title: Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs.
abstract: Exposure to chronic hypoxia during gestation predisposes infants to neonatal pulmonary hypertension, but the underlying mechanisms remain unclear. Here, we test the hypothesis that moderate continuous hypoxia during gestation causes changes in the rho-kinase pathway that persist in the newborn period, altering vessel tone and responsiveness. Lambs kept at 3,801 m above sea level during gestation and the first 2 wk of life were compared with those with gestation at low altitude. In vitro studies of isolated pulmonary arterial rings found a more forceful contraction in response to KCl and 5-HT in high-altitude compared with low-altitude lambs. There was no difference between the effects of blockers of various pathways of extracellular Ca(2+) entry in low- and high-altitude arteries. In contrast, inhibition of rho-kinase resulted in significantly greater attenuation of 5-HT constriction in high-altitude compared with low-altitude arteries. High-altitude lambs had higher baseline pulmonary artery pressures and greater elevations in pulmonary artery pressure during 15 min of acute hypoxia compared with low-altitude lambs. Despite evidence for an increased role for rho-kinase in high-altitude arteries, in vivo studies found no significant difference between the effects of rho-kinase inhibition on hypoxic pulmonary vasoconstriction in intact high-altitude and low-altitude lambs. We conclude that chronic hypoxia in utero results in increased vasopressor response to both acute hypoxia and serotonin, but that rho-kinase is involved only in the increased response to serotonin.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA 92373, USA. ablood@llu.edu
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Blood
authors.forename: Michael H
authors.initials: MH
authors.lastname: Terry
authors.forename: Travis A
authors.initials: TA
authors.lastname: Merritt
authors.forename: Demosthenes G
authors.initials: DG
authors.lastname: Papamatheakis
authors.forename: Quintin
authors.initials: Q
authors.lastname: Blood
authors.forename: Jonathon M
authors.initials: JM
authors.lastname: Ross
authors.forename: Gordon G
authors.initials: GG
authors.lastname: Power
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Longo
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wilson
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000531:Altitude; D000818:Animals; D000831:Animals, Newborn; D062186:Arterial Pressure; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005311:Fetal Hypoxia / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D010547:Persistent Fetal Circulation Syndrome / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D012701:Serotonin / Q000494:pharmacology; D012756:Sheep; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D047428:Protein Kinase Inhibitors; D014662:Vasoconstrictor Agents; D012701:Serotonin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil