Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy

Overload of neonatal and adult cardiomyocytes and multicellular myocardial preparations, which include whole hearts, are accompanied by an enhanced activity of the Na+/H+ exchanger 1 (NHE-1). Exogenous administration of prohypertrophic agents such as angiotensin II (Ang II), endothelin-1 (ET-1), and α1-adrenergic agonists also stimulates NHE-1 activity, which leads to an increased concentration of intracellular Na+ ([Na+]i). Moreover, inhibition of NHE-1 activity prevents the increase in [Na+]i, induces the regression of cardiac hypertrophy, and exerts beneficial effects in experimental heart failure. The present review summarizes the current knowledge of the causative factors and pathophysiological correlation of cardiac overload and NHE-1 activity.Centro de Investigaciones Cardiovasculare

Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy

Overload of neonatal and adult cardiomyocytes and multicellular myocardial preparations, which include whole hearts, are accompanied by an enhanced activity of the Na+/H+ exchanger 1 (NHE-1). Exogenous administration of prohypertrophic agents such as angiotensin II (Ang II), endothelin-1 (ET-1), and α1-adrenergic agonists also stimulates NHE-1 activity, which leads to an increased concentration of intracellular Na+ ([Na+]i). Moreover, inhibition of NHE-1 activity prevents the increase in [Na+]i, induces the regression of cardiac hypertrophy, and exerts beneficial effects in experimental heart failure. The present review summarizes the current knowledge of the causative factors and pathophysiological correlation of cardiac overload and NHE-1 activity.Centro de Investigaciones Cardiovasculare

NHE-1 and NHE-6 Activities : Ischemic and Reperfusion Injury

The study published in this issue of Circulation Research showing that a null mutation of NHE-1 improves the tolerance of the heart to ischemia and reperfusion (I/R) is an important contribution for the following reasons: (1) In the animals with null mutation, contracture during the ischemic period was less and ATP levels were preserved compared with wild-type animals. This observation, on the one hand, provides evidence that protection by downregulation of NHE-1 during the ischemic period itself is indeed possible and, on the other hand, it argues against the suggestion that the exchanger is inactive during this same period. (2) In contrast with chronic blockade of the NHE-1 by pharmacological interventions, the long-term absence of the exchanger does not elicit major compensatory changes that, in turn, might negate the cardioprotective effect of blocking its activity for a relative short term. This point is related to a recent publication showing that long-term treatment with the NHE-1 blocker cariporide is followed by an upregulation of the functional units of the exchanger in a similar way to the well-known tolerance phenomenon following β-adrenergic receptor blockade. The absence of such upregulation negates possible hypersensitivity to ischemia upon withdrawal of the medication. The risk is evident in hearts with upregulation of NHE-1, which gain Na+i more rapidly during ischemia, and show impaired recovery after reperfusion. (3) No additional protection was obtained by adding the NHE-1 blocker eniporide to the NHE-1 null mice, suggesting that there is not another NHE isoform that can be blocked with this compound to add additional protection; the findings additionally hint that the attenuation of the injury obtained by the absence of the sarcolemmal NHE-1 is maximal and, therefore, no further beneficial effect will be detected by blocking the mitochondrial NHE (MNHE).Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Heart mineralocorticoid receptor: past, present and future

Tres ensayos clínicos realizados en el transcurso de los últimos 20 años –RALES, EPHESUS y EMPHASIS-HF- marcaron un nuevo hito en el tratamiento de la insuficiencia cardíaca (IC)1-3. Demostraron que el uso de antagonistas del receptor de mineralocorticoides (MR) agregado a la terapia convencional era capaz de disminuir de forma muy significativa la morbi-mortalidad de estos pacientes. Por este motivo los antagonistas del MR han sido declarados drogas de clase I en las recomendaciones para el tratamiento de la IC. No obstante, no ha sido dilucidado aun con precisión el mecanismo por el cual ejercen tan significativo beneficio. Por otro lado, y lamentablemente, persisten siendo drogas subutilizadas, prescriptas solo a aproximadamente un tercio de los pacientes elegibles4-5. En este artículo de revisión describiremos someramente el camino recorrido por los antagonistas del MR en el tratamiento de la IC, con particular interés en los mecanismos que podrían explicar los beneficios obtenidos con su uso y los desafíos para el futuro.Centro de Investigaciones Cardiovasculare

Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy

Overload of neonatal and adult cardiomyocytes and multicellular myocardial preparations, which include whole hearts, are accompanied by an enhanced activity of the Na+/H+ exchanger 1 (NHE-1). Exogenous administration of prohypertrophic agents such as angiotensin II (Ang II), endothelin-1 (ET-1), and α1-adrenergic agonists also stimulates NHE-1 activity, which leads to an increased concentration of intracellular Na+ ([Na+]i). Moreover, inhibition of NHE-1 activity prevents the increase in [Na+]i, induces the regression of cardiac hypertrophy, and exerts beneficial effects in experimental heart failure. The present review summarizes the current knowledge of the causative factors and pathophysiological correlation of cardiac overload and NHE-1 activity.Centro de Investigaciones Cardiovasculare

Empujando los límites de la medicina

La identificación de las causas moleculares de las enfermedades junto con el desarrollo de la industria biotecnológica en general y de la farmacéutica en particular permiten el desarrollo de mejores métodos de diagnóstico, la identificación de blancos terapéuticos para el desarrollo de fármacos personalizados, y una mejor medicina preventiva. Se han logrado avances en un gran número de aspectos que en otros tiempos hubiesen sido impensables; tales son los casos de las técnicas de resonancia magnética, cirugías a distancia (telemedicina) gracias a Internet2, utilización de microprocesadores con diferentes usos médicos, decodificadores genéticos, utilización de tecnologías inalámbricas, entre otros. Los avances formidables en el campo de la biología molecular de las últimas décadas generan, además una gran cantidad de información que podría resultar inmanejable. Este inmenso caudal de nueva información requiere para su análisis el uso de herramientas de cálculo altamente especializadas.Facultad de Informátic

Na⁺/H⁺ exchanger and myocardial growth

The stretching of a papillary muscle induces a sudden and immediate rise in force, due to an augmentation in myofilament Ca²⁺ responsiveness. During the next 10 to 15 minutes a progressive increase in force develops known as the “slow force response” (SFR), that is due to a progressive increase in Ca²⁺ transient amplitude. The source for this increase in Ca²⁺ transient remained obscure until we proposed a link between Ca²⁺ influx mediated by Na⁺/ Ca²⁺ (NCX) exchange in reverse mode and the activation of the Na⁺/H⁺ exchanger (NHE-1) caused by stretch;1-4 being the increase in the Ca²⁺ transient secondary to the increase in intracellular Na⁺ concentration ([Na+]i). It is known that the increase in [Na⁺]i can induce an increase in intracellular Ca²⁺ levels ([Ca²⁺ ]i) through the NCX either as a result of a decrease in Ca²⁺ efflux (decreased forward mode) or an increase in Ca²⁺ entry (increased reverse mode). The fact that after myocardial stretch there is no increase in diastolic [Ca²⁺ ]i 1,5 as would be expected for a decrease in Ca²⁺ efflux, suggests that the reverse mode of NCX is the mechanism involved in the increase in Ca²⁺ transient.1The SFR, the increase in [Na⁺]i and the increase in Ca²⁺ transient can be abolished by blocking the Angiotensin II (Ang II) AT1 receptors with losartan; the endothelin (ET) ETA receptors by BQ123 and by inhibition of the NHE-1.6Sociedad Argentina de FisiologíaFacultad de Ciencias Médica

Role of autocrine/paracrine mechanisms in response to myocardial strain

Myocardial strain triggers an autocrine/paracrine mechanism known to participate in myocardial hypertrophy development. After the onset of stretch, there is a rapid augmentation in developed tension due to an increase in myofilament calcium sensitivity (the Frank Starling mechanism) followed by a gradual increase in tension over the next 10-15 min. This second phase is called the slow force response (SFR) to stretch and is known to be the result of an increase in calcium transient amplitude. In the present review, we will discuss what is known thus far about the SFR, which is the in vitro equivalent of the Anrep effect and the mechanical counterpart of the autocrine/ paracrine mechanism elicited by myocardial stretch. The chain of events triggered by myocardial stretch comprises: (1) release of angiotensin II, (2) release/formation of endothelin, (3) NADPH oxidase activation and transactivation of the EGFR, (4) mitochondrial reactive oxygen species production, (5) activation of redox-sensitive kinases, (6) NHE-1 hyperactivity, (7) increase in intracellular Na⁺ concentration, and (8) increase in Ca²⁺ transient amplitude through the Na⁺/Ca²⁺ exchanger. The evidence for each step of the intracellular signaling pathway leading to the development of SFR and their relationship with the mechanisms proposed for cardiac hypertrophy development will be analyzed.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Efecto antioxidante del factor de crecimiento similar a insulina 1 (IGF-1) sobre el corazón de ratas hipertensas

Objetivo del trabajo: estudiar en el miocardio de ratas SHR el efecto de una concentración fisiológica de IGF-1 (10 nmol/L) sobre: - la producción de H2O2 y - la actividad de las enzimas superóxido dismutasa (SOD) y catalasa.Facultad de Ciencias Médica

Remodelamiento ventricular izquierdo secundario al entrenamiento en jugadores de rugby

La actividad física en deportistas puede asociarse con adaptaciones eléctricas, estructurales y funcionales del miocardio que configuran el corazón de atleta. Las características de la sobrecarga de trabajo impuesta por la actividad deportiva son las principales responsables de este fenotipo. El rugby es un deporte con moderada carga isométrica y moderada a intensa carga dinámica, pudiendo estas condiciones variar según la posición del jugador en el campo [fowards (F) vs. backs (B)]. Este trabajo se propone analizar las características de adaptación estructural y funcional del ventrículo izquierdo (VI) en jugadores de rugby en relación con su posición en el campo de juego. Párrafo extraído del texto a modo de resumenFacultad de Ciencias Médica