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

Paradoxical effect of hypercapnia on toad heart muscle

Experiments were performed on strips dissected from toad ventricles driven at a constant frequency of 12 beats/min. After equilibration, the Pco2 of the medium was altered from 25 to 95 mm Hg or from 95 to 25 mm Hg. Developed tension (DT) and maximal rate of tension development (dT/dtmax) were recorded during a 30-minute period after the change in Pco2. In the first experimental series at 30°C, increasing Pco2, resulted in a decrease in DT and dT/dtmax, followed by a recovery of contractility that reached levels higher than controls. In the second and third series, performed after the addition to the bath of practolol (1 x 10-6M) or after reserpinization, high Pco2, depressed contractility but the recovery did not surpass control values after 30 minutes of hypercapnia. In this series, when high PcO2 was replaced by low Pco2 there was an increase in DT and dT/dtmax followed by a decrease that reached control levels within a 30-minute period. In the fourth series, at 22°C the significant decreases in DT and dT/dtmax observed after increasing Pco2 were followed by a recovery that surpassed control values. These results define the existence in toad cardiac muscle of a mechanism that tends to return contractility to control levels after a change in Pco2. Within 30 minutes this mechanism, present even after inhibition of catecholamine action, completely counteracts the primary negative inotropic effect of high Pco2 and the positive inotropic action of hypocapnia.Facultad de Ciencias Médica

Comparison of the protective effects of ischemic preconditioning and the Na+ /H+ exchanger blockade

The protective effects of ischemic preconditioning (IP) and Na+/H+ exchanger blockade (NHEb) by two blockers [ethylisopropylamiloride (EIPA) and HOE 642] were compared in the isovolumic perfused rat heart. The impairment in systolic and diastolic function detected in control ischemic hearts (C) exposed to 20 min of ischemia and 30 min of reperfusion was diminished in similar extent by IP and by NHEb with EIPA and HOE 642. At the end of the reperfusion period +dP/dtmax values were 57±9% in C hearts and 94±6%, 82±6% and 104±6% after IP and NHEb with EIPA and HOE 642, respectively. A depletion of ATP levels detected in C hearts after reperfusion (from 20.2±0.8 µmol/g dry weight before ischemia to 6.9±0.7 µmol/g dry weight) was partially prevented by both IP and NHEb with EIPA (9.2±0.7 µmol/g dry weight and 11.1±0.5 µmol/g dry weight, respectively). The ischemic contracture (IC), assessed by the left ventricular end diastolic pressure (LVEDP), observed in C hearts (35±4 mmHg) was not decreased by IP (40±4 mmHg) but it was prevented by NHEb (18±4 mmHg and 10±3 mmHg with EIPA and HOE 642, respectively). The ATP levels at the end of the ischemic period were similar in C and IP hearts (4.1±0.2 µmol/g dry wt vs. 3.3±0.4 µmol/g dry wt) but they were significantly higher after NHEb with HOE 642 (7.0±1.0 µmol/g dry wt). PKC inhibition by chelerythrine abolished the protection induced by IP after reperfusion although not the improvement induced by NHEb with EIPA.Facultad de Ciencias Exacta

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

Letter by Cingolani et al. regarding article, "Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice"

Pokreisz et al. recently published an interesting article in which they show increased cardiac left ventricular phosphodiesterase-5A (PDE5A) expression in patients with heart failure. They also generated a PDE5A transgenic mouse in which overexpression of this cGMP-selective phosphodiesterase worsened ventricular remodeling and function after myocardial infarction. Therefore, the obvious conclusion seems to be that inhibition of PDE5A might protect against postmyocardial infarction remodeling. Although the authors show cGMP to be related to these cardiac architectural changes, they raise new questions about the possible cGMP downstream signaling mechanisms involved.Facultad de Ciencias Médica

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

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

Autocrine stimulation of cardiac Na+-Ca2+ exchanger currents by endogenous endothelin released by angiotensin II

The goal of the present study was to evaluate the effects of Ang II on the current produced by the Na+-Ca2+ exchanger (INCX) working in the reverse mode and the possible autocrine role played by the release of endothelin (ET) in these actions. INCX was studied in isolation in cat cardiac myocytes. Angiotensin II (Ang II) (100 nmol/L) increased INCX at potentials higher than 0 mV (at +60 mV: 2.07±0.22 pA/pF in control versus 2.73±0.22 pA/pF in Ang II, n = 9; P NCX induced by Ang II was prevented by the treatment of the cells with the unspecific blocker of the ET receptors, TAK 044 (1 μmol/L) (at +60 mV: 2.15±0.27 pA/pF in control versus 2.01±0.26 pA/pF in Ang II, n=5, NS). These results show, for the first time, that the effect of Ang II on INCX is the result of the autocrine actions of ET released by the octapeptide.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare