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shown that response to exogenous nitric oxide and a cGMP analogue, 8-Br-cGMP,
is impaired in resistance pulmonary arterioles of the CDH animals. Of note,
pretreatment of CDH resistance pulmonary arterioles with the PDE5 inhibitor
zaprinast completely restored their vasodilatory response to 8-Br-cGMP (Vukcevic
et al.
2005
), suggesting that PDE5 may also be involved with the pathogenesis of
pulmonary hypertension in the infant with CDH.
1.3 Pathophysiology of Pulmonary Hypertension in the Older
Infant
There are two other major classes of infants who develop pulmonary hypertension -
former preterm infants who develop pulmonary hypertension as a result of their
underlying lung disease and infants, both term and preterm, who develop pulmo-
nary hypertension as a result of their congenital heart disease. In both cases, the
disease process begins during the neonatal period, but symptoms may not become
manifest until the infant is several months old. Further, the resulting pulmonary
hypertension is not only a disease of altered vasoreactivity, but it also involves
significant vascular remodeling. The role of PDEs in the pathophysiology of these
infants is just beginning to be elucidated.
1.3.1 Bronchopulmonary Dysplasia and Cor Pulmonale
Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth that
affects approximately 30% of infants (or roughly 10,000 babies per year) with
extreme prematurity (typically defined as a birthweight
1,000 g). BPD results in
significant long-term morbidity in childhood, including poor lung function, dimin-
ished growth, and impaired neurodevelopment (Jobe and Bancalari
2001
; Walsh
et al.
2006
). A recently recognized complication of moderate or severe BPD is
pulmonary hypertension and right-sided heart failure, or cor pulmonale. While the
overall risk of BPD clearly correlates with gestational age and birthweight, it
remains unclear why some infants develop mild or severe disease. Even less is
known about why some infants develop pulmonary hypertension and how to
appropriately treat these infants. Poor outcomes, including mortality, are distress-
ingly common (Jobe and Bancalari
2001
; Khemani et al.
2007
; Mourani et al.
2008
).
Recent clinical trials have laid the foundation for the use of iNO for prevention
of BPD (Ballard et al.
2006
; Kinsella et al.
2006
). Smaller case series also suggest
that the use of iNO may also improve oxygenation in those BPD infants with
established pulmonary hypertension (Mourani et al.
2008
). Additionally, premature
babies are forced to live in an environment with higher oxygen concentrations than
would be encountered during fetal development. Not surprisingly, emerging evi-
dence indicates that oxidative stress may produce significant lung parenchymal and
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