title: Therapeutic hypercapnia prevents inhaled nitric oxide-induced right-ventricular systolic dysfunction in juvenile rats.
abstract: Chronic pulmonary hypertension in the neonate and infant frequently presents with right-ventricular (RV) failure. Current clinical management may include protracted treatment with inhaled nitric oxide (iNO), with the goal of reducing RV afterload. We have previously reported that prolonged exposure to iNO causes RV systolic dysfunction in the chronic hypoxia-exposed juvenile rat, which was prevented by a peroxynitrite decomposition catalyst. Given that inhalation of CO2 (therapeutic hypercapnia) may limit oxidative stress and upregulated cytokine expression in the lung and other organs, we hypothesized that therapeutic hypercapnia would attenuate cytokine-mediated nitric oxide synthase (NOS) upregulation, thus limiting peroxynitrite generation. Sprague-Dawley rat pups were exposed to chronic hypoxia (13% O2) from postnatal day 1 to 21, while receiving iNO (20 ppm) from day 14 to 21, with or without therapeutic hypercapnia (10% CO2). Therapeutic hypercapnia completely normalized RV systolic function, RV hypertrophy, and remodeling of pulmonary resistance arteries in animals exposed to iNO. Inhaled nitric oxide-mediated increases in RV peroxynitrite, apoptosis, and contents of tumor necrosis factor (TNF)-α, interleukin (IL)-1α, and NOS-2 were all attenuated by therapeutic hypercapnia. Inhibition of NOS-2 activity with 1400 W (1 mg/kg/day) prevented iNO-mediated upregulation of peroxynitrite and led to improved RV systolic function. Blockade of IL-1 receptor signaling with anakinra (500 mg/kg/day) decreased NOS-2 content and had similar effects compared to NOS-2 inhibition on iNO-mediated effects, whereas blockade of TNF-α signaling with etanercept (0.4 mg/kg on alternate days) had no effects on these parameters. We conclude that therapeutic hypercapnia prevents the adverse effects of sustained exposure to iNO on RV systolic function by limiting IL-1-mediated NOS-2 upregulation and consequent nitration. Therapeutic hypercapnia also acts synergistically with iNO in normalizing RV hypertrophy, vascular remodeling, and raised pulmonary vascular resistance secondary to chronic hypoxia.
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8.
authors.forename: Kristyn
authors.initials: K
authors.lastname: Dunlop
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8; Department of Physiology, Faculty of Medicine, Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Kiranjot
authors.initials: K
authors.lastname: Gosal
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8.
authors.forename: Crystal
authors.initials: C
authors.lastname: Kantores
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8.
authors.forename: Julijana
authors.initials: J
authors.lastname: Ivanovska
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8.
authors.forename: Rupinder
authors.initials: R
authors.lastname: Dhaliwal
authors.affiliation: Keenan Research Center, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Desjardins
authors.affiliation: Keenan Research Center, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, and Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8; Department of Physiology, Faculty of Medicine, Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8; Division of Neonatology, Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Amish
authors.initials: A
authors.lastname: Jain
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8; Department of Physiology, Faculty of Medicine, Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8; Division of Neonatology, Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McNamara
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8; Department of Physiology, Faculty of Medicine, Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, and Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8; Division of Neonatology, Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8. Electronic address: robert.jankov@sickkids.ca.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jankov
mesh_terms: D000818:Animals; D002245:Carbon Dioxide / Q000097:blood*; D006801:Humans; D006935:Hypercapnia / Q000097:blood*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D007375:Interleukin-1 / Q000378:metabolism; D009569:Nitric Oxide / Q000633:toxicity; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D002245:Carbon Dioxide; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase
keywords: Free radicals; Interleukin-1; Pulmonary hypertension; Reactive nitrogen species; Right ventricle; iNOS