Dysregulation of the Nitric Oxide/Dimethylarginine Pathway in Hypoxic Pulmonary Vasoconstriction-Molecular Mechanisms and Clinical Significance.

The pulmonary circulation responds to hypoxia with vasoconstriction, a mechanism that helps to adapt to short-lived hypoxic episodes. When sustained, hypoxic pulmonary vasoconstriction (HPV) may become deleterious, causing right ventricular hypertrophy and failure, and contributing to morbidity and mortality in the late stages of several chronic pulmonary diseases. Nitric oxide (NO) is an important endothelial vasodilator. Its release is regulated, amongst other mechanisms, by the presence of endogenous inhibitors like asymmetric dimethylarginine (ADMA). Evidence has accumulated in recent years that elevated ADMA may be implicated in the pathogenesis of HPV and in its clinical sequelae, like pulmonary arterial hypertension (PAH). PAH is one phenotypic trait in experimental models with disrupted ADMA metabolism. In high altitude, elevation of ADMA occurs during long-term exposure to chronic or chronic intermittent hypobaric hypoxia; ADMA is significantly associated with high altitude pulmonary hypertension. High ADMA concentration was also reported in patients with chronic obstructive lung disease, obstructive sleep apnoea syndrome, and overlap syndrome, suggesting a pathophysiological role for ADMA-mediated impairment of endothelium-dependent, NO-mediated pulmonary vasodilation in these clinically relevant conditions. Improved understanding of the molecular (dys-)regulation of pathways controlling ADMA concentration may help to dissect the pathophysiology and find novel therapeutic options for these diseases.

Glomerular Endothelial Cell Crosstalk With Podocytes in Diabetic Kidney Disease.

Diabetes is the main cause of renal failure worldwide. Complications of the kidney micro-and macro-circulation are common in diabetic patients, leading to proteinuria and can progress to end-stage renal disease. Across the complex interplays aggravating diabetes kidney disease progression, lesions of the glomerular filtration barrier appear crucial. Among its components, glomerular endothelial cells are known to be central safeguards of plasma filtration. An array of evidence has recently pinpointed its intricate relations with podocytes, highly specialized pericytes surrounding glomerular capillaries. During diabetic nephropathy, endothelial cells and podocytes are stressed and damaged. Besides, each can communicate with the other, directly affecting the progression of glomerular injury. Here, we review recent studies showing how in vitro and in vivo studies help to understand pathological endothelial cells-podocytes crosstalk in diabetic kidney disease.

Renin-Angiotensin System Blockade Associated with Statin Improves Endothelial Function in Diabetics / Bloqueio do Sistema Renina-Angiotensina Associado a Estatina Melhora a Função Endotelial em Diabéticos

Abstract Background: Studies suggest that statins have pleiotropic effects, such as reduction in blood pressure, and improvement in endothelial function and vascular stiffness. Objective: To analyze if prior statin use influences the effect of renin-angiotensin-aldosterone system inhibitors on blood pressure, endothelial function, and vascular stiffness. Methods: Patients with diabetes and hypertension with office systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 80 mmHg had their antihypertensive medications replaced by amlodipine during 6 weeks. They were then randomized to either benazepril or losartan for 12 additional weeks while continuing on amlodipine. Blood pressure (assessed with ambulatory blood pressure monitoring), endothelial function (brachial artery flow-mediated dilation), and vascular stiffness (pulse wave velocity) were evaluated before and after the combined treatment. In this study, a post hoc analysis was performed to compare patients who were or were not on statins (SU and NSU groups, respectively). Results: The SU group presented a greater reduction in the 24-hour systolic blood pressure (from 134 to 122 mmHg, p = 0.007), and in the brachial artery flow-mediated dilation (from 6.5 to 10.9%, p = 0.003) when compared with the NSU group (from 137 to 128 mmHg, p = 0.362, and from 7.5 to 8.3%, p = 0.820). There was no statistically significant difference in pulse wave velocity (SU group: from 9.95 to 9.90 m/s, p = 0.650; NSU group: from 10.65 to 11.05 m/s, p = 0.586). Conclusion: Combined use of statins, amlodipine, and renin-angiotensin-aldosterone system inhibitors improves the antihypertensive response and endothelial function in patients with hypertension and diabetes.

Resumo Fundamentos: Estudos sugerem que as estatinas possuem efeitos pleotrópicos, como melhora da função endotelial, da rigidez vascular e redução da pressão arterial. Objetivo: Analisar se o uso prévio de estatina influenciou o efeito sobre a pressão arterial, a função endotelial e a rigidez vascular de drogas inibidoras do sistema renina-angiotensina-aldosterona. Métodos: Pacientes hipertensos e diabéticos com pressão arterial de consultório sistólica ≥ 130 mmHg e/ou diastólica ≥ 80 mmHg tiveram suas medicações anti-hipertensivas substituídas por anlodipino durante 6 semanas. Em seguida, foram randomizados para associação de benazepril ou losartana por mais 12 semanas. Pressão arterial (através da monitorização ambulatorial da pressão arterial), função endotelial (dilatação mediada por fluxo da artéria braquial) e rigidez vascular (velocidade da onda de pulso) foram avaliados antes e após o tratamento combinado. Neste trabalho, uma análise post-hoc foi realizada para comparar pacientes que vinham (grupo CE) ou não (grupo SE) em uso de estatina. Resultados: O grupo CE apresentou maior redução na pressão arterial sistólica nas 24 horas (134 para 122 mmHg, p = 0,007) e na dilatação mediada por fluxo da artéria braquial (6,5 para 10,9%, p = 0,003) quando comparado com o grupo SE (137 para 128 mmHg, p = 0,362, e 7,5 para 8,3%, p = 0,820). Não houve diferença estatisticamente significante na velocidade de onda de pulso (grupo CE 9,95 para 9,90 m/s, p = 0,650 e grupo SE 10,65 para 11,05 m/s, p = 0,586). Conclusão: O uso combinado de estatinas, anlodipino e inibidores do sistema renina-angiotensina-aldosterona melhora a resposta anti-hipertensiva e a função endotelial em pacientes hipertensos e diabéticos.

Función endotelial y estados hipertensivos del embarazo: Velocidad de la onda del pulso carótido-radial como método alternativo para detectar disfunción endotelial en embarazadas

Resumen La preeclampsia constituye una causa mayor de morbimortalidad materno-fetal que cursa con una disfunción endotelial (DFE) generalizada. Detectar la DFE subclínica durante el embarazo contribuiría en su identificación precoz y anticiparía su tratamiento. Se ha propuesto utilizar los cambios en la velocidad de la onda del pulso carótido-radial (VOPcr) para evaluar la DFE en pacientes con enfermedad arterial. Sin embargo, se desconocen los alcances de dicha técnica en la evaluación de la DFE durante el embarazo. Objetivo: evaluar y comparar los cambios de la VOPcr en embarazadas y mujeres no embarazadas. Material y método: participaron embarazadas sanas (ES; n = 13), preeclámpticas (PE; n = 7), hipertensas sin proteinuria (HNP; n = 6) y mujeres no embarazadas (NE; n = 32). Se cuantificó la VOPcr (mecanotransductores), el diámetro arterial braquial (ultrasonido) y la velocidad sanguínea braquial (Doppler) antes (basal) y después de realizar un estímulo isquémico (esfigmomanometría). Resultados: la VOPcr disminuyó en ES (6,9 ± 1,5 a 6,0 ± 0,9 m/s, p < 0,001) y en NE (8,1 ± 0,9 a 7,4 ± 0,9 m/s; p < 0,001); no se obtuvieron cambios en HNP (6,6 ± 1,4 a 6,7 ± 1,0 m/s; p = 0,91) y en PE se observó una tendencia al aumento (6,0 ± 0,7 a 6,4 ± 0,8 m/s; p = 0,10). El DVOPcr% (porcentaje de cambio de la VOPCr basal versus postisquemia) fue distinto comparando ES con HNP (-11,9% versus +2,2%; p < 0,01), con NE (-11,9% versus -8,5%; p < 0,05) y con PE (-11,9 versus +6,2%; p < 0,01), respectivamente, sin encontrar diferencias entre HNP y PE (p = 1,00). Conclusión: las ES mostraron una reactividad vascular aumentada respecto a NE y HNP/PE evaluada por DVOPcr%, evidenciando en HNP/PE una respuesta vascular alterada. La VOPcr podría desempeñar un importante rol en el estudio de la DFE durante el embarazo, con una potencial aplicación clínica en la predicción de la preeclampsia.

Circulação periférica em pacientes com insuficiência aórtica crônica e indicação de troca valvar / Peripheral circulation in patients with chronic aortic insufficiency and valve replacement indication

Introdução: O recente aperfeiçoamento da ultra-sonografia permitiu a análise estrutural e funcional do vaso. Casuística e Métodos: 36 pacientes com insuficiência aórtica e indicação de troca valvar, divididos em grupos com pressão arterial diastólica (PAD) superior e inferior a 50mmHg, avaliados antes e seis meses após a cirurgia. A função arterial compreendeu a complacência, distensibilidade e a função endotelial pela dilatação fluxo-mediada e nitrato-mediada. Conclusão: A complacência e a distensibilidade foram maiores no grupo com menor PAD e diminuíram após a cirurgia. A disfunção endotelial foi presente em insuficiência aórtica crônica independente do nível da pressão arterial diastólica.

Introduction: The recent improvement of ultrasonography made possible a functional and structural analysis of the vessel. Methods: 36 patients with aortic insufficiency and valve replacement need, divided in 2 groups with diastolic blood pressure (DBP) above and below 50mmHg. Checked twice: before and 6 months after surgery. The arterial function comprised compliance, distensibility and endothelial function through flow-mediated dilatation and nitrate-mediated dilatation. Conclusion: The compliance and distensibility were higher in the group with lower DBP and decreased after surgery. Endothelial dysfunction was present in chronic aortic insufficiency no matter the level of DBP.