Esclerose sistêmica e o fenômeno de Raynaud: manejo terapêutico / Systemic sclerosis and Raynaud's phenomenon: therapeutic management

O fenômeno de Raynaud (FRy) caracteriza-se por episódios reversíveis de vasoespasmos de extremidades, que ocorrem usualmente após estresse ou exposição ao frio. O FRy pode ser primário ou secundário a uma série de condições, principalmente a doenças do espectro da esclerose sistêmica (ES). Na ES, o FRy costuma ser mais grave, e lesões isquêmicas de extremidades são frequentes. Nos últimos anos, avanços no estudo da fisiopatologia do FRy e da doença vascular na ES propiciaram o surgimento de novas opções terapêuticas para esta manifestação. Os bloqueadores de canal de cálcio devem ser utilizados como tratamento de primeira escolha para o FRy. Novas drogas, como os inibidores da fosfodiesterase V e os prostanoides, podem ser utilizados em pacientes com FRy grave, e a bosentana (antagonista do receptor da endotelina-1) é indicada para a prevenção de úlceras digitais recorrentes.

Raynaud's phenomenon (RP) is characterized by episodic vasospasm of the extremities, usually in response to stress or cold exposure. It can be primary or secondary to several conditions, especially systemic sclerosis-related diseases. In systemic sclerosis (SSc), RP is usually more severe and digital ischemic lesions are a frequent problem. In recent years, advances in the understanding of the pathophysiology of RP and of SSc vasculopathy led to the development of new therapeutic options for this condition. Calcium-channel blockers are the first choice for the treatment of RP. New drugs including phosphodiesterase type V inhibitors and prostanoids can be used for severe RP, and bosentan (endothelin-1 receptor antagonist) for prevention of recurrent digital ulcers.

Update on diagnosis and treatment of resistant hypertension

Resistant hypertension is an increasingly common medical problem, and patients with this condition are at a high risk of cardiovascular events. The prevalence of resistant hypertension is unknown, but data from clinical trials suggest that 20% to 30% of hypertensive individuals may be resistant to antihypertensive treatment. The evaluation of these patients is focused on identifying true resistant hypertension and contributing and secondary causes of hypertension, including hyperaldosteronism, obstructive sleep apnea, chronic kidney disease, renal artery stenosis, and pheochromocytoma. Treatment includes removal of contributing factors, appropriate management of secondary causes, and use of effective multidrug regimens. More established approaches, such as low dietary salt and mineralocorticoid receptor blockers, and new technologies, such as carotid stimulation and renal denervation, have been used in the management of patients with resistant hypertension

Pulmonary arterial hypertension in children: a medical update.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980's, prior to the current treatment era, idiopathic pulmonary arterial hypertension (IPAH) carried a poor prognosis with a 10 month median survival for children after diagnosis. However, in 1995 continuous intravenous epoprostenol was approved for the treatment of severe PAH, improving hemodynamics, quality of life, exercise capacity, functional class and survival. In the past decade there have been further advances in the treatment of PAH; however, there is still no cure. While much of the groundbreaking clinical research has been performed in adults, children have also seen the benefits of PAH novel therapies. The target population among pediatric patients is expanding with the recent recognition of pulmonary hypertension as a risk factor for sickle cell disease patients. With rapid advances, navigating the literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations provides insights into the management of pediatric PAH patients.

Arterial atherosclerosis in patients with chronic kidney disease and its relationship with serum and tissue

We investigated the correlation between atherosclerosis and tissue and serum levels of endothelin-1 in patients with chronic kidney disease [CKD]. Arterial samples were obtained from 35 patients with CKD during arteriovenous fistula placement. Thirty-one patients with cardiovascular disease who underwent coronary artery bypass graft [CABG] were selected as the atherosclerotic group, and a piece of their aorta punched during CABG was obtained. Also, a small piece of the renal artery was dissected during donation in 24 kidney donors [control group]. Tissue endothelin-1 level was measured and atherosclerosis grading was determined by pathologic examination. Serum levels of endothelin-1 were also measured in the three groups. The mean tissue endothelin-1 levels were 10.73 +/- 7.57 pg/ mL, 12.16 +/- 3.95 pg/mL, and 0.93 +/- 1.06 pg/mL in the patients with CKD, those with CABG, and donors, respectively [P < .001]. The mean serum endothelin-1 level was 25.23 +/- 15.15 pg/mL in the patients with CKD, 21.13 +/- 17.22 pg/mL in the patients with CABG, and 2.66 +/- 1.51 pg/mL in the donors [P < .001]. Atherosclerosis grades correlated with tissue endothelin-1 level [r = 0.823, P < .001] and serum endothelin-1 level [r = 0.608, P < .001] in the patients with CKD. Multiple regression analysis showed tissue endothelin-1 level as the main predicting factor of atherosclerosis [P < .001]. Tissue endothelin-1 concentration is more important than serum endothelin-1 or lipids levels in prediction of atherosclerosis. Thus, blockade of tissue endothelin-1 receptors with its antagonists may prevent atherosclerosis progression

Myocardial Protective Effect of Tezosentan, an Endothelin Receptor Antagonist, for Ischemia-Reperfusion Injury in Experimental Heart Failure Models

The myocardial protective effects of endothelin antagonist in ischemic cardiomyopathy (ICMP), doxorubicin-induced cardiomyopathy (DOX) and pressure-overload hypertrophy by transverse aortic constriction (TAC) models have been predicted to be different. The objective of this experiment, therefore, is to evaluate the myocardial protective effect of tezosentan, an endothelin receptor antagonist, in various experimental heart failure models. Sprague-Dawley rats (6-8 weeks old, 200-300 g) were randomized to three experimental groups (n=30 each): ICMP; DOX; and TAC group. Each of these groups was randomly assigned further to the following subgroups (n=10 each): sham-operated ischemia-reperfusion subgroup (SHAM); tezosentan treated ischemia-reperfusion subgroup (Tezo); and tezosentan non-treated ischemia-reperfusion subgroup (N-Tezo). Total circulatory arrest was induced for 1 hr, followed by 2 hr of reperfusion. The left ventricular developed pressure, peak positive and negative first derivatives, and coronary blood flow were significantly different (P<0.05) among the SHAM, Tezo, and N-Tezo subgroups of the ICMP group at 30 min of reperfusion, but there were no statistically significant differences among the subgroups of the DOX and TAC groups. In conclusion, tezosentan, an endothelin receptor antagonist, showed myocardial protection effects only on the ischemic cardiomyopathy rat model, but not in the non-ischemic heart failure rat models.

Doença veno-oclusiva pulmonar: alternativas diagnósticas e terapêuticas / Pulmonary veno-occlusive disease: diagnostic and therapeutic alternatives

A doença veno-oclusiva pulmonar (DVOP) é uma causa rara de hipertensão pulmonar. A biópsia cirúrgica era usualmente necessária para seu diagnóstico; entretanto, sua morbidade, mortalidade e seu impacto limitado levantou a discussão sobre o diagnóstico não-invasivo. Apresentamos um caso de uma paciente com dispnéia progressiva, hipoxemia e hipertensão pulmonar no cateterismo. A tomografia computadorizada revelou espessamento septal e micronódulos difusos. O lavado broncoalveolar revelou hemorragia alveolar oculta. Iniciou-se tratamento com antagonista da endotelina, que resultou em melhora clínica e funcional. A hemorragia alveolar oculta é uma característica da DVOP capaz de diferenciá-la da hipertensão pulmonar idiopática. Acreditamos que sua presença, associada à tomografia característica, seja suficiente para o diagnóstico de DVOP.

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. Surgical biopsy was usually required for diagnostic confirmation. However, the morbidity, mortality and limited benefit of this procedure have generated discussion regarding noninvasive diagnostic techniques. We present the case of a female patient with progressive dyspnea, hypoxemia and pulmonary hypertension, the last diagnosed via catheterization. Computed tomography revealed septal thickening and diffuse micronodules. Bronchoalveolar lavage revealed occult alveolar hemorrhage. Treatment with an endothelin antagonist was started, resulting in symptomatic and functional improvement. Occult alveolar hemorrhage differentiates PVOD from idiopathic pulmonary hypertension. We believe that this finding, in combination with characteristic tomographic findings, is sufficient to establish a diagnosis of PVOD.

[Treatment of hormone-resistant prostate cancer]

Two recent randomized Phase-three studies [TAX 327 and SWOG 9916] have demonstrated that Docetaxel improved the survival rate of patients with hormone-resistant prostate cancer. Other drugs such as Mitoxantrone, vinorelbine, saraplatin and Epothilone are recommended as second-line treatment where Docetaxel treatment has failed. Treatment with Atrasentan, an endothelin-receptor antagonist, or other inhibitors of angiogenesis combined with Docetaxel is presently under evaluation. Zoledronic acid, alone or in association with chemotherapy, and the use of radioisotopes [strontium-89, samarium 153 and radium 223] are palliative treatment options for multiple painful bone metastases in hormone-resistant cancer. Collectively, these treatment options reduce the risk of mortality, prevent the complications associated with disease progression and improve the patients' quality of life. Better understanding of the alternative pathways for androgen receptor signaling, the role of estrogen receptors, cytokines and stromal growth factors contributing to hormone resistance may lead to new treatment strategies

Endothelin-1 receptors play a minor role in the protection against acute Trypanosoma cruzi infection in mice

Chagas' disease, caused by the protozoan Trypanosoma cruzi, is a major cause of cardiovascular disability in countries where it is endemic. Damage to the heart microvasculature has been proposed to be an important factor in the pathogenesis of heart dysfunction. Endothelin-1 (ET-1) is a potent vasoconstrictor and exerts its effects via specific ET A and ET B receptors. A few studies have suggested a role for ET-1 and its receptors in the pathogenesis of Chagas' disease. We investigated the effects of treatment with bosentan, an ET A/ET B receptor antagonist, on the course of T. cruzi infection (Y strain) in C57Bl/6 mice. Treatment with bosentan (100 mg kg-1 day-1) was given per os starting day 0 after infection until sacrifice. Bosentan significantly increased myocardial inflammation, with no effects on parasitemia. Although the total number of nests was similar, a lower number of intact amastigote nests was found in the heart of bosentan-treated animals. Bosentan failed to affect the infection-associated increase in the cardiac levels of the cytokines IFN-g and TNF-a and the chemokines CCL2/MCP-1, CCL3/MIP-1a and CCL5/RANTES. In vitro, pre-incubation with ET-1 (0.1 æM) 4 h before infection enhanced the uptake of the parasites by peritoneal macrophages, and this effect was abrogated when macrophages were pre-treated with bosentan (1 æM) 15 min before incubation with ET-1. However, ET-1 did not alter killing of intracellular parasites after 48 h of in vitro infection. Our data suggest that bosentan-treated mice have a delay in controlling parasitism which is compensated for exacerbated inflammation. Infection is eventually controlled in these animals and lethality is unchanged, demonstrating that ET-1 plays a minor role in the protection against acute murine T. cruzi infection.

Acciones de endotelina 1 y angiotensina II en embarazos complicados con preeclampsia / Endothelin 1 and angiotensin II in preeeclampsia

Introduction. It is generally thought that development of hypertension in preeclampsia (PE) is due to generalized endothelial dysfunction and/or results from an imbalance in the production and/or action of vasoactive factors, resulting in higher citosolic Ca2+ concentration which in turn leads to vasoconstriction and decreased blood pressure perfusion in organs, including the fetoplacental unit. Among vasoactive factors involved in blood pressure regulation, endothelin 1 (ET-1) and angiotensin II (Ang II) regulate citosolic Ca2+ concentrations and therefore are considered in this review. PE is associated with higher circulating and placental ET-1 levels, observation that explains, at least in part, vasoconstriction and oxidative stress. Higher and lower Ang II sensitivity seen in PE and normal pregnancy, respectively, could not be explained by changes in renin-angiotensin system components, including Ang II receptors (ATI). During normal pregnancy, ATI receptors are found as monomers and are inactivated by reactive oxygen species (ROS) leading to lower Ang II sensitivity. In contrast, PE is associated with increased ATl/bradicinin receptors (B2) heterodimers which are resistant to inactivation by ROS, maintaining increased ATI-receptor stimulated signaling in PE. In adittion, AT-1 agonistic antibodies (AT1-AA) obtained from PE women increases intracellular Ca2+, NADPH oxidase components and ROS, effects not observed with normal pregnancy AT1-AA. Conclusion. High ET-1 levels, the presence of AT1/B2 receptor heterodimers and increased AT1-AA are involved, at least in part, in the hypertensive and oxidative stress states in PE.

Introducción. Se reconoce que el desarrollo de la hipertensión en la preeclampsia (PE) resulta del daño endotelial generalizado y/o de la falta de equilibrio en la producción y/o acción de agentes vasoactivos, lo que conlleva al incremento en la concentración citosólica de Ca2+ que resulta en vasoconstricción y disminución de la perfusión sanguínea en los órganos, incluyendo la unidad fetoplacentaria. Dentro de los factores vaso-activos que regulan la presión arterial, en la presente revisión se consideró a la endotelina 1 (ET-1) y a la angiotensina II (Ang II), factores que regulan la concentración citosólica de Ca2+. En comparación con el embarazo normal, la PE se asocia con mayor concentración en suero y placenta de ET-1, lo que explica en parte la vasoconstricción y el estado de estrés oxidativo. La respuesta exagerada en la PE y el estado de refractariedad en el embarazo normal a la Ang II no pueden explicarse por componentes del sistema renina-angiotensina, incluyendo a los receptores de Ang II (ATI). Durante el embarazo normal los receptores AT-1 se encuentran en forma de monómeros y son inactivados por las especies reactivas de oxígeno (ROS), lo que se asocia con menor respuesta a Ang II. En cambio, la respuesta exagerada a la Ang II durante la PE puede deberse a la heterodimerizacion de los receptores ATI con los de bradicinina (B2), estado que les confiere resistencia a la inactivación por las especies reactivas de oxígeno (ROS), lo que explica el incremento en la concentración del Ca2+ intracelular. Además, los anticuerpos agonistas del receptor ATI (AT1-AA) de mujeres PE aumenta la concentración de Ca2+ intracelular, de la NADPH oxidasa y de ROS, efectos que no se presentan al utilizar AT1-AA de embarazadas normotensas. Conclusión. Las altas concentraciones de ET-1, la presencia de receptores ATI en forma de heterodimeros ATI/ B2 y el aumento en los AT1-AA explican en parte, el estado de hipertensión y de estrés oxidativo de la PE.

Effect of bosentan on the production of proinflammatory cytokines in a rat model of emphysema

Endothelin (ET) receptor antagonists have been developed to produce a reduction of ET related effects in various diseases, as well as in animal models of airway inflammation. We aimed to investigate the anti-inflammatory potential of bosentan on a rat model of emphysema. Thirty Wistar male rats were classified as control group (group 1), intratracheally (i.t.) instilled with saline, treated with vehicle solution; elastase group (group 2), i.t. instilled with porcine pancreatic elastase (PPE), treated with vehicle solution; and PPE+bosentan group (group 3), i.t. instilled with PPE, treated with bosentan. The levels of TNF-alpha, IL-1beta, IL-6, and IL-8 in bronchoalveolar lavage fluid (BALF) and lung tissue, cell counts in BALF, and histologic analysis of all groups were evaluated. Neutrophile granulocytes (NG) and alveolar macrophages (AM) were increased more in group 2 than in group 1 (P<0.001, P=0.04, respectively). Compared with group 2, neutrophil granulocyte (NG) and alveolar macrophages (AM) counts were decreased in group 3 (P< 0.001). Histological examination confirmed a diffuse neutrophilic inflammation and irregular alveolar air space enlargement in group 2. Treatment with bosentan partially reduced the enlarged lung volumes. Compared with group 1, the BALF levels of TNF-alpha and IL-6, and the lung tissue levels of IL-1beta, IL-6, and IL-8 were increased in group 2 (P=0.028, P=0.005, P=0.001, P=0.019, P<0.001, respectively). The TNF-alpha and IL-8 levels of BALF (P=0.007, P=0.001, respectively), and the TNF-alpha, IL-1beta, IL-6, and the IL-8 levels of lung tissue (P=0.031, P=0.017, P=0.007, P<0.001) were decreased in group 3 compared to group 2. In conclusion, bosentan decreased the inflammatory response by reducing numbers of inflammatory cells and proinflammatory cytokines.

Treatment of pulmonary arterial hypertension

OBJETIVO: Estabelecer uma revisão acerca do manejo diagnóstico e terapêutico da hipertensão pulmonar na população pediátrica, com ênfase nos aspectos farmacológicos. FONTES DOS DADOS: Busca eletrônica de publicações nas bases de dados MEDLINE/PubMed, LILACS e Cochrane Collaboration. Estabeleceu-se uma estratégia de busca priorizando a identificação de ensaios clínicos (controlados ou não controlados), revisões sistemáticas e diretrizes publicados nos últimos 10 anos. SíNTESE DOS DADOS: Muitos avanços têm sido incorporados ao conhecimento da hipertensão pulmonar nos últimos anos. Aspectos relativos a diferenças nos mecanismos fisiopatológicos da doença entre as diferentes faixas etárias têm modificado o tratamento e o prognóstico dos pacientes. Uma ação combinada de propriedades vasodilatadoras mais seletivas e ação antiproliferativa e o emprego de novas drogas representam princípios fundamentais das novas propostas terapêuticas. Para considerar benefícios associados à utilização dessas novas terapêuticas, é fundamental que cada paciente tenha a sua doença adequadamente diagnosticada, classificado o grau de comprometimento da doença e a sua capacidade de reatividade vascular estabelecida, o que é mais difícil na população pediátrica. CONCLUSÃO: Até o momento, não existe um tratamento que possa ser considerado ideal para o manejo da hipertensão pulmonar. Considerando a possibilidade do emprego de novas drogas, a maioria dos estudos existentes foi conduzida em populações adultas. Poucos dados são disponíveis para crianças, sendo a maioria ensaios clínicos não controlados e séries de casos. Considerando diferenças já estabelecidas entre os mecanismos da doença e aspectos prognósticos entre as diferentes faixas etárias, é difícil afirmar que tais drogas possam ser incorporadas, com as mesmas indicações e os mesmos resultados, ao tratamento da hipertensão pulmonar infantil.

OBJECTIVE: To perform a review of the diagnostic and therapeutic management of pulmonary hypertension in the pediatric population, with emphasis on pharmacological factors. SOURCES: Electronic search of publications on the MEDLINE/PubMed, LILACS and Cochrane Collaboration databases. The search strategy adopted gave priority to the identification of clinical trials (controlled or uncontrolled), systematic reviews and directives published during the last 10 years. SUMMARY OF THE FINDINGS: Many advances have been incorporated into our understanding of pulmonary hypertension during recent years. Issues related to differences in the pathophysiological mechanism of the disease between different age groups have altered both the treatment and prognosis of patients. The combined effect of more selective vasodilatory properties and antiproliferative action and the employment of new drugs are the basic principles of new treatment proposals. In order to be able to gauge the benefits associated with the use of these new therapies, it is of fundamental importance that all patients have their disease correctly diagnosed, the degree of functional compromise classified and their vascular reactivity capacity established, which is more difficult with pediatric patients. CONCLUSIONS: To date there is no treatment that can be considered ideal for the management of pulmonary hypertension. With reference to the possibility of employing new drugs, the majority of studies that have been published were undertaken with adult populations. Few data are available on children, and the majority of studies are uncontrolled trials or case series. Taking into account differences that have already been established between different age groups in terms of disease mechanisms and prognostic aspects, it is difficult to claim that these drugs can be incorporated into the treatment of childhood pulmonary hypertension with the same indications and results.

The effect of nitric oxide/endothelins system on the hepatic ischemia/reperfusion injury / 华中科技大学学报（医学）（英德文版）

The relationship between the hepatic ischemia/reperfusion (I/R) injury and the balance of nitric oxide/endothelins (NO/ET) was studied. The changes of the ratio of NO/ET and the hepatic injury were observed in a rat hepatic I/R model pretreated with several tool drugs. In the acute phase of hepatic I/R injury, the ratio of plasma NO/ET was reduced from 1.58 +/- 0.20 to 0.29 +/- 0.05 (P < 0.01) and the hepatic damage deteriorated. NO donor L-Arg and ET receptor antagonist TAK-044 could alleviate the hepatic I/R injury to some degree, whereas NO synthase inhibitor L-NAME aggravated the damage. It was concluded that the hepatic I/R injury might be related with the disturbance of the NO/ET balance. Regulation of this balance might have an effect on the I/R injury.