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1 Department of Pediatrics, Harbor-UCLA Research and Education Institute Inc., University of California, Los Angeles School of Medicine, Torrance, CA, USA
* To whom correspondence should be addressed. E-mail: ygao{at}gcrc.rei.edu.
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 intra-pulmonary arteries and veins of near-term fetal lambs were first incubated for 4 hours under hypoxic and normoxic conditions (Po2 of 30 and 140 mmHg, respectively) and then contracted with endothelin-1. 8-Br-cGMP, a cell membrane permeable analogue of cGMP, induced a greater relaxation in vessels incubated in normoxia than in hypoxia. Rp-8-Br-PET-cGMPS, a selective inhibitor of PKG, attenuated relaxation induced by 8-Br-cGMP (10-4 M and 3x10-4 M). In the presence of Rp-8-Br-PET-cGMPS, the differential responses to 8-Br-cGMP 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 hypoxia. Both vessel types showed significant increase in cGMP-stimulated PKG activity after 4 h 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.
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