Abstract 2105: Selective Modulation Of ANP-Dependent Dilation In The Pulmonary Vasculature By PDE 5 Inhibitors: A Novel Combination Therapy For Pulmonary Hypertension?
BACKGROUND Pulmonary hypertension (PH) has a high mortality, in part because of the paucity of pulmonary-specific vasodilators. We have shown previously that the phosphodiesterase (PDE) 5 inhibitor Sildenafil (SILD) augments dilation to atrial natriuretic peptide (ANP) in the pulmonary, but not systemic, vasculature. This suggests that cGMP-mediated vasodilation by ANP is regulated by PDE 5 specifically in the pulmonary vascular bed, and herein we have investigated whether modulation of the natriuretic peptide system might beneficial in the treatment of PH.
METHODS Male Sprague-Dawley rats were pre-treated with Ecadotril (ECAD; neutral endopeptidase inhibitor; blocks ANP hydrolysis) 60mg/kg/day by gavage, SILD 30mg/kg/day in the drinking water, or a combination of both, and subjected to 2 weeks of hypoxia (10% oxygen) to induce PH. Hypoxic and normoxic controls were also included. At 2 weeks, pulmonary, right ventricular and systemic pressures were determined by fluid filled catheterisation in anaesthetised animals, which were then euthanised and hearts and lungs excised for further analysis.
RESULTS Untreated hypoxic animals showed elevated mean pulmonary artery pressure (PAP; 28.9±2.2 mmHg) as compared to normoxia controls (18.44±1.9 mmHg; P<0.05). Both SILD- (24.07±0.5mmHg) and ECAD- (25.45±1.4mmHg) treated animals showed a reduction in PAP with a further drop (21.27±1.4mmHg; P<0.05) in the SILD ± ECAD group. Similarly, hypoxia-induced increases in right ventricular systolic pressure were reversed by SILD ± ECAD. However, systemic blood pressure was unchanged in all groups. Hypoxia resulted in right ventricular hypertrophy (increased right to left ventricle weight ratio) in control animals (0.50±0.10) versus normoxia (0.27±0.01), and this was attenuated by all treatments (SILD 0.40±0.01, ECAD 0.42±0.01, SILD ± ECAD 0.37±0.01; P<0.05). Vascular remodelling in the lung (% muscularised vessels) was also reduced by each treatment. Finally, combination treatment increased plasma cGMP levels that correlated strongly with reduced PAP (r=−0.77).
CONCLUSIONS These data suggest that SILD plus ECAD has a synergistic effect to selectively lower PAP in PH. This combination treatment is likely to have therapeutic benefit in treating PH.