Na + /H + exchange inhibition attenuates left ventricular remodeling and preserves systolic function in pressure-overloaded hearts

Laboratorio di Farmacologia, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy.
British Journal of Pharmacology (Impact Factor: 4.84). 03/2004; 141(3):526-32. DOI: 10.1038/sj.bjp.0705631
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ABSTRACT Cardiac hypertrophy is a homeostatic response to elevated afterload. Na+/H+ exchanger (NHE) inhibition reduces the hypertrophic response in animal models of left ventricular hypertrophy (LVH) and myocardial infarction. We examined the effect of chronic treatment with cariporide, a selective inhibitor of Na+/H+ exchanger isoform 1 (NHE-1), on left ventricular (LV) systolic and diastolic function under pressure overload conditions. Male CD-1 mice were randomized to receive either a control diet or an identical diet supplemented with 6000 p.p.m. of cariporide. Cardiac pressure overload was induced by thoracic aortic banding. LV dimension and systolic and diastolic function were assessed in sham and banded mice by echocardiography and cardiac catheterization 2 and 5 weeks after surgery. Histological analysis was also performed. After 2 weeks of pressure overload, the vehicle-treated banded mice (Veh-Bd) had enhanced normalized LV weight (about +50%) and normal chamber size and function, whereas cariporide-treated banded mice (Car-Bd) showed a preserved contractility and systolic function despite a marked attenuation of LVH. Diastolic function did not differ significantly among groups. After 5 weeks, the Veh-Bd developed LV chamber enlargement and systolic dysfunction as evidenced by a 16% increase in LV end-diastolic diameter, a 36% decrease in myocardial contractility, and a 26% reduction in percent fractional shortening. In contrast, Car-Bd showed an attenuated increase in LV mass, normal chamber size, and a maintained systolic function. A distinct histological feature was that in banded mice, cariporide attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. In conclusion, the results of the present study indicate that (i) the hypertrophic response to pressure overload is dependent on NHE-1 activity, and (ii) at the 5-week stage, banding-induced deterioration of LV performance is prevented by NHE-1 inhibition.British Journal of Pharmacology (2004) 141, 526-532. doi:10.1038/sj.bjp.0705631

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Available from: Simona federica maria Gaudi, Sep 25, 2015
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    • "Hearts were fixed in 10% buffered formalin (BioOptica, Milan, Italy), embedded in paraffin and cut into 5 mm sections . Histological analysis was performed as described previously (Marano et al., 2004). Specifically, LV sections were stained with haematoxylin and eosin for the measurement of myocyte cross-sectional area or by the sirius red / picric acid method to determine LV fibrosis by quantitative morphometry (Morphometric, Universal Imaging Corporation, Downingtown, PA, USA). "
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    ABSTRACT: Cell cycle regulators are regarded as essential for cardiomyocyte hypertrophic growth. Given that the β-adrenoceptor antagonist propranolol blunts cardiomyocyte hypertrophic growth, we determined whether propranolol alters the expression of cell cycle-related genes in mouse hearts subjected to pressure overload. Pressure overload was induced by transverse aortic constriction (TAC), whereas the expression levels of 84 cell cycle-related genes were assayed by real-time PCR. Propranolol (80 mg·kg(-1) ·day(-1) ) was administered in drinking water for 14 days. Two weeks after surgery, TAC caused a 46% increase in the left ventricular weight-to-body weight (LVW/BW) ratio but no significant changes in cell cycle gene expression. Propranolol, at plasma concentrations ranging from 10 to 140 ng·mL(-1) , blunted the LVW/BW ratio increase in TAC mice, while significantly increasing expression of 10 cell cycle genes including mitotic cyclins and proliferative markers such as Ki67. This increase in cell cycle gene expression was paralleled by a significant increase in the number of Ki67-positive non-cardiomyocyte cells as revealed by immunohistochemistry and confocal microscopy. β-Adrenoceptor signalling was critical for cell cycle gene expression changes, as genetic deletion of β-adrenoceptors also caused a significant increase in cyclins and Ki67 in pressure overloaded hearts. Finally, we found that metoprolol, a β(1) -adrenoceptor antagonist, failed to enhance cell cycle gene expression in TAC mice. Propranolol treatment enhances cell cycle-related gene expression in pressure overloaded hearts by increasing the number of cycling non-cardiomyocyte cells. These changes seem to occur via β(2) -adrenoceptor-mediated mechanisms.
    British Journal of Pharmacology 05/2011; 164(8):1917-28. DOI:10.1111/j.1476-5381.2011.01504.x · 4.84 Impact Factor
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    • "Histological analysis was performed as reported previously (Marano et al., 2004). Briefly, LV sections were cut and stained with haematoxylin and eosin for measurement of myocyte cross-sectional area or with the Sirius red/picric acid method to determine LV fibrosis by quantitative morphometry (Metamorph 6.1). "
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    ABSTRACT: Pathological cardiac hypertrophy is associated with the expression of a gene profile reminiscent of foetal development. The non selective beta-adrenoceptor antagonist propranolol is able to blunt cardiomyocyte hypertrophic response in pressure-overloaded hearts. It remains to be determined whether propranolol also attenuates the expression of hypertrophy-associated foetal genes. To address this question, the foetal gene programme, of which atrial natriuretic peptide (ANP), the beta-isoform of myosin heavy chain (beta-MHC), and the alpha-skeletal muscle isoform of actin (skACT) are classical members, was induced by thoracic aortic coarctation (TAC) in C57BL/6 mice, or by phenylephrine, a selective alpha(1)-adrenoceptor agonist, in cultured rat neonatal cardiomyocytes. In TAC mice, the left ventricular weight-to-body weight (LVW/BW) ratio increased by 35% after 2 weeks. Levels of ANP, beta-MHC and skACT mRNA in the left ventricles increased 2.2-fold, 2.0-fold and 12.1-fold, respectively, whereas alpha-MHC and SERCA mRNA levels decreased by approximately 50%. Although propranolol blunted cardiomyocyte growth, with approximately an 11% increase in the LVW/BW ratio, it enhanced the expression of ANP, beta-MHC and skACT genes (10.5-fold, 27.7-fold and 22.7-fold, respectively). Propranolol also enhanced phenylephrine-stimulated ANP and beta-MHC gene expression in cultured cardiomyocytes. Similar results were obtained with metoprolol, a selective beta(1)-adrenoceptor antagonist, but not with ICI 118551, a beta(2)-adrenoceptor antagonist. Propranolol enhances expression of the hypertrophy-associated foetal genes mainly via the beta(1)-adrenoceptor blockade. Our results also suggest that, in pressure-overloaded hearts, cardiomyocyte growth and foetal gene expression occur as independent processes.
    British Journal of Pharmacology 10/2007; 152(2):216-22. DOI:10.1038/sj.bjp.0707350 · 4.84 Impact Factor
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    • "However, in other models of CH, an increase in the exchanger expression and its normalization by the treatment with NHE-1 inhibitors have been detected (Yoshida and Karmazyn 2000; Kusumoto et al. 2001; Engelhardt et al. 2002). In any case, the enhanced activity of NHE-1, as determined by an increase in the turnover rate or expression of the exchanger, has been linked to the development of CH and its inhibition with the normalization of cardiac mass (Yoshida and Karmazyn 2000; Kusumoto et al. 2001; Camilión de Hurtado et al. 2002; Engelhardt et al. 2002; Ennis et al. 2003; Karmazyn et al. 2003; Chen et al. 2001, 2004; Marano et al. 2004). "
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    ABSTRACT: Na+/H+ exchanger-1 (NHE-1) inhibition induces cardiac hypertrophy regression and (or) prevention in several experimental models, although the intracellular events involved remain unclarified. We aimed to determine whether the calcineurin/NFAT pathway mediates this effect of NHE-1 inhibitors. Spontaneously hypertensive rats (SHR) with cardiac hypertrophy were treated with the NHE-1 inhibitors cariporide and BIIB723 for 30 days. Wistar rats served as normotensive controls. Their hearts were studied by echocardiography, immunoblotting, and real-time RT-PCR. Cytoplasmic Ca2+ and calcineurin Abeta expression were measured in cultured neonatal rat ventricular myocytes (NRVM) stimulated with endothelin-1 for 24 h. NHE-1 blockade induced cardiac hypertrophy regression (heart mass/body mass=3.63+/-0.07 vs. 3.06+/-0.05 and 3.02+/-0.13 for untreated vs. cariporide- and BIIB723-treated SHR, respectively; p<0.05) and decreased myocardial brain natriuretic peptide, calcineurin Abeta, and nuclear NFAT expressions. Echocardiographic evaluation demonstrated a reduction in left ventricular wall thickness without changes in cavity dimensions or a significant decrease in blood pressure. NHE-1-inhibitor treatment did not affect myocardial stiffness or endocardial shortening, but increased mid-wall shortening, suggesting that a positive inotropic effect develops after hypertrophy regression. Cariporide normalized the increased diastolic Ca2+ and calcineurin Abeta expression observed in ET-1-stimulated NRVM. In conclusion, our data suggest that inactivation of calcineurin/NFAT pathway may underlie the regression of cardiac hyper-trophy induced by NHE-1 inhibition.
    Canadian Journal of Physiology and Pharmacology 04/2007; 85(3-4):301-10. DOI:10.1139/y06-072 · 1.77 Impact Factor
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