319
to respiratory functional parameters, higher PaO 2 and lung diffusing capacity at rest
and during maximal exercise were described after ExT in hypoxia-induced PAH [ 24 ].
Concerning to vascular function, a single bout of exercise was able to transiently nor-
malize PAP in MCT-induced PAH, revealing an exercise-induced “window” of pulmo-
nary hypertension alleviation [ 67 ]. This effect was associated with increased lung
nitric oxide synthase (eNOS) activation, supporting a mechanism of acute NO-mediated
pulmonary vasodilatation [ 67 ]. A greater increase in total eNOS expression was also
observed after chronic HIIT, paralleled by a decrease in total PVR [ 30 ]. In contrast,
eNOS expression and activity was reduced in lung tissue homogenates after less
intense but continuous ExT [ 30 , 35 ]. The exposure of the pulmonary vasculature to a
pulsatile flow-shear stimulus was proposed to explain the greater levels of eNOS
obtained with HIIT [ 30 ]. In hypoxia-induced PAH, despite decreasing small pulmonary
vessel muscularization, chronic exercise failed to properly modulate the nitric oxide
synthase-soluble guanylyl cyclase-cyclic guanosine monophosphate-phosphodiester-
ase (NOS-sGC- cGMP-PDE) axis (at the mRNA level), in order to promote vasodilation
[ 84 ]. Moreover, ExT failed to improve pulmonary artery vascular reactivity in hypoxia-
induced PAH, as the responsiveness to vasoconstrictor (ET-1, epinephrine or potassium
chloride) or vasodilator (acetylcholine or sodium nitro-prusside) substances remained
increased and decreased, respectively, as in their sedentary counterparts [ 85 ]. The dif-
ferences in the animal models as well as in the exercise training protocols (imposing
variable flow-mediated shear force) may partially explain the different results. Besides
NO pathway, ExT was shown to increase H 2 O 2 /VEGF/p-Akt axis in the lungs of MCT
rats after training [ 32 ], suggesting a beneficial role of exercise in angiogenesis and col-
lateral blood flow. However, no change in RV afterload estimated by AT/ET ratio was
noted. Figure 17.3 summarizes the main changes modulated by ExT in the lungs.
5 Conclusion
Despite the obvious differences between animal models and exercise training pro-
grams, the available pre-clinical data consistently signal a beneficial effect of ExT
on RV function in PAH that is mainly dependent on the stage of the disease, exercise
intensity and mode. These benefits occurred even in the presence of persistent RV
afterload and were associated with the development of an adaptive cardiac pheno-
type. Regarding the impact of ExT on the lungs, the evidence is very limited and it
is not clear if exercise improves pulmonary vascular resistance through NO-mediated
pulmonary vasodilatation, modulation of pulmonary artery architecture or both.
Acknowledgment QOPNA and CIAFEL research units are supported by Fundação para a Ciência
e Tecnologia (FCT), European Union, QREN, FEDER and COMPETE (UID/QUI/00062/2013 and
UID/DTP/00617/2013, respectively). DMG and RNF received an individual grant from the same
organization (SFRH/BPD/90010/2012 and SFRH/BD/91067/2012, respectively).
17 Exercise Training in Pulmonary Hypertension and Right Heart Failure: Insights...