Phosphodiesterase 5A Inhibition Induces Na ⁺ /H ⁺ Exchanger Blockade and Protection Against Myocardial Infarction

Abstract

Abstract-Acute phosphodiesterase 5A inhibition by sildenafil or EMD360527/5 promoted profound inhibition of the cardiac Na ϩ /H ϩ exchanger (NHE-1), detected by the almost null intracellular pH recovery from an acute acid load (ammonium prepulse) in isolated papillary muscles from Wistar rats. Inhibition of phosphoglycerate kinase-1 (KT5823) restored normal NHE-1 activity, suggesting a causal link between phosphoglycerate kinase-1 increase and NHE-1 inhibition. We then tested whether the beneficial effects of NHE-1 inhibitors against the deleterious postmyocardial infarction (MI) remodeling can be detected after sildenafil-mediated NHE-1 inhibition. MI was induced by left anterior descending coronary artery ligation in Wistar rats, which were randomized to placebo or sildenafil (100 mg kg Ϫ1 day Ϫ1 ) for 6 weeks. Sildenafil significantly increased left ventricular phosphoglycerate kinase-1 activity in the post-MI group without affecting its expression. MI increased heart weight/body weight ratio, left ventricular myocyte cross-sectional area, interstitial fibrosis, and brain natriuretic peptide and NHE-1 expression. Sildenafil blunted these effects. Neither a significant change in infarct size nor a change in arterial or left ventricular systolic pressure was detected after sildenafil. MI decreased fractional shortening and the ratio of the maximum rate of rise of LVP divided by the pressure at the moment such maximum occurs, effects that were prevented by sildenafil. Intracellular pH recovery after an acid load was faster in papillary muscles from post-MI hearts (versus sham), whereas sildenafil significantly inhibited NHE-1 activity in both post-MI and sildenafil-treated sham groups. We conclude that increased phosphoglycerate kinase-1 activity after acute phosphodiesterase 5A inhibition blunts NHE-1 activity and protects the heart against post-MI remodeling and dysfunction.

Gender differences in cardiac left ventricular mass and function: Clinical and experimental observations

“…LV weight was divided by tibial length to determine the LVMI. In 2 rats out of each group ventricular tissue was fixed in buffered 10% formaldehyde and paraffin embedded to stain with picrosirius red for determining collagen volume fraction as previously described [17]. Perivascular collagen was excluded from this measurement.…”

Hydrogen Sulfide Regulates Na+/H+ Exchanger Activity via Stimulation of Phosphoinositide 3-Kinase/Akt and Protein Kinase G Pathways

“…Because activation of PI3K/Akt (Snabaitis et al, 2008) or PKG (Pérez et al, 2007) inhibits NHE-1 activity, we examined whether the effect of H 2 S involves these pathways. As shown in Fig.…”

Decreased Activity of the Na + /H + Exchanger by Phosphodiesterase 5A Inhibition Is Attributed to an Increase in Protein Phosphatase Activity

“…This is in line with our previous results in which PDE5A inhibition after coronary artery ligation significantly ameliorated postmyocardial remodeling and left ventricular dysfunction in rats. 16 It is important to note that NHE-1 inhibition through SIL seems not to influence cardiac function and growth under basal conditions, probably limiting by this way potential undesired effects. Based on our previous and present findings, as well as those from others, 13,15,37,38 PDE5A inhibition seems to emerge as an important therapeutic target.…”

“…In a recent study we reported a possible link between both therapeutic strategies: chronic treatment with SIL improved postmyocardial infarction remodeling and function through PKGdependent inhibition of the NHE-1. 16 However, other cellular targets have been also proposed to underlie the cardioprotective effect of SIL. 15,36 In the present study we provide insight into the intracellular pathway involved in the NHE-1-inhibitory effect of SIL, supporting a critical role of PP1 in NHE-1 dephosphorylation and inhibition.…”

“…Interestingly, we recently demonstrated that the beneficial effect exerted by PDE5A inhibition, on postmyocardial infarction remodeling in rats, was accompanied by a PKG-dependent inhibition of NHE-1 activity. 16 It was also reported that, in renal mesangial cells, an increase in PKG activity induced NHE-1 inhibition during recovery from an acidic load. 17 The present study was designed to gain further insight into the cellular mechanism involved in the induction of NHE-1 inhibition by PDE5A inhibition.…”