Chronic inhibition of the Na⁺/H⁺‐ exchanger causes regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling

Abstract

Background and purpose: Increased activity of the Na þ /H þ -exchanger (NHE-1) in heart failure underlies raised [Na þ ] i causing disturbances of calcium handling. Inhibition of NHE-1, initiated at the onset of pressure/volume overload, prevents development of hypertrophy, heart failure and remodelling. We hypothesized that chronic inhibition of NHE-1, initiated at a later stage, would induce regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling. Experimental approach: Development of heart failure in rabbits was monitored electrocardiographically and echocardiographically, after one or three months. Cardiac myocytes were also isolated. One group of animals were treated with cariporide (inhibitor of NHE-1) in the diet after one month. Cytoplasmic calcium, sodium and action potentials were measured with fluorescent markers and sarcoplasmic reticulum calcium content by rapid cooling. Calcium after-transients were elicited after rapid pacing. Sodium channel current (I Na ) was measured using patch-clamp techniques. Key results: Hypertrophy and heart failure developed after one month and progressed during the next two months. After one month, dietary treatment with cariporide was initiated. Two months of treatment reduced hypertrophy and heart failure, duration of action potential QT-interval and QRS, and restored sodium and calcium handling and the incidence of calcium after-transients. In cardiac myocytes, parameters of I Na were not changed by cariporide. Conclusion and implications:In rabbit hearts with hypertrophy and signs of heart failure one month after induction of pressure/volume overload, two months of dietary treatment with the NHE-1 inhibitor cariporide caused regression of hypertrophy, heart failure and ionic and electrophysiological remodelling.

Na+–H+ exchanger inhibitor prevents early death in hereditary cardiomyopathy

“…These results suggest that an increase in NHE-1 density could persist during the development of cardiomyopathy and continue to contribute to the development of cardiac lesions leading to HF and early death of HCMHs. These results are in agreement with various lines of evidence showing the involvement of NHE-1 in cardiac pathologies related to increases of [Na + ] i and [Ca 2+ ] i levels, such as in hypertrophy and HF leading to early death (Engelhardt et al 2002;Chahine et al 2005;Darmellah et al 2007;Baartscheer et al 2008;Karmazyn et al 2008Karmazyn et al , 1999. In line with the latter results, a recent study using a rabbit HF model showed that cariporide treatment for 2 months following the development of cardiac hypertrophy restored cardiomyocyte [Na + ] i and [Ca 2+ ] i handling, and reduced hypertrophy and signs of HF (Baartscheer et al 2008).…”

“…In these pathologies, overload of intracellular Na + ([Na + ] i ) was also reported (Meng and Pierce 1991;Bkaily and Jacques 1994;Karmazyn 2001;Karmazyn et al 2003;Chahine et al 2005;Cingolani and Ennis 2007), which could be due, in part, to an increase in Na + influx caused by upregulation of cardiac Na + -H + exchanger isoform-1 (NHE-1) activity (Meng and Pierce 1991;Karmazyn 2001;Karmazyn et al 2003;Cingolani and Ennis 2007). This sodium overload could consequently lead to a calcium overload due to the increased activity of the sodium-calcium exchanger (NCX) (Chahine et al 2005;Baartscheer et al 2008). Studies using animal models of HF (Yoshida and Karmazyn 2000;Engelhardt et al 2002;Loennechen et al 2002;Chen et al 2004;Baartscheer et al 2008;Karmazyn et al 2008) as well as isolated cardiomyocytes (Karmazyn et al 2003) have demonstrated the beneficial effect of NHE-1 blockade in preventing cardiac hypertrophy.…”

“…This sodium overload could consequently lead to a calcium overload due to the increased activity of the sodium-calcium exchanger (NCX) (Chahine et al 2005;Baartscheer et al 2008). Studies using animal models of HF (Yoshida and Karmazyn 2000;Engelhardt et al 2002;Loennechen et al 2002;Chen et al 2004;Baartscheer et al 2008;Karmazyn et al 2008) as well as isolated cardiomyocytes (Karmazyn et al 2003) have demonstrated the beneficial effect of NHE-1 blockade in preventing cardiac hypertrophy. In addition, the levels of angiotensin II (Ang II), which is a hypertrophic factor and an indirect activator of NHE-1 (Karmazyn 2001), were elevated during the development of HF (Nakamura et al 1994).…”

Silencing of Sodium–Hydrogen Exchanger 1 Attenuates the Proliferation, Hypertrophy, and Migration of Pulmonary Artery Smooth Muscle Cells via E2F1

“…Studies also showed that the inhibition of NHE1 by inhibitors attenuated the hypertrophy of cardiomyocytes (23)(24)(25)(26)(27). Because we also found a significant decrease in the medial wall thickness of pulmonary arteries in NHE1-deficient mice with decreased hypoxic pulmonary hypertension and vascular remodeling (11), we hypothesized that the effects of NHE1 on hypoxia-induced PASMC hypertrophy were also mediated via E2F1.…”

“…Studies indicated the relationship between NHE1 and myocardial hypertrophy, showing that the inhibition of NHE1 activity by inhibitors reduced cardiac hypertrophy in animals and cultured cardiomyocytes (23)(24)(25)(26)(27). The increased medial wall thickness of pulmonary arteries in pulmonary hypertension and vascular remodeling is involved not only in the proliferation of PASMCs, but also in the hypertrophy of PASMCs.…”