title: Intermittent hypoxia augments pulmonary vascular smooth muscle reactivity to NO: regulation by reactive oxygen species.
abstract: Intermittent hypoxia (IH) resulting from sleep apnea can lead to pulmonary hypertension. IH causes oxidative stress that may limit bioavailability of the endothelium-derived vasodilator nitric oxide (NO) and thus contribute to this hypertensive response. We therefore hypothesized that increased vascular superoxide anion (O(2)(-)) generation reduces NO-dependent pulmonary vasodilation following IH. To test this hypothesis, we examined effects of the O(2)(-) scavenger tiron on vasodilatory responses to the endothelium-dependent vasodilator ionomycin and the NO donor S-nitroso-N-acetylpenicillamine in isolated lungs from hypocapnic-IH (H-IH; 3 min cycles of 5% O(2)/air flush, 7 h/day, 4 wk), eucapnic-IH (E-IH; cycles of 5% O(2), 5% CO(2)/air flush), and sham-treated (air/air cycled) rats. Next, we assessed effects of endogenous O(2)(-) on NO- and cGMP-dependent vasoreactivity and measured O(2)(-) levels using the fluorescent indicator dihydroethidium (DHE) in isolated, endothelium-disrupted small pulmonary arteries from each group. Both E-IH and H-IH augmented NO-dependent vasodilation; however, enhanced vascular smooth muscle (VSM) reactivity to NO following H-IH was masked by an effect of endogenous O(2)(-). Furthermore, H-IH and E-IH similarly increased VSM sensitivity to cGMP, but this response was independent of either O(2)(-) generation or altered arterial protein kinase G expression. Finally, both H-IH and E-IH increased arterial O(2)(-) levels, although this response was more pronounced following H-IH, and H-IH exposure resulted in greater protein tyrosine nitration indicative of increased NO scavenging by O(2)(-). We conclude that IH increases pulmonary VSM sensitivity to NO and cGMP. Furthermore, endogenous O(2)(-) limits NO-dependent vasodilation following H-IH through an apparent reduction in bioavailable NO.
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-0001, USA. cenorton@salud.unm.edu
authors.forename: Charles E
authors.initials: CE
authors.lastname: Norton
authors.forename: Nikki L
authors.initials: NL
authors.lastname: Jernigan
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: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D045462:Endothelium-Dependent Relaxing Factors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000503:physiopathology; D016857:Hypocapnia / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D015759:Ionomycin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011086:Polycythemia / Q000378:metabolism / Q000503:physiopathology; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D016166:Free Radical Scavengers; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D013481:Superoxides; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D015759:Ionomycin; D026423:S-Nitroso-N-Acetylpenicillamine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP