title: Differential effects of chronic hypoxia and intermittent hypocapnic and eucapnic hypoxia on pulmonary vasoreactivity.
abstract: Intermittent hypoxia (IH) resulting from sleep apnea can lead to pulmonary hypertension (PH) and right heart failure, similar to chronic sustained hypoxia (CH). Supplemental CO(2), however, attenuates hypoxic PH. We therefore hypothesized that, similar to CH, IH elicits PH and associated increases in arterial endothelial nitric oxide synthase (eNOS) expression, ionomycin-dependent vasodilation, and receptor-mediated pulmonary vasoconstriction. We further hypothesized that supplemental CO(2) inhibits these responses to IH. To test these hypotheses, we measured eNOS expression by Western blot in intrapulmonary arteries from CH (2 wk, 0.5 atm), hypocapnic IH (H-IH) (3 min cycles of 5% O(2)/air flush, 7 h/day, 2 wk), and eucapnic IH (E-IH) (3 min cycles of 5% O(2), 5% CO(2)/air flush, 7 h/day, 2 wk) rats and their respective controls. Furthermore, vasodilatory responses to the calcium ionophore ionomycin and vasoconstrictor responses to the thromboxane mimetic U-46619 were measured in isolated saline-perfused lungs from each group. Hematocrit, arterial wall thickness, and right ventricle-to-total ventricle weight ratios were additionally assessed as indexes of polycythemia, arterial remodeling, and PH, respectively. Consistent with our hypotheses, E-IH resulted in attenuated polycythemia, arterial remodeling, RV hypertrophy, and eNOS upregulation compared with H-IH. However, in contrast to CH, neither H-IH nor E-IH increased ionomycin-dependent vasodilation. Furthermore, H-IH and E-IH similarly augmented U-46619-induced pulmonary vasoconstriction but to a lesser degree than CH. We conclude that maintenance of eucapnia decreases IH-induced PH and upregulation of arterial eNOS. In contrast, increases in pulmonary vasoconstrictor reactivity following H-IH are unaltered by exposure to supplemental CO(2).
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-0001, USA.
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Snow
authors.forename: Vanessa
authors.initials: V
authors.lastname: Kitzis
authors.forename: Charles E
authors.initials: CE
authors.lastname: Norton
authors.forename: Samantha N
authors.initials: SN
authors.lastname: Torres
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Johnson
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Kanagy
authors.forename: Benjimen R
authors.initials: BR
authors.lastname: Walker
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Resta
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D002245:Carbon Dioxide / Q000097:blood; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000503:physiopathology; D016857:Hypocapnia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen / Q000097:blood; D011086:Polycythemia / Q000209:etiology / Q000503:physiopathology; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D007476:Ionophores; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D002245:Carbon Dioxide; D015759:Ionomycin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D010100:Oxygen