Mini review: Myocardial impact of NHE1 regulation by Sildenafil

ESCUDERO, DAIANA S.; PEREZ, NESTOR G.; DIAZ, ROMINA G.

Frontiers in Cardiovascular Medicine

Frontiers Media SA

Lugar: Lausanne; Año: 2021

The cardiac Na+/H+ exchanger (NHE1) is a membrane glycoprotein fundamental forproper cell functioning due its multiple housekeeping tasks including regulation ofintracellular pH, Na+ concentration, and cell volume. In the heart, hyperactivation ofNHE1 has been linked to the development of different pathologies. Several studies inanimal models that reproduce the deleterious effects of ischemia/reperfusion injury orcardiac hypertrophy have conclusively demonstrated that NHE1 inhibition providescardioprotection. Unfortunately, NHE1 inhibitors failed to reproduce these effects inthe clinical arena. The reasons for those discrepancies are not apparent yet. However,a reasonable clue to consider would be that drugs that completely abolish theexchanger activity including its essential housekeeping function may not be the besttherapeutic approach. Therefore, interventions tending to specifically reduce itshyperactive state without affecting its basal activity emerge as a novel potential goldstandard. In this regard, a promising goal seems to be the modulation of thephosphorylation state of the cytosolic tail of the exchanger. Recent own experimentsdemonstrated that Sildenafil, a Phosphodiesterase 5A inhibitor drug that has beenwidely used for the treatment of erectile dysfunction, is able to decrease NHE1phosphorylation and hence, to reduce its hyperactivity. In connection, growingevidence demonstrates cardioprotective properties of Sildenafil against differentcardiac pathologies, with the distinctive characteristic of directly affecting cardiactissue without altering blood pressure. This mini-review was aimed to focus on theregulation of NHE1 activity by Sildenafil. For this purpose, experimental data reportingSildenafil effects in different animal models of heart disease will be discussed.