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.

Keywords: NHE1; PDE5A; cardiac mechanism; intracellular pathways; sildenafil.

Figure 1

Inhibition of NHE1 activity by Sildenafil. Original traces (thin lines) and its regression approximations (thick lines) of the recovery of pH_i after 10 min of sustained acidosis in Control (absence of Sildenafil); 1 mM Sildenafil (SIL); 1 mM Sildenafil plus 10 μM of the p38MAPK inhibitor SB202190 (SIL+SB); and Sildenafil plus 1 nM of Okadaic Acid (SIL+OKA) used to selectively inhibit PP2A. Sildenafil blunted pH_i recovery after the acidic challenge, an effect that was reverted either by p38MAPK or PP2A inhibition. Adapted from Díaz et al. (59) with permission from Elsevier.

Figure 2

Putative mechanism of cardiac actions of Sildenafil following acute or chronic treatment. Left panel: Acute Sildenafil effects comprise the classical action on BK_Ca channels, and the novel cGMP/PKG mediated NHE1 dephosphorylation and inactivation [Adapted from Díaz et al. (59) with permission from Elsevier] involving a sequential activation of p38MAPK and PP2A. Right panel: Chronic Sildenafil effects includes inhibition of TRPC and L-type Ca⁺² channels, and prevention of NHE1 hyperactivation, all together leading to a decrease in the Ca⁺² overload-triggered calcineurin/NFAT deleterious pathway. Furthermore, mitochondrial actions of Sildenafil involving mBK_Ca channel opening, mNHE1 inhibition, and membrane potential maintenance reduce the probability of MPTP opening and ROS release, contributing to cardioprotection.