Abstract 9578: Chronic Phosphodiesterase Type 5 Inhibition by Sildenafil Causes Regression of Heart Failure: Insights into Molecular and Cellular Mechanisms

Abstract

Background: Sildenafil (SIL), a selective inhibitor of PDE5 has been shown to exert profound beneficial effects in heart failure (HF). However, whether and by what mechanisms SIL can stop the progression of HF, or maybe even reverse the clinical route remain unknown. We tested the hypothesis that chronic SIL would improve intrinsic myocyte function and [Ca 2+ ] i regulation and reverse HF-induced detrimental alterations on cardiac SERCA2a, β-adrenergic receptors (AR) and nitric oxide synthase (NOS) isoforms, thus playing a salutary role in HF. Methods: We evaluated LV and myocyte function and the protein levels of myocyte β 1 - and β 3 - AR, SR Ca 2+ -ATPase (SERCA2a), phospholamban (PLB), and 3 NOS in 3 groups of male rats (8/group) for a period of 3 months (M): 1) HF , 3 M after receiving isoproterenol (ISO) (170 mg/kg sq for 2 days); 2) HF/SIL , 2 M after ISO, then SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and 3) Controls . Results: Versus C, ISO-treated rats progressed to severe HF at 3 M with significantly reduced LV contractility (E ES , 0.7 vs 1.1 mmHg/μl), and slowed LV relaxation. LV myocyte contraction (dL/dt max , 77 vs 136 μm/sec), relaxation (dR/dt max , 62 vs 104 μm/sec) and [Ca 2+ ] iT (0.15 vs 0.24) were significantly decreased accompanied by a diminished myocyte inotropic response to ISO (10 -8 M) superfusion. These abnormalities were associated with concomitant significant decreases in myocyte protein levels of β 1 -AR (0.23 vs 0.64), SERCA2a (0.46 vs 0.80), PLB Ser16 /PLB ratio, and eNOS (0.28 vs 0.46), but increased protein levels of β 3 -AR (0.23 vs 0.10) and iNOS (0.18 vs 0.08). Chronic SIL treatment prevented HF-caused reduced E ES (1.3 mmHg/μl) and EF (62%) and retained normal dL/dt max (131μm/s), dR/dt max (106 μm/s), and [Ca 2+ ] iT (0.24), and restored normal myocyte contractile response to ISO stimulation. With SIL, protein levels of myocyte β 1 - and β 3 -AR, SERCA2a were normalized to control values, but eNOS was significantly elevated (0.77). Conclusions: Chronic SIL prevents HF-caused downregulation of cardiac β 1 -AR and reverses contrast changes between iNOS and β 3 -AR with SERCA2a and eNOS expression, restores normal myocyte function, [Ca 2+ ] iT , and β-adrenergic reserve, and leads to regression of LV dysfunction in a rat model of progressive HF.