Abstract
Introduction: Low aerobic exercise capacity has been linked with a higher probability of death. We have previously demonstrated that low exercise capacity rats have increased susceptibility to pulmonary arterial hypertension when subjected to chronic hypoxia. Here we investigate the role of 5-HT in conferring susceptibility.
Methods: We exposed high and low exercise capacity rats to a 10% O2 environment for 21 days, +/- daily treatment with a 5-HT inhibitor (pCPA). The animals, bred over 21 generations for high (HCR) or low (LCR) running capacity, differ by 500%. PAH biomarkers were determined in heart, lung and blood.
Results: LCR rats developed significantly greater PAH pathologies compared to HCR with regard to cardiac and pulmonary vessel remodeling, right ventricular (RV) pressure and echocardiographic measures. Cardiac histology demonstrated pCPA treatment ablated the RV hypertrophic response and myocyte apoptosis in both HCR and LCR animals. 5-HT levels in LCR animals were increased in response to hypoxia, yet unchanged in other groups, and levels in both strains were ablated by pCPA treatment. Although pCPA effected reduction in all PAH pathologies in all groups, subtractive analysis revealed no impact on the enhanced vessel remodeling and only a partial effect on RV pressure observed in LCR animals. RV mass and echocardiographic measures of RV function, however, were fully reversed.
Conclusion: These data support our hypothesis that intrinsically low aerobic capacity may predispose individuals to developing pulmonary arterial hypertension, and that the associated dysregulation of the 5-HT pathway principally impacts RV function rather than vessel remodeling.
- © 2011 ERS