S-nitrosocaptopril: acute in-vivo pulmonary vasodepressor effects in pulmonary hypertensive rats

The effects of S-nitrosocaptopril (SNOcap), administered either intravenously or by oral gavage, on pulmonary artery pressure (PAP) were examined in anaesthetised normotensive rats and rats with hypoxic pulmonary hypertension (10% oxygen for 1 week). Mean PAP (MPAP) values in hypoxic and normoxic rats were (mmHg) 26 +/- 1.7 and 15 +/- 1.1, respectively. When given intravenously, 1 mg kg(-1) SNOcap reduced MPAP by 28 and 32% in hypoxic and normoxic rats, respectively. The effects of 2 mg kg(-1) were no greater than those of 1 mg kg(-1). Pulmonary vasoclepressor responses reached equilibrium in 1.7 +/- 0.18 min following intravenous administration. When given orally 30 min before the measurement of PAP, 30 mg kg(-1), but not 10 mg kg(-1), significantly reduced MPAP in hypoxic rats to 17 +/- 1.5 mmHg. These in-vivo data are consistent with previous in-vitro data showing that SNOcap has direct pulmonary vasorelaxant properties in both large and small pulmonary arteries and also show that SNOcap causes pulmonary vasodepression in the setting of pulmonary hypertension. Since SNOcap also inhibits pulmonary vascular angiotensin converting enzyme (ACE) in pulmonary blood vessels (previous study), it would be an interesting drug with which to assess the benefits of direct pulmonary vasodilatation combined with ACE inhibition (which attentuates pulmonary vascular remodelling) in a long-term study in pulmonary hypertension.

Effects of mercury on the arterial blood pressure of anesthetized rats

The available data suggests that hypotension caused by Hg2+ administration may be produced by a reduction of cardiac contractility or by cholinergic mechanisms. The hemodynamic effects of an intravenous injection of HgCl2 (5 mg/kg) were studied in anesthetized rats (N = 12) by monitoring left and right ventricular (LV and RV) systolic and diastolic pressures for 120 min. After HgCl2 administration the LV systolic pressure decreased only after 40 min (99 ± 3.3 to 85 ± 8.8 mmHg at 80 min). However, RV systolic pressure increased, initially slowly but faster after 30 min (25 ± 1.8 to 42 ± 1.6 mmHg at 80 min). Both right and left diastolic pressures increased after HgCl2 treatment, suggesting the development of diastolic ventricular dysfunction. Since HgCl2 could be increasing pulmonary vascular resistance, isolated lungs (N = 10) were perfused for 80 min with Krebs solution (continuous flow of 10 ml/min) containing or not 5 µM HgCl2. A continuous increase in pulmonary vascular resistance was observed, suggesting the direct effect of Hg2+ on the pulmonary vessels (12 ± 0.4 to 29 ± 3.2 mmHg at 30 min). To examine the interactions of Hg2+ and changes in cholinergic activity we analyzed the effects of acetylcholine (Ach) on mean arterial blood pressure (ABP) in anesthetized rats (N = 9) before and after Hg2+ treatment (5 mg/kg). Using the same amount and route used to study the hemodynamic effects we also examined the effects of Hg2+ administration on heart and plasma cholinesterase activity (N = 10). The in vivo hypotensive response to Ach (0.035 to 10.5 µg) was reduced after Hg2+ treatment. Cholinesterase activity (µM h-1 mg protein-1) increased in heart and plasma (32 and 65%, respectively) after Hg2+ treatment. In conclusion, the reduction in ABP produced by Hg2+ is not dependent on a putative increase in cholinergic activity. HgCl2 mainly affects cardiac function. The increased pulmonary vascular resistance and cardiac failure due to diastolic dysfunction of both ventricles are factors that might contribute to the reduction of cardiac output and the fall in arterial pressure.

Efeito de dezesseis semanas de treinamento de resistência aeróbia na função vascular de jovens sedentários

Introdução: Muito embora os estudos apontem para um efeito positivo do exercício físico, em especial o treinamento com exercício aeróbio, sobre a pressão arterial e a distensibilidade arterial, pouco se sabe sobre os efeitos do treinamento com exercício de resistência aeróbia sobre a complacência vascular de indivíduos jovens saudáveis. Objetivos: Avaliar o efeito de 16 semanas de treinamento de resistência aeróbia sobre a função vascular e a pressão arterial de indivíduos jovens sedentários. Métodos: Foram avaliados 56 voluntários (de ambos os sexos, na faixa etária de 18 à 29 anos) antes e após 16 semanas de treinamento com corrida 3 vezes por semana. As medidas de pressão arterial foram realizadas de acordo com a VI Diretrizes Brasileiras de Hipertensão e a velocidade de onda de pulso (VOP) foi realizada com a utilização de um gravador automático computadorizado e os resultados foram analisados pelo programa Complior®. Resultados: Dos 56 indivíduos que participaram do presente estudo, 44 eram do sexo masculino (78,5%) e 12 do sexo feminino (21,5 %). Eles apresentaram idade de 22 ± 3 anos, estatura de 1,75 ± 0,07 metros, circunferência de cintura de 79,6 ± 7,8 cm e PAM de 79 ± 6,4 mmHg. O treinamento promoveu redução da FC repouso (69 ± 7,0 vs. 61 ± 7,1; p<0,05) e aumento do VO2pico (43,3 ± 7,3 vs. 50,1 ± 7,2; p<0,05). Entretanto, pressão arterial sistólica (107 ± 9,4 vs. 110 ± 10), pressão arterial diastólica (63 ± 5,7 vs. 62 ± 5,5), pressão de pulso (44 ± 7,0 vs. 48 ± 7,0) e VOP (6,5 ± 1,1 vs. 6,5 ± 1,1) não apresentaram alteração após o treinamento físico (p>0,05). Conclusões: Podemos concluir que 16 semanas de treinamento de resistência aeróbia foram capazes de aumentar a aptidão cardiorrespiratória, porém não provocaram alterações sobre a velocidade de onda de pulso e pressão arterial em voluntários saudáveis e sedentários. Sugere-se que a ausência de adaptações vasculares após o treinamento seja devido às características da amostra – indivíduos jovens e saudáveis.

Caracterização da função vascular periférica pela resposta hemodinâmica da alteração postural passiva do membro inferior

O estudo da função vascular periférica tem beneficiado do desenvolvimento de diversas técnicas e metodologias de avaliação o as quais permitem caracterizar a função com um mínimo de invasibilidade. O estudo do significado de diversas variáveis transcutâneas tem ajudado a melhor compreender as complexas relações que regem a perfusão dos tecidos in vivo. No presente estudo procurámos avaliar o perfil de resposta de um grupo de indivíduos saudáveis jovens de ambos os sexos (n=23, 22,4 ± 2,2 anos), a uma manobra dinâmica (provocação) envolvendo a variação postural passiva do membro inferior (A: elevação da perna e B: decúbito dorsal) de modo a caracterizar a função vascular periférica por meio de variáveis transcutâneas (tc). A perfusão local medida por Fluxometria de Laser Doppler (LDF) , a Perda Trans-epidérmica de água (PTEA) as pressões parciais de oxigénio e dióxido de carbono transcutâneos e a oximetria de pulso foram escolhidas e, um intervalo de confiança de 95% adoptado. LDF, PTEA e tcpO 2 são, manifestamente, as variáveis que melhor permitem seguir o processo em cada fase experimental. Em A foram registadas, durante a provocação, diferenças significativas na perfusão sanguínea e na pressão transcutânea de oxigénio e PTEA, especialmente nas mulheres, enquanto que o perfil de resposta obtido em B foi idêntico em ambos os grupos e comparável B hiperémia reactiva. Qualquer dos protocolos permitiu evidenciar uma relação inversamente recíproca entre a PTEA e o LD. Os resultados obtidos confirmam a utilidade destas metodologias na avaliação da função vascular periférica, confirmando as relações entre PTEA e LDF as quais devem ser adequadamente aprofundadas.

Aurícula direita: mecânica e sobrecarga de volume

Mestrado em Tecnologia de Diagnóstico e Intervenção Cardiovascular - Ramo de especialização: Ultrassonografia Cardiovascular

Pulmonary Hypertension in Portugal: First Data from a Nationwide Registry

Introduction. Pulmonary arterial hypertension (PAH) is a rare disease that must be managed in specialized centers; therefore, the availability of epidemiological national data is critical. Methods. We conducted a prospective, observational, and multicenter registry with a joint collaboration from five centers from Portugal and included adult incident patients with PAH or chronic thromboembolic pulmonary hypertension (CTEPH). Results. Of the 79 patients enrolled in this study, 46 (58.2%) were classified as PAH and 33 patients (41.8%) as CTEPH. PAH patients had a mean age of 43.4 ± 16.4 years. Idiopathic PAH was the most common etiology (37%). At presentation, PAH patients had elevated right atrial pressure (RAP) (7.7 ± 5.9mmHg) and mean pulmonary vascular resistance (11.4 ± 6.5 Wood units), with a low cardiac index (2.7 ± 1.1 L⋅min−1 m−2); no patient was under selective pulmonary vasodilators; however, at follow-up, most patients were on single (50%), double (28%), or triple (9%) combination vasodilator therapy. One-year survival was 93.5%, similar to CTEPH patients (93.9%), that were older (60.0 ± 12.5 years) and had higher RAP (11.0 ± 5.2mmHg,

Pulmonar Vascular Changes in the Plain Chest Film of Cardiac Patients

The correct interpretation of chest film on cardiac patients is very important. The most important feature is the radiographic appearance of the pulmonary vascularity. Four different patterns of pulmonary vascularity are considered: normal, decreased, increased and uneven. The different diseases associated with each type are mentioned. From the pulmonary vascular pattern one can deduct hemodynamic data which are important for the diagnosis, grade of severity and follow-up.

Association Between Hemodynamic Profile, Physical Capacity and Quality of Life in Pulmonary Hypertension

Background: No studies have described and evaluated the association between hemodynamics, physical limitations and quality of life in patients with pulmonary hypertension (PH) without concomitant cardiovascular or respiratory disease. Objective: To describe the hemodynamic profile, quality of life and physical capacity of patients with PH from groups I and IV and to study the association between these outcomes. Methods: Cross-sectional study of patients with PH from clinical groups I and IV and functional classes II and III undergoing the following assessments: hemodynamics, exercise tolerance and quality of life. Results: This study assessed 20 patients with a mean age of 46.8 ± 14.3 years. They had pulmonary capillary wedge pressure of 10.5 ± 3.7 mm Hg, 6-minute walk distance test (6MWDT) of 463 ± 78 m, oxygen consumption at peak exercise of 12.9 ± 4.3 mLO2.kg-1.min-1 and scores of quality of life domains < 60%. There were associations between cardiac index (CI) and ventilatory equivalent for CO2 (r=-0.59, p <0.01), IC and ventilatory equivalent for oxygen (r=-0.49, p<0.05), right atrial pressure (RAP) and 'general health perception' domain (r=-0.61, p<0.01), RAP and 6MWTD (r=-0.49, p<0.05), pulmonary vascular resistance (PVR) and 'physical functioning' domain (r=-0.56, p<0.01), PVR and 6MWTD (r=-0.49, p<0.05) and PVR index and physical capacity (r=-0.51, p<0.01). Conclusion: Patients with PH from groups I and IV and functional classes II and III exhibit a reduction in physical capacity and in the physical and mental components of quality of life. The hemodynamic variables CI, diastolic pulmonary arterial pressure, RAP, PVR and PVR index are associated with exercise tolerance and quality of life domains.

Lowering Pulmonary Wedge Pressure after Heart Transplant: Pulmonary Compliance and Resistance Effect

AbstractBackground:Right ventricular (RV) afterload is an important risk factor for post-heart transplantation (HTx) mortality, and it results from the interaction between pulmonary vascular resistance (PVR) and pulmonary compliance (CPA). Their product, the RC time, is believed to be constant. An exception is observed in pulmonary hypertension because of elevated left ventricular (LV) filling pressures.Objective:Using HTx as a model for chronic lowering of LV filling pressures, our aim was to assess the variations in RV afterload components after transplantation.Methods:We retrospectively studied 159 patients with right heart catheterization before and after HTx. The effect of Htx on hemodynamic variables was assessed.Results:Most of the patients were male (76%), and the mean age was 53 ± 12 years. HTx had a significant effect on the hemodynamics, with normalization of the LV and RV filling pressures and a significant increase in cardiac output and heart rate (HR). The PVR decreased by 56% and CPA increased by 86%. The RC time did not change significantly, instead of increasing secondary to pulmonary wedge pressure (PWP) normalization after HTx as expected. The expected increase in RC time with PWP lowering was offset by the increase in HR (because of autonomic denervation of the heart). This effect was independent from the decrease of PWP.Conclusion:The RC time remained unchanged after HTx, notwithstanding the fact that pulmonary capillary wedge pressure significantly decreased. An increased HR may have an important effect on RC time and RV afterload. Studying these interactions may be of value to the assessment of HTx candidates and explaining early RV failure after HTx.

Palliative Senning in the Treatment of Congenital Heart Disease with Severe Pulmonary Hypertension

Background:Transposition of the great arteries (TGA) is the most common cyanotic cardiopathy, with an incidence ranging between 0.2 and 0.4 per 1000 live births. Many patients not treated in the first few months of life may progress with severe pulmonary vascular disease. Treatment of these patients may include palliative surgery to redirect the flow at the atrial level.Objective:Report our institutional experience with the palliative Senning procedure in children diagnosed with TGA and double outlet right ventricle with severe pulmonary vascular disease, and to evaluate the early and late clinical progression of the palliative Senning procedure.Methods:Retrospective study based on the evaluation of medical records in the period of 1991 to 2014. Only patients without an indication for definitive surgical treatment of the cardiopathy due to elevated pulmonary pressure were included.Results:After one year of follow-up there was a mean increase in arterial oxygen saturation from 62.1% to 92.5% and a mean decrease in hematocrit from 49.4% to 36.3%. Lung histological analysis was feasible in 16 patients. In 8 patients, pulmonary biopsy grades 3 and 4 were evidenced.Conclusion:The palliative Senning procedure improved arterial oxygen saturation, reduced polycythemia, and provided a better quality of life for patients with TGA with ventricular septal defect, severe pulmonary hypertension, and poor prognosis.

Treating pulmonary hypertension in pediatrics.

INTRODUCTION: Pulmonary hypertension is a hemodynamic condition occurring rarely in pediatrics. Nevertheless, it is associated with significant morbidity and mortality. When characterized by progressive pulmonary vascular structural changes, the disease is called pulmonary arterial hypertension (PAH). It results in increased pulmonary vascular resistance and eventual right ventricular failure. In the vast majority of cases, pediatric PAH is idiopathic or associated with congenital heart disease, and, contrary to adult PAH, is rarely associated with connective tissue, portal hypertension, HIV infection or thromboembolic disease. AREAS COVERED: This article reviews the current drug therapies available for the management of pediatric PAH. These treatments target the recognized pathophysiological pathways of PAH with endothelin-1 receptor antagonists, prostacyclin analogs and PDE type 5 inhibitors. New treatments and explored pathways are briefly discussed. EXPERT OPINION: Although there is still no cure for PAH, quality of life and survival have been improved significantly with specific drug therapies. Nevertheless, management of pediatric PAH remains challenging, and depends mainly on results from adult clinical trials and pediatric experts. Further research on PAH-specific treatments in the pediatric population and data from international registries are needed to identify optimal therapeutic strategies and treatment goals in the pediatric population.

Discrepancy between antihypertensive effect and angiotensin converting enzyme inhibition by captopril

Captopril, an inhibitor of angiotensin converting enzyme, was administered twice daily to 13 hypertensive patients for a mean period of 9 weeks. Continuous blood pressure control in the ambulatory patients was established with a portable blood pressure recorder. Notwithstanding, in eight patients with normal renal function, plasma converting enzyme was found to resume normal activity before administration of the morning dose of captopril. Only in 5 patients with impaired renal function did some blockade of plasma converting enzyme persist for more than 12 hours. Measured plasma converting enzyme activity seemed to reflect total conversion of angiotensin I, including conversion in the pulmonary vascular bed, since changes in its activity were closely paralled by changes in plasma aldosterone levels. Bradykinin accumulation seems unlikely when converting enzyme and thus, presumably, kininase II has resumed normal activity. Captopril administration does not seem to alter plasma epinephrine or norepinephrine levels. Blood pressure reduction in the face of normal angiotensin converting enzyme activity is probably due to hyporesponsiveness of the arterioles to pressor hormones, which may be due to specific renin-related and/or nonspecific effects of captopril.

Transfer factor for carbon monoxide: a glance behind the scene.

The transfer factor for carbon monoxide (TLCO) is widely used in pulmonary function laboratories because it represents a unique non-invasive window on pulmonary microcirculation. The TLCO is the product of two primary measurements, the alveolar volume (VA) and the CO transfer coefficient (KCO). This test is most informative when VA and KCO are examined, together with their product TLCO. In a normal lung, a low VA due to incomplete expansion is associated with an elevated KCO, resulting in a mildly reduced TLCO. Thus, in case of low VA, a seemingly "normal KCO" must be interpreted as an abnormal gas transfer. The most common clinical conditions associated with an abnormal TLCO are characterised by a limited number of patterns for VA and KCO: incomplete lung expansion, discrete loss of alveolar units, diffuse loss of alveolar units, emphysema, pulmonary vascular disorders, high pulmonary blood volume, alveolar haemorrhage.

Mechanisms for suppressing NADPH oxidase in the vascular wall

Oxidative stress underlies many forms of vascular disease as well as tissue injury following ischemia and reperfusion. The major source of oxidative stress in the artery wall is an NADPH oxidase. This enzyme complex as expressed in vascular cells differs from that in phagocytic leucocytes both in biochemical structure and functions. The crucial flavin-containing catalytic subunits, Nox1 and Nox4, are not found in leucocytes, but are highly expressed in vascular cells and upregulated with vascular remodeling, such as that found in hypertension and atherosclerosis. The difference in catalytic subunits offers the opportunity to develop "vascular specific" NADPH oxidase inhibitors that do not compromise the essential physiological signaling and phagocytic functions carried out by reactive oxygen and nitrogen species. Nitric oxide and targeted inhibitors of NADPH oxidase that block the source of oxidative stress in the vasculature are more likely to prevent the deterioration of vascular function that leads to stroke and heart attack, than are conventional antioxidants. The roles of Nox isoforms in other inflammatory conditions are yet to be explored.

Perinatal Hypoxia Enhances Cyclic Adenosine Monophosphate-mediated BKCa Channel Activation in Adult Murine Pulmonary Artery.

Exposure to perinatal hypoxia results in alteration of the adult pulmonary circulation, which is linked among others to alterations in K channels in pulmonary artery (PA) smooth muscle cells. In particular, large conductance Ca-activated K (BKCa) channels protein expression and activity were increased in adult PA from mice born in hypoxia compared with controls. We evaluated long-term effects of perinatal hypoxia on the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway-mediated activation of BKCa channels, using isoproterenol, forskolin, and dibutyryl-cAMP. Whole-cell outward current was higher in pulmonary artery smooth muscle cells from mice born in hypoxia compared with controls. Spontaneous transient outward currents, representative of BKCa activity, were present in a greater proportion in pulmonary artery smooth muscle cells of mice born in hypoxia than in controls. Agonists induced a greater relaxation in PA of mice born in hypoxia compared with controls, and BKCa channels contributed more to the cAMP/PKA-mediated relaxation in case of perinatal hypoxia. In summary, perinatal hypoxia enhanced cAMP-mediated BKCa channels activation in adult murine PA, suggesting that this pathway could be a potential target for modulating adult pulmonary vascular tone after perinatal hypoxia.