Oxygen modulates nitric oxide production selectively in fetal pulmonary endothelial cells.
Acute hypoxia causes pulmonary hypertension in the fetus and newborn that is contrasted by systemic hypotension or normotension. To better understand the role of nitric oxide (NO) in this specific pulmonary vascular response, we determined the acute effects of decreased oxygenation on NO production in ovine fetal pulmonary and systemic (mesenteric) endothelial cells. NO was assessed by measuring cGMP accumulation in fetal vascular smooth muscle (VSM) cells during co-culture incubations of endothelium and VSM (40 s) in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Changes in cGMP were dependent on the endothelium and on NO synthase and guanylate cyclase activity. At high O2 (680 mm Hg), basal NO was detectable and NO increased 6- to 10-fold with bradykinin or A23187. In pulmonary endothelium, basal NO fell 58% at pO2 = 150 mm Hg and 51% at 40 mm Hg versus 680 mm Hg, while NO with bradykinin fell 56% and 63%, respectively. NO with A23187, however, was unchanged at 150 mm Hg, but it fell 56% at 40 mm Hg. In contrast, in systemic endothelium basal and stimulated NO production were not altered at lower O2. Findings were similar using pulmonary or systemic detector VSM cells, and exogenous L-arginine had no effect. Thus, decreased O2 acutely attenuates NO production specifically in fetal pulmonary endothelial cells. This process is not related to changes in O2 or L-arginine availability as substrates for NO synthase; alternatively, it may be partially mediated by specific effects of O2 on pulmonary endothelial cell calcium homeostasis.
Shaul
P W
PW
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063.
Wells
L B
LB
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000594:Amino Acid Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D005260:Female; D006162:Guanylate Cyclase / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007231:Infant, Newborn; D008168:Lung / Q000098:blood supply / Q000196:embryology*; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase; D009599:Nitroprusside / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D010547:Persistent Fetal Circulation Syndrome / Q000209:etiology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects; D012756:Sheep
D009599:Nitroprusside; D009569:Nitric Oxide; D000001:Calcimycin; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D010100:Oxygen; D001920:Bradykinin; D015056:1-Methyl-3-isobutylxanthine