Abstract 15848: Restoration of Normal Cardiomyocyte Basal and β-Adrenergic Receptor (AR) Subtype Modulation in Heart Failure by Chronic Phosphodiesterase Type 5 Inhibition With Sildenafil

Abstract

Background: We have shown that Sildenafil (SIL), a selective PDE5 inhibitor reversed left ventricular (LV) dysfunction and β- adrenergic receptors (AR) desensitization in heart failure (HF). However the mechanism is not yet clear. Recent evidence suggests that normal myocardial performance depend on the balance in cardiomyocyte β 3 -, β 1 -, and β 2 -AR. Pivotal restructuring of β-AR system resulting in decline of β-adrenergic reserve plays a crucial role in the development of HF. We assessed the hypothesis that chronic SIL would prevent HF-induced abnormalities of β-AR subtype-stimulated regulation on intrinsic LV myocyte function and [Ca 2+ ] i regulation, thus restoring cardiac function. Methods: Studies were conducted in 3 groups (10/group) of rats: 1) HF, 12 weeks (W) after receiving isoproterenol (ISO) (170 mg/kg sq for 2 days); 2) HF/SIL, 8W after receiving ISO, SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and 3) controls. After 12W, we compared LV myocyte contractile and [Ca 2+ ] iT responses to β-AR subtype stimulation by random exposure of myocytes to ISO (10 -8 M) or a selective β 1 -, β 2 -, or β 3 -agonist, Norepinephrine (NE, 10 -7 M), Zinterol (ZIN, 10 -5 M) and BRL-37,344 (BRL, 10 -8 M), respectively, during drug superfusion. Results: Only ISO-treated rats had HF showed 46% decreased LV contractility (E ES ) and extensive LV myocardium fibrosis. Compared with normal myocytes (N), in HF myocytes, basal cell contractility (dL/dt max , HF: 77 vs N: 136 μm/s), relaxation and [Ca 2+ ] iT all significantly decreased. ISO-stimulated dL/dt max (31% vs 67%) was attenuated accompanied by a diminished NE-mediated increase in dL/dt max (13% vs 49%), but enhanced BRL-induced decreases in dL/dt max (-29% vs -16%).The response of dL/dt max (25% vs 15%) to ZIN was increased. Importantly, in HF/SIL myocytes, the basal dL/dt max (139 μm/s) and [Ca 2+ ] iT remained close to control values with preserved β-stimulated positive modulation on cell contraction. The increases in dL/dt max in response to ISO (70%) and NE (44%) were similar as in normal myocytes, but repose to ZIN (27%) was enhanced. Conclusions: Chronic SIL reverses β-adrenergic signaling defects, resensitizing the β-AR subtype system modulation on LV myocytes function, thus playing a salutary role in HF.