Atenuação da remodelação ventricular após infarto agudo do miocárdio / Attenuation of ventricular remodeling after myocardial acute infarction

Após o infarto agudo do miocárdio podem ocorrer complexas alterações da arquitetura ventricular, envolvendo tanto a região infartada como a região não infartada. Há alguns anos, essas alterações passaram a ser designadas como remodelação ventricular pós-infarto. Do ponto de vista clínico, a remodelação está associada ao pior prognóstico após a oclusão coronária. Assim, a remodelação predispõe o coração infartado à ruptura ventricular e é o substrato fisiopatológico para a posterior formação do aneurisma ventricular. Cronicamente, a remodelação está associada com maior prevalência de arritmias malignas, principalmente a taquicardia ventricular sustentada e a fibrilação ventricular. O aspecto mais relevante da remodelação pós-infarto, no entanto, é que esse processo desempenha papel fundamental na fisiopatologia da disfunção ventricular. Aspecto a ser considerado refere-se ao fato de que a evolução do processo de remodelação pode ser modificado por meio de diversas intervenções terapêuticas. Entre as estratégias para atenuar a remodelação ventricular destacam-se: terapia de reperfusão, inibidores da enzima conversora da angiotensina e antagonistas da angiotensina II, betabloqueadores, antagonistas da aldosterona e dispositivos de assistência circulatória.

After acute myocardial infarction (AMI), complex changes in ventricular architecture may occur involving the infarcted and the non-infarcted region. This set of adaptations, which includes changes in the composition, mass, volume and geometry of the heart, is known as myocardial remodeling. In relation to clinical significance, the intensity of the ventricular remodeling process is directly associated with worse prognosis, due to the higher incidence of aneurysm formation, ventricular rupture and arrhythmia, and is also associated with the progression of ventricular dysfunction. A relevant aspect to be considered is that a number of strategies have been employed to prevent or mitigate the process of ventricular remodeling following AMI, for instance: reperfusion therapy, angiotensin converting enzyme inhibitors and angiotensin II antagonists, beta-adrenergic receptor blockade, aldosterone antagonists, and left ventricular assist devices.

Endogenous angiotensin II modulates nNOS expression in renovascular hypertension

Nitric oxide (NO) influences renal blood flow mainly as a result of neuronal nitric oxide synthase (nNOS). Nevertheless, it is unclear how nNOS expression is modulated by endogenous angiotensin II, an inhibitor of NO function. We tested the hypothesis that the angiotensin II AT1 receptor and oxidative stress mediated by NADPH oxidase contribute to the modulation of renal nNOS expression in two-kidney, one-clip (2K1C) hypertensive rats. Experiments were performed on male Wistar rats (150 to 170 g body weight) divided into 2K1C (N = 19) and sham-operated (N = 19) groups. nNOS expression in kidneys of 2K1C hypertensive rats (N = 9) was compared by Western blotting to that of 2K1C rats treated with low doses of the AT1 antagonist losartan (10 mg·kg-1·day-1; N = 5) or the superoxide scavenger tempol (0.2 mmol·kg-1·day-1; N = 5), which still remain hypertensive. After 28 days, nNOS expression was significantly increased by 1.7-fold in the clipped kidneys of 2K1C rats and by 3-fold in the non-clipped kidneys of 2K1C rats compared with sham rats, but was normalized by losartan. With tempol treatment, nNOS expression increased 2-fold in the clipped kidneys and 1.4-fold in the non-clipped kidneys compared with sham rats. The changes in nNOS expression were not followed by changes in the enzyme activity, as measured indirectly by the cGMP method. In conclusion, AT1 receptors and oxidative stress seem to be primary stimuli for increased nNOS expression, but this up-regulation does not result in higher enzyme activity.

Sodium tanshinone IIA sulfonate attenuates angiotensin II-induced collagen type I expression in cardiac fibroblasts in vitro

Cardiac fibrosis occurs after pathological stimuli to the cardiovascular system. One of the most important factors that contribute to cardiac fibrosis is angiotensin II (Ang II). Accumulating studies have suggested that reactive oxygen species (ROS) plays an important role in cardiac fibrosis and sodium tanshinone IIA sulfonate (STS) possesses antioxidant action. We therefore examined whether STS depresses Ang II-induced collagen type I expression in cardiac fibroblasts. In this study, Ang II significantly enhanced collagen type I expression and collagen synthesis. Meanwhile, Ang II depressed matrix metalloproteinase-1 (MMP-1) expression and activity. These responses were attenuated by STS. Furthermore, STS depressed the intracellular generation of ROS, NADPH oxidase activity and subunit p47(phox) expression. In addition, N-acetylcysteine the ROS scavenger, depressed effects of Ang II in a manner similar to STS. In conclusion, the current studies demonstrate that anti-fibrotic effects of STS are mediated by interfering with the modulation of ROS.

Avances en el tratamiento de la insuficiencia cardíaca / Advances in heart failure treatment

El síndrome de insuficiencia cardíaca tiene alta prevalencia e incidencia en el mundo desarrollado, como también en los países con un nivel de desarrollo intermedio, como Chile. Se cree que este fenómeno obedece, en gran medida, al progresivo envejecimiento de la población. Además, las principales causas del síndrome son muy prevalentes (cardiopatía coronaria e hipertensión arterial sistémica). Esta situación ha impuesto una enorme carga económica sobre los sistemas de salud de las diversas naciones, ya que la insuficiencia cardiaca se ha convertido en la principal causa de hospitalización en personas mayores de 65 años. La cardiología preventiva tiene un rol importante que jugar en disminuir la incidencia de nuevos casos del síndrome. En esta revisión se tratan brevemente los siguientes aspectos: 1) avances en la comprensión fisiopatológica de esta condición; 2) insuficiencia cardiaca con función sistólica preservada; 3) algunos avances farmacológicos; 4) anemia e insuficiencia cardíaca; 5) dispositivos e insuficiencia cardíaca; 6) rol de la cirugía en la insuficiencia cardíaca.

Sodium tanshinone IIA sulfonate depresses angiotensin II-induced cardiomyocyte hypertrophy through MEK/ERK pathway

Cardiomyocyte hypertrophy is a major cause of morbidity and mortality worldwide. The aim of this study is to determine the effects of sodium tanshinone IIA sulfonate (STS) on cardiomyocyte hypertrophy induced by angiotensin II (Ang II) in vivo and in vitro. In long-term treatment, adult Wistar rats were infused with Ang II for three weeks via osmotic mini-pumps and some of them were given intragastrically of STS. Left ventricle was isolated; the ratio of left ventricular weight to body weight and systolic blood pressure (SBP) were determined and heart morphometry was assessed after hematoxylin and eosin staining. Results indicated STS inhibited Ang II-induced increases in myocyte diameter and decreased the LVW/BW ratio independent of decreasing systolic blood pressure. In vitro, treatment of cultured cardiomyocytes with STS inhibited Ang II-induced increase in cell size, protein synthesis, ANP expression, activation of extracellular signal-regulated kinase (ERK) and ERK kinase (MEK). Then we reexamined the mechanism of STS-induced anti-hypertrophic effects. Results revealed MEK inhibitor U0126 (20 microM) markedly enhanced STS-induced depressions in [3H]leucine incorporation and ANP expression. In conclusion, MEK/ERK pathway plays a significant role in the anti-hypertrophic effects of STS.

Angiotensin II antagonists: clinical experience in the treatment of hypertension, prevention of cardiovascular outcomes and renal protection in diabetic nephropathy and proteinuria / Antagonistas da angiotensina II: experiência clínica com o tratamento da hipertensão, prevenção de desfechos cardiovasculares e proteção renal na nefropatia diabética e proteinúria

Angiotensin II antagonists (AIIAs) were introduced to treat hypertension about 10 years ago. During this period they were evaluated not only in terms of efficacy and safety but also in several large studies with clinical outcomes. They are efficacious in all clinical forms of hypertension and are effective also in all ethnic groups. Cardiovascular and renal protection in proteinuric diabetic nephropathy beyond blood pressure reduction was proved in major clinical studies: Losartan Intervention For Endpoint reduction in hypertension study (LIFE), Reduction of Endpoint in Non-Insulin dependent Diabetes Mellitus with the AII Antagonist Losartan (RENAAL) and Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT). Their blood pressure independent protective effect is also mentioned by the blockade of AT1 receptor. As a class AIIs have a tolerability profile similar to placebo.

Os antagonistas da angiotensina II (AAIIs) foram introduzidos para o tratamento da hipertensão arterial há cerca de 10 anos. Durante esse período eles foram avaliados não apenas em termos de eficácia e segurança, mas também em vários estudos grandes com desfechos clínicos. Os AAIIs são eficazes em todas as formas clínicas de hipertensão e, também, em todos os grupos étnicos. Os principais estudos clínicos em pacientes diabéticos com nefropatia e proteinúia comprovaram, além da redução da pressão arterial, proteção cardiovascular e renal: "Losartan Intervention For Endpoint reduction in hypertension study" (LIFE), "Reduction of Endpoint in Non-Insulin dependent Diabetes Mellitus with the AII Antagonist Losartan" (RENAAL) e "Irbesartan Type 2 Diabetic Nephropathy Trial" (IDNT). O seu efeito protetor independente da pressão sanguínea também é mencionado pelo bloqueio do receptor AT1. Os AAIIs, como classe medicamentosa, apresentam um perfil de tolerabilidade semelhante ao placebo.

Angiotensin-II behaves as an endogenous pro-inflammatory molecule.

Angiotensin-II regulates vascular tone, stimulates the release of pro-inflammatory cytokines, activates NF-kappaB, increases oxidant stress, and suppresses nitric oxide synthesis, and thus, it functions as an inflammatory molecule. Since ACE is present in many tissues, this suggests that angiotensin-II may play a significant role in atherosclerosis, congestive cardiac failure, stroke, bipolar disorder, schizophrenia, dementia, Alzheimer's disease, psoriasis, atopic and non-atopic dermatitis, eczema, several acute and chronic inflammatory diseases, and cancer, conditions in which inflammation is an aetiopathogenic factor. Thus, ACE inhibitors and/or angiotensin-II receptor blockers could be of benefit in these conditions. Furthermore, structural analogues of ACE inhibitors and angiotensin-II receptor blockers could be developed that possess anti-inflammatory actions without significant action on the cardiovascular system.

Analysis of heart rate variability in hypertensive patients before and after treatment with angiotensin II-converting enzyme inhibitors / Análise da variabilidade da freqüência cardíaca em pacientes hipertensos, antes e depois do tratamento com inibidores da enzima conversora da angiotensina II

OBJETIVO: Comparar a variabilidade de freqüência cardíaca em indivíduos normotensos e hipertensos e observar o comportamento do sistema nervoso autônomo após terapia com inibidores da enzima conversora de angiotensina II. MÉTODO: Estudados 286 pacientes com diagnóstico de hipertensão arterial, pela 1ª vez, e divididos em 4 grupos, conforme a pressão arterial diastólica (PAD): grupo A - PAD<90 mmHg; grupo B - PAD 90-99 mmHg; grupo C - PAD 100-109 mmHg; grupo D - PAD>110 mmHg. Os pacientes do grupo A (normais) e do grupo C (HA moderada), somando 110 e 79 pacientes, respectivamente, submeteram-se ao Holter-ECG 24h com análise de variabilidade de freqüência cardíaca no domínio do tempo (DT) e no domínio da freqüência (DF). O grupo C foi tratado com inibidores da ECA durante 3 meses, e após esse período novamente avaliado com Holter-ECG 24h e variabilidade da freqüência cardíaca, e os valores comparados com os normotensos. RESULTADOS: Os parâmetros SDNN, PNN50 (DT) e o espectro LF (DF) foram significativamente diferentes para os dois grupos, com valores notadamente diminuídos em hipertensos (p<0,05). Pacientes do grupo C, após tratamento com IECA, mostraram-se recuperados em todas as variáveis da variabilidade da freqüência cardíaca, apresentando valores próximos aos dos normotensos. CONCLUSAO: A variabilidade da freqüência cardíaca mostrou-se reduzida em hipertensos quando comparados aos normotensos, apontando para uma queda no reflexo baroceptor. Observou-se ainda a presença de um ajuste autonômico funcional após terapia anti-hipertensiva com IECA, indicando recuperação do tônus parassimpático.

Angiotensin II receptor blocker attenuates overexpression of vascular endothelial growth factor in diabetic podocytes

VEGF expressed in glomerular podocytes, is known to increase vascular permeability to macromolecules. Angiotensin II can stimulate the release of VEGF, and the protective effects of angiotensin II antagonist against diabetic glomerular injury suggest that the angiotensin II-induced VEGF is an important pathogenetic mechanism in the development of proteinuria during diabetic nephropathy although this mechanism is not fully understood. In this study, the changes of VEGF expression was examined in the experimental diabetic nephropathy to determine whether these changes were modified by renoprotective intervention by blockers of angiotensin II receptors. The streptozotocin- induced diabetic rats were treated with L-158,809, a blocker of angiotensin II receptors, for 12 weeks. Age-matched rats with L-158,809 served as controls. RT-PCR and immunohistochemistry were used to assess and quantify gene and protein expression of VEGF. A progressive increase in urinary protein excretion was observed in diabetic rats. Glomerular VEGF expression was significantly higher in diabetic rats than in the control groups, with a significant reduction in glomerular VEGF expression and proteinuria in L-158,809- treated diabetic rats. VEGF mRNA was also significantly higher in diabetic kidneys than in the control groups, with a significant reduction in VEGF mRNA in L-158,809-treated diabetic kidneys. These results demonstrates that VEGF expression is significantly increased in diabetic podocytes, and angiotensin II receptor antagonist attenuated these changes in VEGF expression and prevented the development of proteinuria in vivo. Attenuation of increased VEGF expression in podocytes could contribute to the renoprotective effects of angiotensin II receptor antagonists in diabetic nephropathy.

Inibição da angiotensina II em modelo de isquemia/reperfusão em cão: efeitos sobre a infiltração leucocitária, atividade das isoenzimas da sintase de óxido nítrico e função contrátil / Angiotensin II inhibition during myocardial ischmia-repercusion in dogs: effects on leukocyte infiltration, nitric oxide synthase isoenzyms activity and left ventricular ejection fraction

Os leucócitos são importantes na lesão de reperfusão, sofrendo influência do óxido nítrico e da angiotensina II (AII). Esse estudo avaliou o efeito da inibição da AII sobre a infiltração leucocitária, atividade das isoenzimas da sintase de óxido nítrico (SON) e função contrátil ventricular, em modelo de infarto e reperfusão em cão. Um grupo foi tratado com captopril, outro com losartan e um terceiro foi o controle. A atividade de mieloperoxidase foi menor e a recuperação da FE na reperfusão foi melhor nos grupos tratados com captopril e losartan. A atividade da SON constitutiva não foi diferente, mas a da SON induzida foi menor no grupo losartan, comparado aos grupos captopril e controle.Leukocytes play significant role in reperfusion injury. Nitric oxide and angiotensin II (AII) may influence it. This study evaluated the AII inhibition effect on leukocyte infiltration, nitric oxide synthase (NOS) activity and left ventricular ejection fraction (LVEF), in model of myocardial ischemic- reperfusion in dog. Three groups were selected to receive captopril, losartan or saline solution. The myeloperoxidase activity was lower and the recovery of the LVEF at the reperfusion period was better, in the groups under captopril and losartan. Constitutive NOS activity was not statistically different, but inducible NOS was lower in losartan group than was in the captopril and control groups...

O efeito do bloqueio concomitante da ciclooxigenase e do receptor AT1 em ratos com nefropatia crônica estabelecida / A combined treatment of losartan and a nonsteroidal antiinflammatory affords superior protection of the remnant kidney

Para avaliar-se o papel da angiotensina II (AII) e dos produtos de degradação da ciclo-oxigenase (COx) nas nefropatias progressivas, ratos submetidos a ablação renal de 5/6 receberam losartan, um bloqueador de receptores AT1, e nitroflurbiprofen, um inibidor da COx. O tratamento combinado foi muito mais eficiente em interromper ou promover a regressão das alterações funcionais e histológicas que qualquer das monoterapias. Houve diminuição da infiltração renal de células inflamatórias e células expressando COx-2 e AII / Rats with 5/6 renal ablation received losartan, an AT1 receptor blocker, and nitroflurbiprofen, a cyclooxygenase (COx) inhibitor in order to evaluate the role of angiotensin II (AII) and COx end products in the progressive nephropathies. By acting on two distinct mechanisms, combined treatment exerted far more efficient protection than either monotherapy, arresting or promoting regression of functional and histologic manifestations of this model. There was a decrease in the number of infiltrating inflammatory cells and abnormal renal COx-2 and AII...

Ligand-induced endocytosis and nuclear localization of angiotensin II receptors expressed in CHO cells

A construct (AT1R-NF) containing a "Flag" sequence added to the N-terminus of the rat AT1 receptor was stably expressed in Chinese hamster ovary cells and quantified in the cell membrane by confocal microscopy after reaction with a fluorescein-labeled anti-Flag monoclonal antibody. Angiotensin II bound to AT1R-NF and induced endocytosis with a half-time of 2 min. After 60-90 min, fluorescence accumulated around the cell nucleus, suggesting migration of the ligand-receptor complex to the nuclear membrane. Angiotensin antagonists also induced endocytosis, suggesting that a common step in the transduction signal mechanism occurring after ligand binding may be responsible for the ligand-receptor complex internalization

Efecto de antagonistas de los receptores de angiotensina II y alfa2 adrenérgicos sobre la liberación de óxido nítrico inducida por angiotensina II / Effect of angiotensin II and alpha2 adrenergic receptor antagonists on angiotensin II-stimulated nitric oxide release

El objetivo del presente trabajo fue caracterizar la interacción entre el sistema adrenérgico y la liberación de óxido nítrico (ON) estimulada por angiotensina II en aorta de conejo. Anillos de aorta torácica se colocaron en un baño de órgano aislado. Se equilibró durante 30 min, se lavó y se agregó angiotensina II a diferentes dosis, dejándose actuar 20 min. En otro grupo se efectuaron dos estimulaciones con un intervalo de 60 min. Los antagonistas de angiotensina II: losartan, PD 123319 y Sar1-Leu8-angiotensina II; y el antagonista a2 adrenérgico (yohimbina), todos 10-5 M, y L-NAME o D-NAME 10-2 M, se agregaron antes de estimular con angiotensina II 10-6 M o 5.10-6 M. A otro grupo, además de losartan o PD 123319, se agregó yohimbina. La determinación de nitritos se realizó con el reactivo de Griess. La angiotensina II 10-8 M hasta 10-6 M, incrementó la producción de metabolitos de ON medidos como nitritos con respecto al control. A dosis mayores hubo una disminución con respecto a 10-6 M La liberación de nitritos inducida por angiotensina II cayó en la segunda estimulación con la hormona en todos los casos, mientras el L-NAME la bloqueó. Los antagonistas de angiotensina II la incrementaron sólo a dosis máxima de la hormona, efecto anulado por yohimbina. Asimismo, yohimbina disminuyó la producción de nitritos a dosis de angiotensina II 5.10-6 M pero no 10-6 M. Estos resultados permiten postular que la liberación de ON inducida por angiotensina II sería en parte mediada por estimulación de receptores a2. Los antagonistas de angiotensina II desenmascararían este efecto a dosis máxima de la hormona, mientras que a dosis supramáximas prevalecerían mecanismos inhibitorios que serían compensados por activación a2

Empleo de medicamentos para el tratamiento de la hipertensión / Medication for treatment of hypertension

La autora expone acerca de la hipertensión arterial como un factor de riesgo importante en las enfermedades cardiovasculares y se detiene en la descripción de los fármacos más habituales para el tratamiento de este síntoma

Eritrocitosis post-transplante renal / Post-renal transplantation erythrocytosis

La eritrocitosis post-transplante es una entidad caracterizada por un hematocrito superior al 51 por ciento, tiene una prevalencia del 10 al 15 por ciento en los pacientes transplantados renales, y puede manifestarse en cualquier momento post-transplante. La eritrocitosis post-transplante se asocia a hipertensión arterial, por aumento de la volemia, y es un factor predisponente a la trombosis vascular, por aumento de la viscosidad sanguínea. Tanto la angiotensina II como el Insulin Growth Factor I y otros compuestos han sido postulados como posibles mediadores del aumento de la eritropoyesis. La eritropoyetina se encuentra en valores aumentados en esta entidad, aunque existen casos en los cuales la misma se encuentra en valores normales o disminuídos. Independientemente de estos niveles, los inhibidores de la enzima convertidora de angiotensina, o recientemente los inhibidores del receptor de angiotensina II, son las drogas de elección para tratar en forma efectiva y segura la eritrocitosis post-trasnplante.