Myocardial Impact of NHE1 Regulation by Sildenafil

Abstract

The cardiac Na+/H+ exchanger (NHE1) is a membrane glycoprotein fundamental for proper cell functioning due its multiple housekeeping tasks, including regulation of intracellular pH, Na+ concentration, and cell volume. In the heart, hyperactivation of NHE1 has been linked to the development of different pathologies. Several studies in animal models that reproduce the deleterious effects of ischemia/reperfusion injury or cardiac hypertrophy have conclusively demonstrated that NHE1 inhibition provides cardioprotection. Unfortunately, NHE1 inhibitors failed to reproduce these effects in the clinical arena. The reasons for those discrepancies are not apparent yet. However, a reasonable clue to consider would be that drugs that completely abolish the exchanger activity, including that its essential housekeeping function may not be the best therapeutic approach. Therefore, interventions tending to specifically reduce its hyperactive state without affecting its basal activity emerge as a novel potential gold standard. In this regard, a promising goal seems to be the modulation of the phosphorylation state of the cytosolic tail of the exchanger. Recent own experiments demonstrated that Sildenafil, a phosphodiesterase 5A inhibitor drug that has been widely used for the treatment of erectile dysfunction is able to decrease NHE1 phosphorylation, and hence reduce its hyperactivity. In connection, growing evidence demonstrates cardioprotective properties of Sildenafil against different cardiac pathologies, with the distinctive characteristic of directly affecting cardiac tissue without altering blood pressure. This mini-review was aimed to focus on the regulation of NHE1 activity by Sildenafil. For this purpose, experimental data reporting Sildenafil effects in different animal models of heart disease will be discussed.

From Diabetes Care to Heart Failure Management: A Potential Therapeutic Approach Combining SGLT2 Inhibitors and Plant Extracts

“…In rodent and rabbit models of diabetes [29], the inhibition of NHE-1 by SGLT2i and modulation of intramyocardial Ca 2+ and Na + fluxes seem to have a beneficial impact on diastolic myocardial function [29,30]. This effect can be connected to enhanced SERCA activity and to antifibrotic effects [31,32].…”

Na+/H+ Exchanger 1, a Potential Therapeutic Drug Target for Cardiac Hypertrophy and Heart Failure

“…In the heart, the exacerbated activity of NHE1 has been associated with pathological cardiac processes. In several animal models which reproduce the detrimental effects of ischemia-reperfusion injury (IRI) or cardiac hypertrophy, NHE1 inhibition is demonstrated to be cardioprotective [ 18 ]. Extensive studies have investigated the role of NHE1 in cardiac hypertrophy and heart failure, which indicates that NHE1 may serve as a potential drug target.…”