Abstract 13200: Acute Inhibition of Phosphodiesterase Type 5A (PDE5) with Sildenafil Augments Contractility of LV and Myocyte in Heart Failure

Abstract

Background: Sildenafil (SIL), a selective inhibitor of cGMP-specific PDE5 has been shown to exert profound cardioprotection in various cardiac pathologies. This beneficial action has been attributed to its selective vasodilatation effect. However, recent studies indicate that SIL may augment cGMP signaling and produce direct cardiac inotropic modulation, thus affords its cardioprotection in heart failure (HF). Whether SIL plays a role in cardiac contractile behavior in HF remains undetermined. SIL has been reported variably to have a positive, negative or no inotropic effect on cardiac contractility in HF. These disparate observations may be due to the confounding effects of loading conditions and dosage of SIL. We tested the hypothesis that SIL evokes positive modulation on cardiac contractility which importantly contributes to its beneficial action in HF. Methods: We measured Left ventricular (LV) contractility changes after SIL (0.4 mg/kg, iv), and compared myocyte contractile and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses to SIL (10 -6 M) in 8 rats with isoproterenol (ISO)-induced HF (3 months after 170 mg/kg sq for 2 days). LV contractility was measured by pressure-volume analysis. Results: Compared with normal controls, ISO-treated rats had established HF after ISO at 3 months with significantly elevated plasma norepinephrine, LV dilatation, and decreased ejection fraction (EF, 29% vs 61%). Compared with baseline, acute administration of SIL caused no change in LV systolic blood pressure and heart rate, but increased EF (43% vs 29 %). LV time constant of relaxation (t) (12.2 vs 15.1 ms) decreased. The slopes of LV pressure-volume relations of E ES (49%, 0.92 vs 0.61 mmHg/μl) and M SW (42%, 97.4 vs 68.6 mmHg) were increased, indicating significantly enhanced LV contractility. These responses were accompanied with about 24% increases in cell contraction (dL/dt max , 97.1 vs 78.3 μm/s) and relaxation (dR/dt max , 63.7 vs 51.5 μm/s) and relatively unchanged [Ca 2+ ] iT (0.149 vs 0.137), while myocyte Ca 2+ sensitivity was enhanced. Conclusions: In HF, positive inotropic effect is induced by acute inhibiting PDE5 with clinically-relevant concentrations of SIL. The cardiostimulatory and vasodilatory actions of SIL make it suitable for the treatment of HF.