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(Hypertension. 2007;49:1095.)
© 2007 American Heart Association, Inc.

Original Articles

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

Néstor G. Pérez; Martín R. Piaggio; Irene L. Ennis; Carolina D. Garciarena; Celina Morales; Eduardo M. Escudero; Oscar H. Cingolani; Gladys Chiappe de Cingolani; Xiao-Ping Yang; Horacio E. Cingolani

From the Centro de Investigaciones Cardiovasculares (N.G.P., M.R.P., I.L.E., C.D.G., E.M.E., G.C.d.C., H.E.C.), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina; Instituto de Fisiopatología Cardiovascular (C.M.), Departamento de Patología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; the Department of Medicine (O.H.C.), Reading Hospital and Medical Center, West Reading, Pa; and the Hypertension and Vascular Research Division (X-P.Y.), Department of Internal Medicine, Henry Ford Hospital, Detroit, Mich.

Correspondence to Horacio E. Cingolani, Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, UNLP, 60 y 120 (1900) La Plata, Argentina. E-mail cicmes{at}infovia.com.ar

Acute phosphodiesterase 5A inhibition by sildenafil or EMD360527/5 promoted profound inhibition of the cardiac Na⁺/H⁺ 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^–1 day^–1) 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.

Key Words: basic science • membrane transport/ion channels • hypertrophy/remodeling • physiology/function • myocardial infarction • Na⁺/H⁺ exchanger • PDE5A inhibition