Chronic Inhibition of Na+/H+-Exchanger in the Heart

Antonius      Baartscheer

Abstract

The incidence and prevalence of heart failure (HF) has increased over the last decades. The main reasons for this increase are the ageing population and an increase in survival rate after myocardial infarction and other cardiovascular diseases. Although, pharmacotherapy has significantly improved survival, the prognosis of HF is still rather poor. Total mortality is high and approximately half of the deaths are sudden and unexpected. Angiotensin-converting-enzyme (ACE)-inhibitors generally given with diuretic and digoxin are the standard treatment for patients with HF. Despite the established benefits of ACE-inhibitors there is a need for new pharmacological tools for the treatment of HF. Recent experimental evidence has shown that activity of the Na+/H+-exchanger in the heart (NHE-1) is increased in HF. Because NHE-1 exchanges intracellular H+ for extracellular Na+ in a one by one stoichiometry, the intracellular ionic changes resulting from increased activity, will be a increased pHi and intracellular sodium ([Na+]i). Activation of NHE-1 results only in a small increase in pHi, under physiological conditions where bicarbonate-dependent mechanisms are active. However, a considerable increase in [Na+]i was always present. The elevation of [Na+]i might be responsible for the increase of intracellular calcium ([Ca2+]i) levels mediated by the Na+/Ca2+-exchanger (NCX). Increases in [Na+]i, pHi and [Ca2+]i, features of cardiac myocytes isolated from failing hearts, are recognized as a cell growth signal And thus may play a role in the hypertrophic response, cellular remodeling and finally the development of HF. Acute application of cariporide, an inhibitor of NHE-1, on failing myocytes not only normalized [Na+]i but also cytoplasmic and sarcoplasmic reticulum calcium handling and the propensity to develop delayed after depolarizations (DADs). In several animal models of HF it has been shown the chronic inhibition of NHE-1 attenuates the development of hypertrophy and whole heart remodeling. Recently, in a volume and pressure overload model of HF in rabbits it has been demonstrated that chronic treatment also prevents the development of HF and cellular ionic and electrophysiological remodeling. Therefore, chronic treatment with an inhibitor of NHE-1 might prove beneficial in patients at risk of developing HF, especially when given at an early stage.

Keywords: Pathophysiology, heart failure, hypertrophy, remodeling, Na/H-exchanger, cariporide, sodium, pH