiopathic pulmonary arterial hypertension (IPAH) in humans, a condition that affects 300 new patients each year in the US. The factors that trigger IPAH are poorly understood but an increase in reactive oxygen species in the circulation coincides with the onset of these conditions. Broiler chickens (n=583) were fed a control diet (CTL), containing 3,200 kcal of ME / kg of feed, 23% CP, 1.55% (wt / wt) Arginine (Arg) and 40 IU of VE (alpha-tochopherol) / kg of feed; a high-Arg diet (HA), CTL diet plus 0.8% (wt / wt) supplemental L-Arg HCl; or a high Arg and vitamin diet (AEC), the HA diet plus 200 IU ?-tochopherol / kg of feed and 500 mg of ascorbic acid / L of drinking water 500 mg ascorbic acid / L of water (exp. 1 and 2) or Kg feed (exp. 3). Supplemented broilers were either exposed to hypobaric hypoxia or had a primary bronchus occluded (PBO) to induce PHS. Also, medial thickness was assessed in male broiler and Leghorn (n =80) chickens fed a CTL diet and subjected to pulmonary artery occlusion (PAO). The results show that supplementation with Arg and VE plus VC have an additive effect on the velocity at which the pulmonary arterial pressure returned to basal levels in hypoxic chickens challenged with epinephrine. Also, supplementation increased xanthine oxidase (XO) activity in the vicinity of the pulmonary endothelium with no effect on NAD(P)H-oxidase activity or oxidative stress in hypoxic chickens subjected to PBO. These enzymes are upregulated in humans with IPAH. Furthermore, supplementation reduced pulmonary artery reactivity to phenylephrine in hypoxemic broilers. Unsupplemented broiler chickens had a lower specific lung weight compared to unsupplemented Leghorns. Hypoxemic broilers showed thicker resistant pulmonary arteries and were more hypertensive than hypoxemic Leghorns. Leghorns were more hypoxemic and resistant to PHS than broilers. In conclusion, Arg and VE plus VC show an additive effect in the improvement of cardiovascular performance of hypoxemic broilers as well as in restoring reactivity to phenylephrine in hypoxemic pulmonary rings. Also, supplementation shows an additive effect in restoring XO activity in hypoxic broilers. Leghorns had a better ventilation capacity and better pulmonary vasodilation capacity than broiler chickens.

No description available.

Chronic neonatal pulmonary hypertension (PHT) frequently presents with rightventricular (RV) dysfunction. In neonatal rats exposed to chronic hypoxia, RV dysfunction is reversed by sustained rescue treatment with a Rho-kinase (ROCK) inhibitor – the caveat being systemic hypotension. We therefore examined the reversing effects of pulmonary-selective ROCK inhibition. Rat pups were exposed to air or hypoxia from birth for 21 days and received sustained rescue treatment with aerosolized Fasudil (81 mg/ml t.i.d for 15 min) or i.p. Y27632 (15 mg/kg b.i.d) from days 14-21. Inhaled Fasudil normalized pulmonary vascular resistance, and reversed pulmonary vascular remodeling but did not improve RV systolic function. Systemic, but not pulmonary-selective, ROCK inhibition attenuated increased RV ROCK activity. Our findings indicate that RV dysfunction in chronic hypoxic PHT is not merely a result of increased afterload, but rather may be due to increased activity of ROCK in the right ventricle.

Chronic neonatal pulmonary hypertension (PHT) frequently presents with rightventricular (RV) dysfunction. In neonatal rats exposed to chronic hypoxia, RV dysfunction is reversed by sustained rescue treatment with a Rho-kinase (ROCK) inhibitor – the caveat being systemic hypotension. We therefore examined the reversing effects of pulmonary-selective ROCK inhibition. Rat pups were exposed to air or hypoxia from birth for 21 days and received sustained rescue treatment with aerosolized Fasudil (81 mg/ml t.i.d for 15 min) or i.p. Y27632 (15 mg/kg b.i.d) from days 14-21. Inhaled Fasudil normalized pulmonary vascular resistance, and reversed pulmonary vascular remodeling but did not improve RV systolic function. Systemic, but not pulmonary-selective, ROCK inhibition attenuated increased RV ROCK activity. Our findings indicate that RV dysfunction in chronic hypoxic PHT is not merely a result of increased afterload, but rather may be due to increased activity of ROCK in the right ventricle.

Submitted by ALICIA CRISTINA SUMAN null (aliciasuman@hotmail.com) on 2016-08-22T23:59:23Z No. of bitstreams: 1 Tese Alicia Suman.pdf: 1146493 bytes, checksum: d897435ea1f94d5b32f63cf38cfeff2f (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-08-24T17:22:28Z (GMT) No. of bitstreams: 1 suman_ac_me_bot.pdf: 1146493 bytes, checksum: d897435ea1f94d5b32f63cf38cfeff2f (MD5) / Made available in DSpace on 2016-08-24T17:22:28Z (GMT). No. of bitstreams: 1 suman_ac_me_bot.pdf: 1146493 bytes, checksum: d897435ea1f94d5b32f63cf38cfeff2f (MD5) Previous issue date: 2016-07-01 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A Doença de Chagas é uma doença progressiva e incapacitante, principalmente quando a função cardiopulmonar é acometida. É possível também que, esta associação esteja relacionada com a fraqueza muscular respiratória devido ao processo incapacitante, mostra alguns sintomas como, cansaço aos esforços e fadiga, que pode exacerbar-se quando associada à Hipertensão Pulmonar, e como sintomas inicias apresenta uma importante dispneia e considerável limitação nas atividades de vida diária. O presente estudo teve como objetivo avaliar a musculatura respiratória, qualidade de vida, perfil de ansiedade e depressão em pacientes com forma crônica indeterminada de Doença de Chagas associada à Hipertensão Pulmonar. Foram avaliados 107 pacientes, separados em três grupos: G1(grupo controle, n=08), G2 (grupo chagásico, n=93) e G3 (grupo chagásico sugestivo de hipertensão pulmonar, n=06). Todos os indivíduos foram submetidos à avaliação clínica, da espirometria pré e pós-broncodilatador, distância percorrida no teste de caminhada de seis minutos, avaliação da musculatura respiratória através da mensuração da PImáx e PEmáx, avaliação do estado de saúde, por meio do Medical Outcomes Study 36 - item Short-Form Health Survey (SF - 36) e da Escala Hospitalar de Ansiedade e Depressão. Os pacientes avaliados tinham idade média de 55 ± 8,8 anos, sendo 58 do sexo masculino (54%), 23 % eram tabagistas, em relação à classe funcional, 53 indivíduos do G2 estavam na classe funcional I e 5 indivíduos do G3 estavam na classe funcional II. Não houve diferença estatisticamente significante entre os três grupos estudados na avaliação da PImáx e PEmáx. Grupo 3 apresenta diferença estatisticamente significativa na distância real percorrida no teste de caminhada de seis minutos em relação ao grupo 1 e grupo 2; e para a distância prevista o G1 (p<0,05) foi estatisticamente significante em relação ao G3. Os valores espirométricos, avaliação da escala hospitalar e ansiedade e depressão- HAD e o questionário SF-36 não diferiram entre os grupos. Portanto, pacientes com a forma crônica indeterminada da doença de chagas associada à HP, não apresentam comprometimento significativo em relação à musculatura respiratória, espirometria e nas avaliações de qualidade de vida através da escala hospitalar de ansiedade e depressão e SF-36, porém na distância percorrida no teste de caminhada de seis minutos mostrou-se com baixa tolerância ao exercício. / Chagas Disease is progressive and incapacitating, especially when cardiopulmonary function is affected. It may be related to respiratory muscular weakness due to an incapacitating process, causing such symptoms as: tiredness upon exertion and fatigue, which may be exacerbated when associated with Pulmonary Hypertension. The present study aimed to evaluate the respiratory musculature, quality of life, profile of anxiety and depression in patients with indeterminate chronic Chagas Disease associated with Pulmonary Hypertension. We evaluated 107 patients, separated into three groups: G1(control group, n=08), G2 (Chagastic group, n=93) and G3 (Chagastic group suggestive of Pulmonary Hypertension, n=06). All individuals were submitted to clinical evaluation, spirometry, six-minute walking test, evaluation of respiratory musculature by measurement of PImax and PEmax, evaluation health state and hospital scale of anxiety and depression. In the evaluation of PImax and PEmax, there was no statistically significant difference among the three groups studied. G3 differed statistically in the real distance covered in the six-minute walking test in relation to G1 and G2; and for the predicted distance, G1 (p<0.05) was statistically significant in relation to G3. The spirometric values, evaluation of the Hospital Anxiety and Depression Scale (HADS) and the SF-36 questionnaire did not differ among the groups. Therefore, patients with the indeterminate chronic form of Chagas Disease associated with PH, did not show significant impairment in relation to the variables studied, except for the six-minute walking test, which revealed low exercise tolerance.

Orientador: Hugo Hyung Bok Yoo / Resumo: A Doença de Chagas é uma doença progressiva e incapacitante, principalmente quando a função cardiopulmonar é acometida. É possível também que, esta associação esteja relacionada com a fraqueza muscular respiratória devido ao processo incapacitante, mostra alguns sintomas como, cansaço aos esforços e fadiga, que pode exacerbar-se quando associada à Hipertensão Pulmonar, e como sintomas inicias apresenta uma importante dispneia e considerável limitação nas atividades de vida diária. O presente estudo teve como objetivo avaliar a musculatura respiratória, qualidade de vida, perfil de ansiedade e depressão em pacientes com forma crônica indeterminada de Doença de Chagas associada à Hipertensão Pulmonar. Foram avaliados 107 pacientes, separados em três grupos: G1(grupo controle, n=08), G2 (grupo chagásico, n=93) e G3 (grupo chagásico sugestivo de hipertensão pulmonar, n=06). Todos os indivíduos foram submetidos à avaliação clínica, da espirometria pré e pós-broncodilatador, distância percorrida no teste de caminhada de seis minutos, avaliação da musculatura respiratória através da mensuração da PImáx e PEmáx, avaliação do estado de saúde, por meio do Medical Outcomes Study 36 - item Short-Form Health Survey (SF - 36) e da Escala Hospitalar de Ansiedade e Depressão. Os pacientes avaliados tinham idade média de 55 ± 8,8 anos, sendo 58 do sexo masculino (54%), 23 % eram tabagistas, em relação à classe funcional, 53 indivíduos do G2 estavam na classe funcional I e 5... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Chagas Disease is progressive and incapacitating, especially when cardiopulmonary function is affected. It may be related to respiratory muscular weakness due to an incapacitating process, causing such symptoms as: tiredness upon exertion and fatigue, which may be exacerbated when associated with Pulmonary Hypertension. The present study aimed to evaluate the respiratory musculature, quality of life, profile of anxiety and depression in patients with indeterminate chronic Chagas Disease associated with Pulmonary Hypertension. We evaluated 107 patients, separated into three groups: G1(control group, n=08), G2 (Chagastic group, n=93) and G3 (Chagastic group suggestive of Pulmonary Hypertension, n=06). All individuals were submitted to clinical evaluation, spirometry, six-minute walking test, evaluation of respiratory musculature by measurement of PImax and PEmax, evaluation health state and hospital scale of anxiety and depression. In the evaluation of PImax and PEmax, there was no statistically significant difference among the three groups studied. G3 differed statistically in the real distance covered in the six-minute walking test in relation to G1 and G2; and for the predicted distance, G1 (p<0.05) was statistically significant in relation to G3. The spirometric values, evaluation of the Hospital Anxiety and Depression Scale (HADS) and the SF-36 questionnaire did not differ among the groups. Therefore, patients with the indeterminate chronic form of Chagas... (Complete abstract click electronic access below) / Mestre

Made available in DSpace on 2015-05-14T13:00:11Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1807154 bytes, checksum: 7aebebd024c49081a819ffba28e2ccae (MD5) Previous issue date: 2009-12-21 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Cissampelos sympodialis Eichl. (Menispermaceae) is a plant species used in popular medicine in Northeast of Brazil, whose pharmacological effects shows a great potential in treatment of respiratory diseases. Fosfodiesterase inhibition and smooth muscle relaxant effects are attributed to its leaves extract. Sildenafil, an oral fosfodiesterase type 5 inhibitor, is a drug used in treatment of pulmonary hypertension by vasodilatory effects through a cyclic guanosine 3´,5´-monophosphate (cGMP) dependent mechanism. This study was designed to investigate chronic effects of Cissampelos sympodialis extract in monocrotaline (MCT) induced pulmonary hypertension in rats, using sildenafil as a reference drug. After a single subcutaneous injection of MCT, rats were randomized to receive repeated administration of saline, sildenafil, Cissampelos sympodialis extract or both twice a day for 4 weeks. In the last day of treatment, animals were submitted to a median toracotomy to access pulmonary pressure. Four weeks after MCT injection, there was a significant development of pulmonary hypertension (60.19 ± 6.81), in contrast with SHAM group (32.77 ± 1.80). The increases in pulmonary mean pressure, ratio of right ventricular weight to body weight and thickening of the precapillary artery wall were significantly attenuated in the Cissampelos sympodialis extract (37.40 ± 3.76; 0.63 ± 0.04; 57.33 ± 5.04; respectively) and Sildenafil groups (34.57 ± 3.85; 0.68 ± 0.04; 57.00 ± 4.07; respectively), when compared to control group (52.65 ± 4.05; 1.14 ± 0.07; 89.43 ± 1.29; respectively). Combination therapy (32.16 ± 3.65; 0.86 ± 0.02; 64.62 ± 7.28; respectively) with sildenafil and extract had no additive effects in this model. These results suggest that therapy with oral Cissampelos sympodialis extract and sildenafil attenuates the development of monocrotaline induced pulmonary hypertension and that combination therapy has no additional effects compared with sildenafil or extract given alone. / Cissampelos sympodialis Eichl. (Menispermaceae) é uma planta usada na medicina popular do Nordeste do Brasil, cujos efeitos farmacológicos apresentam um grande potencial no tratamento de doenças respiratórias. Efeitos sobre o relaxamento de músculo liso e inibição de fosfodiesterases são atribuídos ao extrato das folhas de C. sympodialis. Sildenafil, um inibidor da fosfodiesterase do tipo 5, é uma droga usada no tratamento da hipertensão pulmonar pelo seu efeito vasodilatador, causado por um mecanismo dependente de 3´, 5´-monofosfato de guanosina cíclica (GMPc). Este estudo foi desenhado para investigar os efeitos crônicos do extrato de Cissampelos sympodialis em ratos com hipertensão pulmonar induzida pela monocrotalina (MCT), usando o sildenafil como droga de referência. Após uma injeção subcutânea única de MCT, ratos foram randomizados para receber duas doses diárias de salina, sildenafil, extrato de Cissampelos sympodialis ou ambos, durante quatro semanas. No último dia de tratamento, os animais foram submetidos a uma toracotomia mediana para medição das pressões pulmonares. Houve um desenvolvimento significante de hipertensão pulmonar, após quatro semanas, nos ratos submetidos à injeção de MCT (60,19 ± 6,81), em contraste com o grupo SHAM (32,77 ± 1,80). O aumento da pressão arterial pulmonar média, relação entre o peso do ventrículo direito e o peso do animal e espessamento da parede das artérias pré-capilares pulmonares foram significantemente atenuados pelo uso do extrato de Cissampelos sympodialis (37,40 ± 3,76; 0,63 ± 0,04; 57,33 ± 5,04; respectivamente) e sildenafil (34,57 ± 3,85; 0,68 ± 0,04; 57,00 ± 4,07; respectivamente) em relação ao grupo controle (52,65 ± 4,05; 1,14 ± 0,07; 89,43 ± 1,29; respectivamente). A terapia combinada (32,16 ± 3,65; 0,86 ± 0,02; 64,62 ± 7,28; respectivamente) com sildenafil e extrato não provocou efeitos aditivos em relação ao tratamento isolado com cada um deles neste modelo. Estes resultados sugerem que a terapia oral com extrato de Cissampelos sympodialis e sildenafil atenua o desenvolvimento da hipertensão pulmonar induzida pela monocrotalina e que a terapia combinada não traz efeitos adicionais, quando comparados com o emprego do sildenafil ou do extrato de Cissampelos sympodialis isoladamente.

Chronic damage to pulmonary vessels leads to pulmonary hypertension (PH). Different forms of PH are quite frequent and are associated with significant morbidity and mortality. The treatment of PH is most successful, if its cause can be identified and removed before irreversible damage to the pulmonary vascular bed occurs. For patients, in whom the elimination of the underlying cause is not possible or where the cause is unknown, the treatment is aimed at reduction of pulmonary vascular resistance and improvement of cardiac and circulatory response to pressure overload of the right ventricle. One option for the PH treatment is modification of metabolism of cyclic guanosine monophosphate (GMP), which is the second messenger of nitric oxide and induces vascular vasodilation. Cyclic GMP is degraded by phosphodiesterases (PDE 5). In the clinical part, we tested the hypothesis that acute inhibition of PDE5 by sildenafil provides more selective pulmonary vasodilation than high doses of prostaglandin E1 (PGE1). The study showed that the vasodilator effects of sildenafil on pulmonary circulation is more pronounced than in the systemic circulation and that sildenafil had a greater ability to detect reversible component precapillary PH due to advanced chronic heart failure than PGE1. The aim of our...

INTRODUÇÃO: As Hemoglobinopatias podem ser divididas em Talassemias e Doença Falciforme (DF), mas do ponto de vista clínico, ambas apresentam um quadro de anemia hemolítica crônica, o que acarreta uma série de complicações, entre estas a Hipertensão Pulmonar (HP). Estima-se que cerca de 20-40% da população com DF/talassemia apresente HP, sendo que este diagnóstico está associado a uma elevada morbi-mortalidade. Poucos estudos avaliaram esta prevalência em crianças. O Objetivo deste estudo foi avaliar a prevalência desta complicação na população pediátrica, e associá-la com características clínicas e laboratoriais. MÉTODOS: Estudo de Corte Transversal, com avaliação de 45 pacientes com diagnóstico de DF ou Talassemia maior/ intermédia entre 3-18 anos, atendidos de forma consecutiva no ambulatório de Hemoglobinopatias do HCPA. Os pacientes foram submetidos a um ecocardiograma para estimativa da pressão sistólica da artéria pulmonar, sendo que foi considerado como tendo risco de HP os pacientes com velocidade de regurgitação tricúspide (VRT) ≥ 2,5m/s. Foram obtidos dados clínicos e laboratoriais para avaliação dos parâmetros hemolíticos, função hepática e renal por levantamento de prontuário e comparados os grupos. RESULTADOS: 15% (6/40) dos pacientes apresentaram VRT ≥ 2,5m/s, sugestivo de HP, sendo que destes pacientes todos tinham diagnóstico de Anemia Falciforme (AF). Considerando apenas esta população, a prevalência de HP aumenta para 20% (6/30). A população com VRT ≥ 2,5m/s apresentou média de idade mais elevada, Hb mais baixa, RDW mais alargado, reticulócitos e LDH mais elevado que o grupo com VRT < 2,5m/s. A principal intercorrência clínica nesta população foi a ocorrência de priapismo (p< 0,05). CONCLUSÕES: Os pacientes com Hemoglobinopatias estão em risco aumentado para desenvolvimento de HP desde a infância, principalmente aqueles com AF. Estes pacientes apresentam os parâmetros laboratoriais sugestivos de hemólise alterados, assim como outros sintomas associados ao quadro hemolítico como o priapismo quando comparados com pacientes com VRT normal. Desta forma sugere-se a realização de triagem com ecocardiograma nesta população de forma precoce. / INTRODUCTION: The Hemoglobinopathies can be divided in Thalassemias and Sickle Cell Disease (SCD), but clinically both present with chronic hemolytic anemia, which leads to various complications, one of them being Pulmonary Hypertension (PH). About 20-40% of patients with SCD have PH, and this diagnosis is associated with a high risk of mortality. The objective of this study was to estimate the prevalence of this complication in the pediatric population, and associate clinical and laboratory characteristics. METHODS: A cross sectional descriptive study, with the evaluation of 45 patients with diagnosis of SCD or thalassemia major/intermedia between 3-18 years, which received treatment at the Hemoglobinopathies ambulatory at HCPA. The patients were submitted to an echocardiogram to estimate the pulmonary artery systolic pressure, being considered to have PH patients with a tricuspid regurgitate jet velocity (TRV) ≥ 2.5m/s. Clinical and laboratory data were obtained to evaluate hemolytic parameters, renal and liver function and compared between groups. RESULTS: 15% (6/40) of patients had a TRV ≥ 2.5m/s, suggestive of PH, of which all had Sickle Cell Anemia (SCA). Considering this group of patients alone the prevalence would be of 20% (6/30). Patients with TRV ≥ 2.5m/s had a higher median age, lower hemoglobin count, higher RDW, reticulocyte and DHL then patients with a TRV < 2.5m/s. The major clinical feature was the occurrence of priapism (p<0,05). CONCLUSIONS: Patients with diagnosis of hemoglobinopathies are at higher risk of developing PH since early childhood, especially those with SCA. These patients showed a higher level of hemolytic parameters, as well as symptoms associated with hemolysis, like priapism, when compared with patients with a normal TRV. Therefore, it would be indicated to submit these patients to an echocardiogram routinely in their early years.