Biology Reference
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Fig. 1 Hyperoxia increases PDE5 activity in Ovine FPASMCs. FPASMCs were exposed to 21%
O
2
-5% CO
2
, 50% O
2
-5% CO
2
, or 95% O
2
-5% CO
2
for 24 h, and total protein was harvested.
PDE5-specific activity was measured as the sildenafil-inhibitable fraction of total cGMP hydroly-
sis, normalized for total milligrams of protein (200
m
M cGMP substrate in assay; 100 nM sildenafil
for inhibition). Data are shown as mean
8; read in duplicate).
*
P
SEM (
n
ΒΌ
0.05 vs. 21% O
2
,
<
#
P
0.05 vs. 50% O
2
. Reproduced with permission from Farrow et al. (
2008a
)
<
to norepinephrine compared to vessels from animals resuscitated with 21% oxygen
(Lakshminrusimha et al.
2006
). Use of 100% oxygen ventilation significantly
increased pulmonary vascular PDE5 expression and activity (Fig.
2
) (Farrow et al.
2008a
), indicating that PDE5 activity is an important mediator in the vascular
response to oxygen and hyperoxia. More recently, we reported that ventilation
of PPHN lambs with 100% oxygen results in pulmonary vasoconstriction and
diminished pulmonary vascular relaxation to inhaled NO (Lakshminrusimha et al.
2009b
). Very recent studies indicate that these abnormal responses are mediated in
part by a greatly exaggerated increase in PDE5 activity (Farrow et al.
2010a
,
b
).
Ventilation of healthy control lambs with either 21 or 100% oxygen blunts the
increase in PDE3 expression and activity normally seen in the healthy spontaneously
breathing 1-day lambs, suggesting that PDE3 may be dysregulated by mechanical
forces associated with ventilation rather than by hyperoxia (Chen et al.
2009
). This
dysregulation of PDE3 expression and activity may lead to a disruption of the normal
cAMP signaling within the pulmonary vascular smooth muscle during this critical
transition time. Recent studies have shown that the PDE3 inhibitor milrinone, when
used in conjunction with either iNO or iloprost, can help to restore normal vascular
responses (Chen et al.
2009
; Lakshminrusimha et al.
2009a
).
Thus, idiopathic PPHN is a complex pathological process induced by dis-
ruption of multiple signaling pathways, including the NO-cGMP-PDE5 and
prostacyclin-cAMP-PDE3 pathways, leading to vasoconstriction and structural
remodeling of the vasculature. Postnatal treatment with high levels of oxygen
exacerbates these abnormalities, leading to decreases in cGMP and cAMP and
impaired vasodilation. Inhibitors of PDE5 and PDE3, such as sildenafil and
