Abstract 15295: Molecular Mechanism of Chronic Sildenafil-Caused Regression of Heart Failure: Effects on the Express of Cardiac SR Ca2+-ATPase, Subtype of β-Adrenergic Receptors and Nitric Oxide Synthase Isoforms
Background: Sildenafil (SIL), a selective inhibitor of PDE5 has been shown to exert profound beneficial effects in heart failure (HF). Recently we further found that SIL caused regression of cardiac dysfunction in a rat model with isoproterenol (ISO)-induced progressive HF. However, the molecular basis is unclear. We hypothesized that reversal of HF-induced detrimental alterations on the expressions of cardiac SR Ca2+-ATPase (SERCA2a), β-adrenergic receptors (AR) and nitric oxide synthase (NOS) isoforms by SIL may play a key role for its salutary role in HF.
Methods: Left ventricular (LV) and myocyte function and the protein levels of myocyte β1- and β3- AR, SERCA2a, phospholamban (PLB) and three NOS were simultaneously evaluated in 3 groups of male rats (6/group): HF, 3 months (M) after receiving ISO (170 mg/kg sq for 2 days); HF/SIL, 2 M after receiving ISO, SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and Controls (C).
Results: Compared with controls, ISO-treated rats progressed to severe HF at 3 M after ISO followed by significantly decreased LV contractility (EES, HF: 0.7 vs C: 1.2 mmHg/μl) and slowed LV relaxation, reductions in the peak velocity of myocyte shortening (77 vs 136 μm/sec), relengthening (62 vs 104 μm/sec) and [Ca2+]iT (0.15 vs 0.24) accompanied by a diminished myocyte inotropic response to β-AR agonist, ISO (10-8 M). These abnormalities were associated with concomitant significant decreases in myocyte protein levels of β1-AR (0.23 vs 0.64), SERCA2a (0.46 vs 0.80), PLBSer16/PLB ratio (0.24 vs 0.40) and eNOS (0.28 vs 0.46), but significantly increases in protein levels of β3-AR (0.29 vs 0.10) and iNOS (0.18 vs 0.08) with relatively unchanged nNOS. Chronic SIL prevented the HF-induced decreases in LV and myocyte contraction, relaxation, peak [Ca2+]iT, and restored normal myocyte contractile response to ISO stimulation. With SIL, protein levels of myocyte β1- and β3-AR, SERCA2a were restored close to control values, but eNOS was significantly elevated than controls (0.77).
Conclusions: Chronic SIL prevents HF-caused downregulation of cardiac β1-AR and reverse contrast changes between iNOS and β3-AR with SERCA 2a and eNOS expression, leading to the preservation of LV and myocyte function, [Ca2+]iT, and β-adrenergic reserve.
Author Disclosures: H. Cheng: None. T. Li: None. C. Cheng: None.
- © 2014 by American Heart Association, Inc.