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.

• Authors: Ling Chen, Chang Xun Chen, Xiaohong Tracey Gan, Norbert Beier, Wolfgang Scholz, Morris Karmazyn
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 286 Issue 1 Pg. H381-7 (Jan 2004) ISSN: 0363-6135 [Print] United States
• PMID: 14684366 (Publication Type: Journal Article)

Chemical References

• Guanidines
• N-(2-methyl-4,5-bis(methylsulfonyl)benzoyl)guanidine
• Sodium-Hydrogen Exchangers
• Sulfones
• growth factor-activatable Na-H exchanger NHE-1

Topics

• Animals
• Body Weight (drug effects)
• Cardiac Output, Low (etiology, physiopathology, prevention & control)
• Cardiomegaly (etiology, pathology, physiopathology, prevention & control)
• Cell Line
• Coronary Disease (mortality)
• Guanidines (blood, pharmacology)
• Hemodynamics
• Male
• Mice
• Myocardial Infarction (complications, pathology)
• Myocardium (pathology)
• Myocytes, Cardiac
• Osmolar Concentration
• Rats
• Rats, Sprague-Dawley
• Sodium-Hydrogen Exchangers (antagonists & inhibitors)
• Sulfones (blood, pharmacology)