Abstract 11545: Mechanism of Chronic Phosphodiesterase Type 5 Inhibition-Caused Regression of Heart Failure: Beneficial Effects of Left Ventricular and Myocyte Function, [Ca2+]i Regulation and Beta-Adrenergic Modulation
Background: Phosphodiesterase type 5 (PDE5) inhibition (I) has been shown to exert profound beneficial effects in heart failure (HF). However, the mechanisms are not completely understood. It remains unknown as to whether PDE5 I also exerts a direct protective effect in the cardiomyocytes independent of its vascular/hypotensive effect or presence of other cell types in HF. We tested the hypothesis that chronic PDE I with sildenafil (SIL) would improve intrinsic left ventricular (LV) myocyte function and [Ca2+]i regulation, thus playing a salutary role in HF.
Methods: Plasma levels of norepinephrine (NE), LV and myocyte functional responses were compared in 3 groups of rats (8/group) for a period of 3 months (M): 1) isoproterenol (ISO)-treated, 3 M after receiving ISO (170 mg/kg sq for 2 days); 2) HF/SIL, 2 M after receiving ISO, then SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and 3) controls.
Results: Compared with controls, ISO-treated rats had HF onset at 1 M after ISO and progressed to HF at 3 M with about 5-fold elevated plasma NE (1158 vs 227 pg/ml) and LV dilatation associated with increased myocyte length (ML, 149 vs 117 μm). Ejection fraction (31% vs 60%) and LV contractility (EES, 0.7 vs 1.1 mmHg/μl) were decreased. LV time constant of relaxation (τ) (16.4 vs 11.0 ms) was increased accompanied with about 40% reduction in cell contraction (dL/dtmax, 77 vs 136 μm/s), relaxation (dR/dtmax, 62 vs 104 μm/s) and decreased [Ca2+]i transient ([Ca2+]iT) (0.16 vs 0.24). HF myocyte response to β-AR stimulation (ISO, 10-8 M) was attenuated with significantly less increases in dL/dtmax (32% vs 79%) and [Ca2+]iT (18% vs 34%). Treatment with SIL caused no change in LV systolic blood pressure and heart rate, but increased EES (1.3 mmHg/μl) and EF (62%), decreased τ (8.9 ms) and corrected the elevation of plasma NE (199 pg/ml) with retained normal ML (119 μm), dL/dtmax (131μm/s), dR/dtmax (106 μm/s), and [Ca2+]iT (0.24). ISO-induced increases in dL/dtmax (74%), dR/dtmax and [Ca2+]iT also returned close to normal levels.
Conclusions: Chronic sildenafil prevents HF-induced sympathetic nervous system activation, restores normal myocyte basal and β-AR stimulated contraction and relaxation, and leads to regression of LV dysfunction in a rat model of progressive HF.
- © 2013 by American Heart Association, Inc.