Phosphodiesterase 5A inhibition induces Na+/H+ exchanger blockade and protection against myocardial infarction.

PEREZ NG; PIAGGIO MR; ENNIS IL; GARCIAREA CD; MORALES C; ESCUDERO EM; CINGOLANI OH; CHIAPPE DE CINGOLANI GE; YANG XP; CINGOLANI O

HYPERTENSION

Lippincott Williams & Wilkins

Año: 2007 vol. 49 p. 1095 - 1103

0194-911X

Acute phosphodiesterase 5A (PDE5A) inhibition by sildenafil or EMD360527/5 promoted profound inhibition of the cardiac Na+/H+ exchanger (NHE-1), detected by the almost null pHi recovery from an acute acid load (ammonium prepulse) in isolated papillary muscles from Wistar rats. Inhibition of PKG-1 (KT5823) restored normal NHE-1 activity, suggesting a causal link between PKG-1 increase and NHE-1 inhibition. We then tested if the beneficial effects of NHE-1 inhibitors against the deleterious post myocardial 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 (100mg·kg–1·day–1) for six weeks. Sildenafil significantly increased left ventricular PKG-1 activity in the post-MI group without affecting its expression. MI increased heart weight to 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 in arterial or left ventricular systolic pressure was detected after sildenafil. MI decreased fractional shortening and the (+dP/dt)/P ratio, effects which were prevented by sildenafil. pHi recovery after an acid load was faster in papillary muscles from post-MI hearts (vs. sham) while sildenafil significantly inhibited NHE-1 activity in both post-MI and sildenafil-treated sham groups. We conclude that increased PKG-1 activity after PDE5A inhibition blunts NHE-1 activity and protects the heart against post-MI remodeling and dysfunction.