Rationale: Vascular remodeling and right-ventricular (RV) dysfunction are features of refractory pulmonary hypertension (PHT) in human neonates. These features are replicated in rats chronically exposed to hypoxia (13% O2), in which increased pulmonary vascular resistance (PVR) was acutely normalized by Y-27632, a Rho-kinase (ROCK) inhibitor, but not by inhaled nitric oxide. Objective: To examine the reversing effects of sustained ROCK inhibition on haemodynamic (RV dysfunction and increased PVR) and structural (RV hypertrophy and arterial wall remodeling) changes of chronic hypoxic PHT. Methods: Rat pups were exposed to air or hypoxia from birth for up to 21 days and received Y-27632 (15 mg/kg/b.i.d.) or vehicle from day 14. Results: Y-27632 normalised RV dysfunction and reversed remodeling secondary to chronic hypoxia. These changes were accompanied by increased apoptosis of smooth muscle and attenuated endothelin-1 expression in pulmonary arteries. Conclusion: ROCK inhibitors hold promise as a rescue therapy for refractory PHT in neonates.

In this thesis, the monocrotaline (MCT)-induced rat model of pulmonary arterial hypertension (PAH) was used to investigate the role of innate immunity in the pathogenesis of PAH and the mode of action of experimental therapies. The first section of this thesis is an investigation of the therapeutic mechanism of human, early and late-outgrowth endothelial progenitor cells (EPCs) in the MCT-induced, nude rat model of PAH. While late-outgrowth EPCs provided no therapeutic benefit in this model, early EPCs (E-EPCs) prevented the elevation of right ventricular systolic pressure (RVSP, P<0.001) and right ventricular (RV) hypertrophy (P<0.01). Ablation of natural killer (NK) and natural killer T cells with anti-asialo GM-1 antiserum (ASGM-1) enhanced human cell retention in the lung but abrogated the therapeutic capacity of E-EPCs. In vitro studies demonstrated that E-EPCs are similar to monocyte-derived regulatory dendritic cells (DCs) and possess the capacity to stimulate both autologous and rat NK cells in co-culture. Imatinib mesylate has been reported to reverse established PAH both clinically and in the MCT model. Imatinib can also induce NK activation through inhibition of c-kit signaling in DCs, suggesting that imatinib and the DC-like E-EPCs may prevent PAH through a similar, NK-mediated mechanism. In the second section of this thesis, imatinib prevented MCT-induced increases in RVSP (P<0.001) and RV hypertrophy (P<0.01) in immunocompetent Fisher 344 rats, but not in nude rats or Fisher rats following ablation of NK cells and T lymphocytes with ASGM-1. These data suggest that the stimulation of NK activity by imatinib is insufficient to prevent disease in the absence of T lymphocytes. Hyaluronan (HA) fragments are a potent inflammatory stimulus, capable of inducing macrophage activation and DC maturation. In the third section of this thesis, HA synthesis and degradation were investigated in the MCT model of PAH. While the early stages of disease were characterized by enhanced hyaluronidase-1 activity and a loss of high molecular weight (HMW) HA, severe disease was associated with HMW HA synthesis and HA accumulation in the lungs. The early degradation of HMW HA may drive inflammation and stimulate pathological vascular remodeling in PAH.

Pulmonary arterial hypertension (PAH) results from endothelial cell (EC) damage leading to pulmonary vasoconstriction and arteriolar remodeling. Patients with PAH exhibit high pulmonary arterial pressures due to increased pulmonary vascular resistance and die of progressive right-sided heart failure. The pathogenesis of PAH is not completely understood, but involves processes which reflect abnormalities in EC function: an imbalance of vasodilators and constrictors, thrombosis, vascular smooth muscle cell (SMC) hypertrophy and proliferation, and susceptibility to EC apoptosis. Therefore, it is important to investigate possible alterations in the underlying mechanisms that regulate EC structure and function. Krüppel-like factor 2 (KLF2) is a shear-responsive transcription factor, highly expressed in the pulmonary ECs under physiological conditions, and known to maintain EC homeostasis by acting as a master switch for a quiescent profile of EC gene transcription. We hypothesized that Klf2 expression is reduced in models of pulmonary hypertension (PH) and its down-regulation contributes to PH development; conversely, Klf2 overexpression is beneficial, and may represent a novel therapeutic target. The role of KLF2 in PH was characterized in two experimental rat models: the monocrotaline model of severe and lethal PAH, and the chronic hypoxia model of reversible hypoxic PH. In vivo Klf2 expression was manipulated using jetPEI® to enhance or reduce the activity of the KLF2 pathway. Plasmids containing short hairpin Klf2 (shKLF2) or Klf2, or empty plasmids were selectively delivered to the pulmonary microvasculature, and the effect on pulmonary hemodynamics, microvascular structure and function, along with various in vitro functional and molecular assays of EC activity, were assessed. Results suggest that reduced Klf2 expression may be a critical early event in EC activation and initiation of PAH; and, its persistent downregulation may play a role in the transition to a progressive and irreversible process. Data also suggests that an early therapeutic intervention to overexpress Klf2, can prevent the development of PH in both models tested when applied before the “irreversible” microvascular remodeling is present. However, once the full PAH phenotype is established, in particular in the presence advanced arteriolar remodeling, Klf2 gene transfer was unsuccessful in reversing the disease in the MCT model.

In this thesis, the monocrotaline (MCT)-induced rat model of pulmonary arterial hypertension (PAH) was used to investigate the role of innate immunity in the pathogenesis of PAH and the mode of action of experimental therapies. The first section of this thesis is an investigation of the therapeutic mechanism of human, early and late-outgrowth endothelial progenitor cells (EPCs) in the MCT-induced, nude rat model of PAH. While late-outgrowth EPCs provided no therapeutic benefit in this model, early EPCs (E-EPCs) prevented the elevation of right ventricular systolic pressure (RVSP, P<0.001) and right ventricular (RV) hypertrophy (P<0.01). Ablation of natural killer (NK) and natural killer T cells with anti-asialo GM-1 antiserum (ASGM-1) enhanced human cell retention in the lung but abrogated the therapeutic capacity of E-EPCs. In vitro studies demonstrated that E-EPCs are similar to monocyte-derived regulatory dendritic cells (DCs) and possess the capacity to stimulate both autologous and rat NK cells in co-culture. Imatinib mesylate has been reported to reverse established PAH both clinically and in the MCT model. Imatinib can also induce NK activation through inhibition of c-kit signaling in DCs, suggesting that imatinib and the DC-like E-EPCs may prevent PAH through a similar, NK-mediated mechanism. In the second section of this thesis, imatinib prevented MCT-induced increases in RVSP (P<0.001) and RV hypertrophy (P<0.01) in immunocompetent Fisher 344 rats, but not in nude rats or Fisher rats following ablation of NK cells and T lymphocytes with ASGM-1. These data suggest that the stimulation of NK activity by imatinib is insufficient to prevent disease in the absence of T lymphocytes. Hyaluronan (HA) fragments are a potent inflammatory stimulus, capable of inducing macrophage activation and DC maturation. In the third section of this thesis, HA synthesis and degradation were investigated in the MCT model of PAH. While the early stages of disease were characterized by enhanced hyaluronidase-1 activity and a loss of high molecular weight (HMW) HA, severe disease was associated with HMW HA synthesis and HA accumulation in the lungs. The early degradation of HMW HA may drive inflammation and stimulate pathological vascular remodeling in PAH.

Pulmonary arterial hypertension (PAH) results from endothelial cell (EC) damage leading to pulmonary vasoconstriction and arteriolar remodeling. Patients with PAH exhibit high pulmonary arterial pressures due to increased pulmonary vascular resistance and die of progressive right-sided heart failure. The pathogenesis of PAH is not completely understood, but involves processes which reflect abnormalities in EC function: an imbalance of vasodilators and constrictors, thrombosis, vascular smooth muscle cell (SMC) hypertrophy and proliferation, and susceptibility to EC apoptosis. Therefore, it is important to investigate possible alterations in the underlying mechanisms that regulate EC structure and function. Krüppel-like factor 2 (KLF2) is a shear-responsive transcription factor, highly expressed in the pulmonary ECs under physiological conditions, and known to maintain EC homeostasis by acting as a master switch for a quiescent profile of EC gene transcription. We hypothesized that Klf2 expression is reduced in models of pulmonary hypertension (PH) and its down-regulation contributes to PH development; conversely, Klf2 overexpression is beneficial, and may represent a novel therapeutic target. The role of KLF2 in PH was characterized in two experimental rat models: the monocrotaline model of severe and lethal PAH, and the chronic hypoxia model of reversible hypoxic PH. In vivo Klf2 expression was manipulated using jetPEI® to enhance or reduce the activity of the KLF2 pathway. Plasmids containing short hairpin Klf2 (shKLF2) or Klf2, or empty plasmids were selectively delivered to the pulmonary microvasculature, and the effect on pulmonary hemodynamics, microvascular structure and function, along with various in vitro functional and molecular assays of EC activity, were assessed. Results suggest that reduced Klf2 expression may be a critical early event in EC activation and initiation of PAH; and, its persistent downregulation may play a role in the transition to a progressive and irreversible process. Data also suggests that an early therapeutic intervention to overexpress Klf2, can prevent the development of PH in both models tested when applied before the “irreversible” microvascular remodeling is present. However, once the full PAH phenotype is established, in particular in the presence advanced arteriolar remodeling, Klf2 gene transfer was unsuccessful in reversing the disease in the MCT model.

Fundamento: O óxido nítrico inalatório (NOi) tem sido utilizado para controle e tratamento da hipertensão pulmonar (HP) durante ou imediatamente após cirurgias cardiotorácicas. Entretanto, seus efeitos comparados a outras medicações vasodilatadoras ainda são controversos. Objetivo: Revisar sistematicamente os efeitos do NOi comparado com outras medicações vasodilatadoras administrado durante ou imediatamente após cirurgias cardiotorácicas, sobre variáveis hemodinâmicas e oxigenação, em pacientes com HP. Métodos: Foi realizada uma busca sistemática nas bases de dados Cochrane CENTRAL, MEDLINE, Lilacs, PEDro e Embase, além de busca manual em referências de estudos publicados até maio de 2015. Foram incluídos ensaios clínicos randomizados (ECRs) que compararam NOi vs. outras medicações vasodilatadoras (inalatórias ou intravenosas) e que analisaram índice de oxigenação (relação PaO2/FiO2) e variáveis hemodinâmicas como pressão média da artéria pulmonar (PMAP), resistência vascular pulmonar (RVP), fração de ejeção do ventrículo direito (FEVD), saturação venosa mista de oxigênio (SvO2), índice cardíaco (IC), pressão venosa central (PVC), frequência cárdica (FC), pressão arterial média sistêmica (PAM), e resistência vascular sistêmica (RVS). Resultados: Foram identificados 2.561 artigos, totalizando seis ECRs incluídos. O uso do NOi comparado com outras medicações vasodilatadoras não promoveu alterações na relação PaO2/FiO2, PMAP, RVP, IC, FEVD, SvO2, PVC e RVS, entretanto houve redução na FC (-5,47 bpm; IC95%: -10,87 a -0,06) comparado com medicações inalatórias e aumento na PAM (9,30 mmHg; IC95%: 3,94 a 14,65; I2: 86%) comparado com medicações vasodilatadoras intravenosas. Conclusões: O uso do NOi não promoveu alterações na relação PaO2/FiO2 e nas variáveis hemodinâmicas comparado com outras medicações vasodilatadoras, exceto na FC onde houve redução e na PAM onde houve aumento, durante ou imediatamente após cirurgias cardiotorácicas em pacientes adultos com HP. / Introduction: The inhaled nitric oxide (INO) has been used for control and treatment of pulmonary hypertension (PH) during or immediately after cardiothoracic surgery. Although, the effects when compared to other vasodilator medications are still controversial. Objectives: The purpose of this study was to systematically review the effects of INO compared with other vasodilatory drugs administered during or immediately after cardiothoracic surgeries on hemodynamics and oxygenation variables in patients with PH. Methods: A systematic research was conducted in the databases Cochrane CENTRAL, MEDLINE, Lilacs, PEDro e Embase, in addition a manual search at references of published studies until May 2015. Randomised trials (RCTs) were included, comparing INO vs. other vasodilator medications (inhaled or intravenous), that analyzed the oxygenation index (ratio PaO2/FiO2) and hemodynamic variables: mean pulmonary artery pressure (MPAP), pulmonary vascular resistance (PVR), right ventricular ejection fraction (RVEF), mixed venous oxygen saturation (SvO2) , cardiac index (CI), central venous pressure (CVP), cardia rate (HR), mean systemic arterial pressure (MAP) and systemic vascular resistance (SVR). Results: We identified 2561 articles, being only six ECRs included. The use of NOi compared to other vasodilator medications did not change the ratio PaO2/FiO2, MPAP, PVR, CI, RVEF, SvO2, CVP e SVR, however there was a reduction in HR (-5,47 bpm; IC95%: -10,87 a -0,06) compared to inhaled medications and increased MAP (9,30 mmHg; IC95%: 3,94 a 14,65; I2: 86%) compared with intravenous vasodilator medications. Conclusion: The use of INO did not change ratio PaO2/FiO2 and hemodynamic variables, compared with other vasodilator medications, except HR where has been found a reduction, and MAP where has been found an increasing, during or immediately after thoracic cardiovascular surgery in adult patients with HP.

Objetivo: Traduzir e adaptar para o português falado no Brasil a escala Dyspnoea-12. Fornecer dados de validação da escala para pacientes com DPOC e hipertensão pulmonar (HP). Métodos: A versão em inglês da escala Dyspnoea-12 sofreu processo clássico de tradução, até obtenção de versão definitiva em português denominada Dispneia-12-Pt. A escala Dispneia-12-Pt foi aplicada a 51 pacientes com DPOC (33 homens; idade: 66,4±8,1 anos; VEF1: 48,7±17,2%) e 15 com HP de diferentes etiologias (12 mulheres; idade: 45,8±12,7 anos; pressão sistólica da artéria pulmonar: 88±33,2 mmHg). Os voluntários responderam a escala de dispneia do Medical Research Council(MRC), o índice de dispneia basal (IDB), a escala hospitalar de ansiedade e depressão, questionário respiratório de Saint George (QRSG), avaliação funcional respiratória e teste da caminhada dos seis minutos (TC6min). Sessenta voluntários responderam a escala uma segunda vez, duas semanas após a primeira avaliação. Resultados: No grupo DPOC a escala Dispneia-12-Pt apresentou correlações significantes com as escalas MRC (r=0,4641; p=0,0006), IDB (r=0,515; p <0,0001), QRSG (r=0,8113; p<0,0001), ansiedade (r=0,4714; p=0,0005), depressão (0,4139; p=0,0025) e distância percorrida no TC6min (r=0,3293; p=0,0255). No grupo com HP a escala mostrou correlações significantes com as escalas MRC (r=0,5774; p=0,0242), QRSG (r=0,6907; p=0,0044), distância percorrida no TC6min (r=0,7193; p=0,0025) e difusão do monóxido de carbono (r=0,564; p=0,0447). O alfa de Cronbach para os voluntários analisados em um único grupo foi 0,927 e o coeficiente de correlação intraclasse 0,8456. Conclusões: A escala Dispneia-12-Pt apresenta propriedades biométricas aceitáveis e pode ser empregada em pacientes brasileiros com dispneia de diferentes etiologias. / Objective: To translate and to adapt for the Portuguese spoken in Brazil the scale Dyspnoea-12. To obtain validation data, regarding the use of this scale in patients with COPD and pulmonary hypertension (PH). Methods: The English version of the scale Dyspnoea-12 received a formal translation process and the final version was called Dispneia-12-Pt. The latter was applied to 51 COPD patients (33 men; age: 66.4±8.1 years; FEV1: 48.7±17.2 % pred) and 15 subjects with PH from different etiologies (12 women; age: 45.8±12.7 years; systolic pulmonary arterial pressure: 88±33.2 mmHg). The volunteers also answered the Medical Research Council dyspnea scale (MRC), the basal dyspnea index (DBI), the hospital scale of anxiety and depression, the Saint George Respiratory Questionnaire (SGRQ), respiratory functional evaluation and the six minute walk test (6 MWT). Sixty volunteers also answered the Dispneia-12-Pt scale about two weeks after the first evaluation. Results: In the COPD group the Dispneia-12-Br showed significant correlations with the scales MRC (r=0.4641; p=0.0006), BDI (0.515; p<0.0001), SGRQ (r=0.8113; p<0.0001), anxiety (r=0.4714; p=0.0005), depression (0.4139; p=0.0025) and walked distance in the 6 MWT (r=0.3293; p= 0.0255). In the HP group the scale showed significant correlations with the scales MRC (r=0.5774; p=0.0005), SGRQ (r=0.6907; p=0.0044), walked distance in the 6 MWT (0.7193; p=0.0025) and carbon dioxide diffusion capacity (r=0.564; p=0.0447). Cronbach´s alpha calculated for all volunteers evaluated as a whole was 0.927 while the intraclass correlation coefficient was 0.8456. Conclusions: The Dispneia-12-Pt exhibits acceptable biometric properties and may be used as a tool in Brazilian patients with dyspnea of different etiologies.

Orientador: Thais Helena Abraão Thomaz Queluz / Coorientador: Hugo Hyung Bok Yoo / Banca: Frederico Henrique Sobral de Oliveira / Banca: Luiz Cuadrado Martins / Banca: Ricardo Henrique de Oliveira Braga Teixeira / Banca: Vitor Zuniga Dourado / Resumo: A Hipertensão Pulmonar (HP) é definida clinicamente como aumento na pressão vascular pulmonar causada por condições associadas com aumento na pressão arterial pulmonar e/ou venosa. Hemodinamicamente, é definida como aumento na pressão arterial pulmonar média (PAPm) ≥ 25mmHg no repouso, resistência vascular pulmonar (RVP) superior a 4 Unidades Wood, ou quando o gradiente transpulmonar é superior a 10-12 mmHg. Muitos pacientes e clínicos atribuem a dispnéia e fadiga ao descondicionamento físico e à fraqueza muscular global e dos músculos respiratórios, podendo levar o paciente a piora da qualidade de vida. Objetivos: Avaliar a qualidade de vida, a força muscular respiratória (FMR) e a distância percorrida no teste de caminhada de seis minutos (DTC6) em pacientes com hipertensão arterial pulmonar sob tratamento farmacológico específico. Metodologia: Estudo descritivo, prospectivo, série de casos de hipertensão pulmonar em maiores de 18 anos, avaliados no Ambulatório de Hipertensão Pulmonar no período entre fevereiro de 2007 a fevereiro de 2011. Após a consulta médica, foi aplicado o questionário SF-36 para avaliação da qualidade de vida. A seguir, os pacientes foram submetidos à avaliação da força muscular respiratória. Após descanso de 30 minutos, os pacientes realizaram DTC6. Os pacientes foram avaliados em três momentos: M0, sem tratamento farmacológico específico; M1, de dois a quatro meses após tratamento farmacológico específico; e M2, seis meses após M0. Resultados: Havia 16 mulheres e 6 homens, com idade média±DP de 48,46±15,4anos, 21 brancos e 1 não branco, 1 com classe funcional I, 10 com classe funcional II, 9 classe III e 2 classe IV segundo a NYHA modificada para HP. Em relação a qualidade de vida, todos os pacientes avaliados apresentaram... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Pulmonary Hypertension (PH) involves a group of clinical and physiopathological entities with similar characteristics that come from several main diseases. Patients show arterial pulmonary pressure ≥ 25mmHg at rest, pulmonary vascular resistance (PVR) greater than 4 Wood Units, or transpulmonary gradient above 10-12 mmHg. Dyspnea and fatigue are the main symptoms; there is also lack of physical conditioning and global muscle weakness, including respiratory muscles. There are no studies assessing respiratory muscle force (RMF) in this population under specific treatment. Aims: Evaluation of quality of life, RMF and Six Minutes Walk Distance (6MWD) in patients with PH under specific pharmacologic treatment. Patients and Method: This is a descriptive, prospective case series study, of 22 PH patients over 18 years old, from the HC-FMB-UNESP Pulmonary Hypertension Clinic, evaluated at three moments: M0, without specific pharmacologic treatment; M1, two to four months after specific pharmacologic treatment; and M2, six months after M0. In all moments patients were submitted to clinical examination by the physician, RMF was assessed and the 6MWD was performed; then questionnaire SF-36 was applied in order to estimate quality of life. Results: most patients, 16 women and 6 men, average age ± SD 48.5 ± 15.4 years-old, were classified in functional classes II (n=10) and III (n=9) according to NYHA modified for PH. Patients showed improvement in their quality of life, regarding pain (M0 x M2 e M1 x M2), emotional aspect (M0 x M1) and mental health (M0 x M2). As for RMF there was an improvement in maxIP and maxEP (M1 x M2). There was also an improvement in the distance covered in the 6MWD (M0 x M1 and M0 x M2). Correlation between RMF... (Complete abstract click electronic access below) / Doutor

Fundamento: O óxido nítrico inalatório (NOi) tem sido utilizado para controle e tratamento da hipertensão pulmonar (HP) durante ou imediatamente após cirurgias cardiotorácicas. Entretanto, seus efeitos comparados a outras medicações vasodilatadoras ainda são controversos. Objetivo: Revisar sistematicamente os efeitos do NOi comparado com outras medicações vasodilatadoras administrado durante ou imediatamente após cirurgias cardiotorácicas, sobre variáveis hemodinâmicas e oxigenação, em pacientes com HP. Métodos: Foi realizada uma busca sistemática nas bases de dados Cochrane CENTRAL, MEDLINE, Lilacs, PEDro e Embase, além de busca manual em referências de estudos publicados até maio de 2015. Foram incluídos ensaios clínicos randomizados (ECRs) que compararam NOi vs. outras medicações vasodilatadoras (inalatórias ou intravenosas) e que analisaram índice de oxigenação (relação PaO2/FiO2) e variáveis hemodinâmicas como pressão média da artéria pulmonar (PMAP), resistência vascular pulmonar (RVP), fração de ejeção do ventrículo direito (FEVD), saturação venosa mista de oxigênio (SvO2), índice cardíaco (IC), pressão venosa central (PVC), frequência cárdica (FC), pressão arterial média sistêmica (PAM), e resistência vascular sistêmica (RVS). Resultados: Foram identificados 2.561 artigos, totalizando seis ECRs incluídos. O uso do NOi comparado com outras medicações vasodilatadoras não promoveu alterações na relação PaO2/FiO2, PMAP, RVP, IC, FEVD, SvO2, PVC e RVS, entretanto houve redução na FC (-5,47 bpm; IC95%: -10,87 a -0,06) comparado com medicações inalatórias e aumento na PAM (9,30 mmHg; IC95%: 3,94 a 14,65; I2: 86%) comparado com medicações vasodilatadoras intravenosas. Conclusões: O uso do NOi não promoveu alterações na relação PaO2/FiO2 e nas variáveis hemodinâmicas comparado com outras medicações vasodilatadoras, exceto na FC onde houve redução e na PAM onde houve aumento, durante ou imediatamente após cirurgias cardiotorácicas em pacientes adultos com HP. / Introduction: The inhaled nitric oxide (INO) has been used for control and treatment of pulmonary hypertension (PH) during or immediately after cardiothoracic surgery. Although, the effects when compared to other vasodilator medications are still controversial. Objectives: The purpose of this study was to systematically review the effects of INO compared with other vasodilatory drugs administered during or immediately after cardiothoracic surgeries on hemodynamics and oxygenation variables in patients with PH. Methods: A systematic research was conducted in the databases Cochrane CENTRAL, MEDLINE, Lilacs, PEDro e Embase, in addition a manual search at references of published studies until May 2015. Randomised trials (RCTs) were included, comparing INO vs. other vasodilator medications (inhaled or intravenous), that analyzed the oxygenation index (ratio PaO2/FiO2) and hemodynamic variables: mean pulmonary artery pressure (MPAP), pulmonary vascular resistance (PVR), right ventricular ejection fraction (RVEF), mixed venous oxygen saturation (SvO2) , cardiac index (CI), central venous pressure (CVP), cardia rate (HR), mean systemic arterial pressure (MAP) and systemic vascular resistance (SVR). Results: We identified 2561 articles, being only six ECRs included. The use of NOi compared to other vasodilator medications did not change the ratio PaO2/FiO2, MPAP, PVR, CI, RVEF, SvO2, CVP e SVR, however there was a reduction in HR (-5,47 bpm; IC95%: -10,87 a -0,06) compared to inhaled medications and increased MAP (9,30 mmHg; IC95%: 3,94 a 14,65; I2: 86%) compared with intravenous vasodilator medications. Conclusion: The use of INO did not change ratio PaO2/FiO2 and hemodynamic variables, compared with other vasodilator medications, except HR where has been found a reduction, and MAP where has been found an increasing, during or immediately after thoracic cardiovascular surgery in adult patients with HP.

Orientador: Edson Antunes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-09T08:05:23Z (GMT). No. of bitstreams: 1 Freitas_CristianeFonseca_D.pdf: 2119434 bytes, checksum: 58a318beb1d3946d852e010325a6187c (MD5) Previous issue date: 2007 / Resumo: Neste estudo, investigamos os efeitos protetores do BAY 41-2272 sobre a hipertensao pulmonar induzida pelo complexo heparina-protamina e hipoxia em cães anestesiados. Os animais foram anestesiados com pentobarbital sodico (Hypnol, 30mg/kg, iv) combinado com citrato de fentanila (0,01 mg/kg/h, i.v.) e diazepam (0,25mg/kg/h, iv). A hipertensao pulmonar pelo complexo heparina-protamina foi induzida com a administracao de 500 UI/kg de heparina, seguida da administracao de protamina (10 mg/kg). A interacao heparina-protamina causou aumento de aproximadamente 350% da pressao media da arteria pulmonar (PMAP), acompanhado de aumento significativo do indice de resistencia vascular pulmonar (IRVP) e da pressao capilar pulmonar (PcP). Este aumento foi significativo 2 min apos a injecao de protamina, mantendo-se significativamente elevado ate aproximadamente 5 minutos apos administracao da mesma. Ao mesmo tempo em que se detectou a hipertensao pulmonar, observamos reducao significativa da pressao arterial media (PAM). Observamos ainda um aumento significativo da frequencia cardiaca (FC) aos 2 minutos apos administracao da protamina com discreta diminuicao do indice cardiaco (IC). O indice de resistencia vascular sistemica (IRVS) nao sofreu alteracoes significativas. A saturacao do oxigenio (SpO2) foi significativamente diminuida apos a formacao do complexo heparina-protamina. Nos animais tratados com BAY 41-2272 (10 /kg/min, i.v.), observamos reducao marcante do aumento da PMAP, do IRVP e da PcP. Por outro lado, este tratamento potencializou a reducao da PAM. Alem disso, o BAY 41-2272 reduziu significantemente o IRVS e aumentou a FC. A diminuicao da SpO2 foi atenuada significativamente pelo BAY 41- 2272. Os niveis plasmaticos de GMPc foram dosados aos 2 min apos a formacao do complexo heparina-protamina, tendo-se mostrado elevados no grupo tratado com o BAY41-2272. O tempo de tromboplastina parcial ativado (TTPA) nao apresentou alteração significativa no tratamento com o BAY 41-2272. O veiculo do BAY 41-2272 (DMSO 30%) nao alterou significativamente os parametros estudados. A hipertensao pulmonar por hipoxia foi induzida com a instalacao de uma baixa tensao de oxigenio (FiO2=12%). Nesta circunstancia, a PMAP elevou-se em aproximadamente 280% aos 5 minutos, mantendo-se significativamente elevada ate 15 minutos apos instalacao da hipoxia. A elevacao da PMAP foi acompanhada de aumentos significativos no IRVP e PcP. A PAM, IRVS, FC e IC nao apresentaram alterações significativas. A SpO2 diminuiu na presenca da hipoxia. O tratamento com BAY 41-2272 (10 /kg/min, i.v.), reduziu significativamente a PMAP, PcP e IRVP. O IRVS foi significativamente potencializado pelo BAY 41-2272. A PAM, FC e IC nao alteraram significativamente. A diminuicao da SpO2 foi atenuada significativamente pelo BAY 41- 2272. Os niveis plasmaticos de GMPc elevaram-se significativamente no grupo tratado com o BAY 41-2272. Em conclusao, o BAY 41-2272 atenuou a acao vasoconstritora pulmonar induzida pelo complexo heparina-protamina e hipoxia levando a uma prevencao da hipertensao pulmonar. / Doutorado / Farmacologia / Doutor em Farmacologia