Biology Reference
In-Depth Information
abnormal NO-cGMP-PDE5 signaling and excess production of ROS and endo-
thelin (Black et al.
1998
,
2000
,
2001
,
2003
; Lakshminrusimha et al.
2007b
;
Steinhorn et al.
2001
). In this model (Reddy et al.
1996
), an aortopulmonary
shunt is placed in fetal lambs during the last week of gestation, followed by
spontaneous delivery. The lambs have impaired endothelium-dependent vasorelaxa-
tion by 4 weeks of age (Reddy et al.
1996
), associated with complex vascular
changes including increased pulmonary vascular eNOS expression and downstream
derangements such as increased pulmonary sGC protein expression and increased
PDE5 protein expression and activity (Black et al.
1998
,
2001
). Further studies
demonstrate that antioxidants such as superoxide dismutase normalized vascular
reactivity in the shunt vessels and that the ROS in these lambs likely are the result of
uncoupled NOS (Lakshminrusimha et al.
2007b
; Steinhorn et al.
2001
).
Other studies have explored the impact of various treatment strategies on the
NO-cGMP-PDE5 pathway in lambs with congenital heart disease. Inhaled NO
treatment of shunted lambs decreases lung eNOS expression without changing
NOS activity, decreases sGC protein expression, and has no effect on PDE5 protein
expression (Ross et al.
2005
). However, acute withdrawal of the iNO rapidly and
dramatically increases pulmonary vascular resistance by 45% and decreases in
cGMP levels (Ross et al.
2005
). These findings would suggest that the PDE5 in
these lambs becomes the dominant determinant of cGMP concentration after with-
drawal of iNO (Ross et al.
2005
). An additional study attempted to address the role of
cAMP in rebound pulmonary hypertension upon iNO withdrawal (Thelitz et al.
2004
). Treatment of shunt lambs with iNO for 24 h decreased lung cAMP concen-
trations, both during iNO treatment and upon acute withdrawal of iNO. Concomitant
treatment with milrinone, a PDE3 inhibitor, normalized cAMP concentrations during
iNO treatment and upon acute withdrawal. Milrinone also prevented the increase in
pulmonary vascular resistance seen upon acute iNO withdrawal (Thelitz et al.
2004
).
The increased pulmonary vascular resistance seen in these shunted lambs
upon withdrawal of iNO is consistent with the well-known phenomenon of rebound
pulmonary hypertension seen in human infants upon acute withdrawal of iNO
(Atz et al.
1996
). Taken together, these studies suggest that iNO may alter expres-
sion and activity of PDEs, such as PDE3 and PDE5, and that inhibitors of PDE3
and PDE5 may be of clinical utility to treat rebound pulmonary hypertension upon
iNO withdrawal (Ross et al.
2005
; Thelitz et al.
2004
).
2 PDE Inhibitors in Neonatal Pulmonary Hypertension
The initial treatment of the neonate with pulmonary hypertension depends in part
on the underlying disorder. Therapy often includes aggressive support of cardiac
function and perfusion with volume and inotropic agents to enhance cardiac output
and systemic O
2
transport. While most infants require mechanical ventilation to
allow for lung recruitment, an important goal is to avoid postnatal lung injury,
which worsens the degree of pulmonary hypertension (Farrow et al.
2005
).
