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Department of Pediatrics, Harbor-UCLA Research and Education Institute Incorporated, University of California, Los Angeles School of Medicine, Torrance, California 90509
Submitted 2 December 2002 ; accepted in final form 8 May 2003
Cyclic GMP-dependent protein kinase (PKG) plays an important role in
regulating pulmonary vasomotor tone in the perinatal period. In this study, we
tested the hypothesis that a change in oxygen tension affects PKG-mediated
pulmonary vasodilation. Isolated intrapulmonary arteries and veins of
near-term fetal lambs were first incubated for 4 h under hypoxic and normoxic
conditions (PO2 of 30 and 140 mmHg, respectively) and
then contracted with endothelin-1. 8-Bromoguanosine 3',5'-cyclic
monophosphate (8-BrcGMP), a cell membrane-permeable analog of cGMP, induced a
greater relaxation in vessels incubated in normoxia than in hypoxia.
-Phenyl-1,N2-etheno-8-bromoguanosine-3',5'-cyclic
monophosphorothioate, Rp isomer (Rp-8-Br-PET-cGMPS), a selective
inhibitor of PKG, attenuated relaxation induced by 8-BrcGMP
(10-4 and 3 x 10-4 M). In
the presence of Rp-8-Br-PET-cGMPS, the differential responses to
8-BrcGMP between hypoxia and normoxia treatment were abolished in veins but
not in arteries. cGMP-stimulated PKG activity was present in arteries but not
in veins after 4 h of hypoxia. Both vessel types showed significant increase
in cGMP-stimulated PKG activity after 4 h of normoxia. PKG protein (Western
blot analysis) and PKG mRNA levels (quantitative RT-PCR) were greater in veins
but not in arteries after 4-h exposure to normoxia vs. hypoxia. These results
demonstrate that oxygen augments cGMP-mediated vasodilation of fetal pulmonary
arteries and veins. Furthermore, the effect of oxygen on response of the veins
to cGMP is due to an increase in the activity, protein level, and mRNA of
PKG.
protein kinase G; vasodilation; vein; perinatal lung
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