Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition

Abstract

Sodium/hydrogen exchange (NHE) inhibitors show promise as potential therapeutic agents for the treatment of heart failure, but it is not known whether they can reverse the maladaptive remodeling that results in heart failure. We sought to determine the effect of the NHE-1-specific inhibitor EMD-87580 (EMD) on heart failure produced by myocardial infarction in the rat and to assess whether up to 4 wk of treatment delay results in beneficial effects. Male Sprague-Dawley rats were subjected to coronary artery ligation (or a sham procedure) and followed for up to 3 mo, at which time hypertrophy and hemodynamics were determined. EMD was provided in the diet, and treatment commenced immediately or 2-4 wk after ligation. EMD significantly reduced hemodynamic abnormalities, including the elevation in left ventricular end-diastolic pressure, and diminished the loss of systolic function with all treatment protocols. Left ventricular dilatation and hypertrophy, as assessed by heart weight, cell size, and atrial natriuretic peptide (ANP) expression, were similarly reversed to sham or near-sham levels. In addition, the increased plasma ANP and pro-ANP values were reversed to levels not significantly different from sham. Surprisingly, virtually all beneficial effects were identical with all treatment protocols. These effects were observed in the absence of infarct size reduction or blood pressure-lowering effects. Our results suggest that NHE-1 inhibition attenuates and reverses postinfarction remodeling and heart failure with a treatment delay of up to 4 wk after infarction. The effect is independent of infarct size or afterload reduction, indicating a direct effect on the myocardium.

Elevated myocardial Na+/H+exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

“…A variety of stimuli can lead to cardiac hypertrophy, including elevated arterial blood pressure, myocardial infarction, valvular heart disease, and cardiomyopathy (23). NHE1 inhibition has been proven to prevent or induce regression of hypertrophy in several models of cardiac hypertrophy (6,7,18,19,32,35,40). However, it is still largely unknown by what mechanism(s) elevated NHE1 propagates hypertrophic injury, although a number of pathways have been proposed (20,44).…”

“…Hearts were fixed in 10% buffered formalin overnight, embedded in paraffin, and serially sectioned into 5-m slices (6,40). Samples were stained with hematoxylin and eosin (H & E) to evaluate gross morphology and cross-sectional area (CSA) or with picrosirius red to assess fibrosis (41).…”

Excitation-contraction coupling and mitochondrial energetics

“…The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212].…”

“…These defects, potentially aggravated by L-type Ca 2+ channel dysfunction [41,71,81,86,113,131,146,184] or t-tubular derangement [32,86,115,145,184] [17,81,113,115,146,184]. Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,…”

Effects of sabiporide, a specific Na+/H+ exchanger inhibitor, on neuronal cell death and brain ischemia

“…Accordingly, it is expected that the inhibition of NHE might contribute to protect the neuronal cells from excitotoxicity and ischemic injuries by preventing Ca 2+ overload in neuronal cells. There have been accumulating results that the inhibition of NHE has protective effects on cardiac ischemia [4,22]. It has been also reported that the brain ischemic injuries and/or neurotoxicity were attenuated by NHE inhibition in various experimental systems both in in vitro [10] and in vivo models [18].…”