Abstract 18972: Inhibition of Ca2+/Calmodulin-Dependent Phosphodiesterase1A Restores Right Ventricular Dysfunction in Experimental Pulmonary Hypertension
Rationale: In pulmonary hypertension (PH), right ventricular hypertrophy (RVH) develops as a compensatory mechanism to maintain cardiac functions in response to chronic increase in pressure overload and transits to heart failure in the late stage. Phosphodiesterase1A (PDE1A), a Ca2+/calmodulin-activated PDE, plays critical roles by degrading cAMP and cGMP in pulmonary vasculature. However, its cardiac function is unknown. Hereby we aimed to explore if PDE1A is a modulator in governing RV disabilities secondary to PH.
Methods and Results: RVH was developed using a 5-week monocrotaline (MCT)-induced pulmonary hypertensive rat model. In RVH myocytes, PDE1A was 8.7-fold upregulated on mRNA level and 4.8-fold upregulated on protein level detected by quantitative real-time PCR and western blot. At day 21, PH rats were randomized to receive a selective PDE1 inhibitor (PF1141) or vehicle by intravenous infusion. At day 35, cardiopulmonary parameters were monitored noninvasively by echocardiography. In addition to 50%; reversing effect on PH, PF1141 (300ng/kg/min and 750ng/kg/min) dose-dependently raised cardiac output (ml/min) to 61.2±4.1 (P<0.005) and 71.4±5.6 (P<0.01), tricuspid annular plane systolic excursion (mm) to 2.07±0.09 (P<0.01) and 2.45±0.08 (P<0.001), and reduced right ventricular dimension (mm) to 3.85±0.18 (P<0.05) and 3.44±0.07 (P<0.01), as compared to placebo (43.3±2.5, 1.66±0.07, 4.46±0.23, respectively). Furthermore, PF1141 (300ng/kg/min and 750ng/kg/min) markedly prevented RVH with decreased RV/LV+Septum weight ratio from 0.67±0.03 in placebo to 0.51±0.03 (P<0.01) and 0.39±0.04 (P<0.001), RV myocyte size (μm2) from 656±34 in placebo to 455±19 (P<0.001) and 357±18 (P<0.001), and mRNA expression of hypertrophic markers. More importantly, cell shortening (dL/L%;, normalized to diastolic cell length) was lessoned from 8.1±0.2 to 6.4±0.2 with RVH myocytes and raised to 7.6±0.1 (P<0.001, 70%; restore of the pathological reduction on contractility) when exposed to PF1141.
Conclusions: Inhibition of PDE1A not only improves pulmonary function, but also normalizes cardiac performance. This study demonstrates a critical role of PDE1A in RV functions and offers a novel therapeutic approach for the RV dysfunction secondary to PH.
- © 2010 by American Heart Association, Inc.