Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity.
An experimental ovine fetal model for perinatal pulmonary hypertension of the neonate (PPHN) was characterized by altered pulmonary vasoreactivity and structure. Because past studies had suggested impaired nitric oxide-cGMP cascade in this experimental model, we hypothesized that elevated phosphodiesterase (PDE) activity may contribute to altered vascular reactivity and structure in experimental PPHN. Therefore, we studied the effects of the PDE inhibitors zaprinast and dipyridamole on fetal pulmonary vascular resistance and PDE5 activity, protein, mRNA, and localization in normal and pulmonary hypertensive fetal lambs. Infusion of dipyridamole and zaprinast lowered pulmonary vascular resistance by 55 and 35%, respectively, in hypertensive animals. In comparison with control animals, lung cGMP PDE activity was elevated in hypertensive fetal lambs (150%). Increased PDE5 activity was not associated with either an increased PDE5 protein or mRNA level. Immunocytochemistry demonstrated that PDE5 was localized to vascular smooth muscle. We concluded that PDE5 activity was increased in experimental PPHN, possibly by posttranslational phosphorylation. We speculated that these increases in cGMP PDE activity contributed to altered pulmonary vasoreactivity in experimental perinatal pulmonary hypertension.
Hanson
K A
KA
Departments of Pediatrics, Anesthesiology, and Pharmacology, University of Washington School of Medicine, Seattle, Washington 98105-00371, USA.
Ziegler
J W
JW
Rybalkin
S D
SD
Miller
J W
JW
Abman
S H
SH
Clarke
W R
WR
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004176:Dipyridamole / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005865:Gestational Age; D006976:Hypertension, Pulmonary / Q000196:embryology* / Q000201:enzymology / Q000503:physiopathology*; D008168:Lung / Q000196:embryology* / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011247:Pregnancy; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D011688:Purinones / Q000494:pharmacology*; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*
D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D004176:Dipyridamole; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C011145:zaprinast