Journal article
Therapeutic hypercapnia prevents inhaled nitric oxide-induced right-ventricular systolic dysfunction in juvenile rats
Free radical biology & medicine, Vol.69, pp.35-49
04/2014
DOI: 10.1016/j.freeradbiomed.2014.01.008
PMID: 24423485
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.
Details
- Title: Subtitle
- Therapeutic hypercapnia prevents inhaled nitric oxide-induced right-ventricular systolic dysfunction in juvenile rats
- Creators
- Kristyn Dunlop - Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8Kiranjot Gosal - 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 1A8Crystal Kantores - Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8Julijana Ivanovska - Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8Rupinder Dhaliwal - Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8Jean-François Desjardins - Keenan Research Center, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, CanadaKim A Connelly - 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 1A8Amish Jain - 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 1A8Patrick J McNamara - 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 1A8Robert P Jankov - 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
- Resource Type
- Journal article
- Publication Details
- Free radical biology & medicine, Vol.69, pp.35-49
- DOI
- 10.1016/j.freeradbiomed.2014.01.008
- PMID
- 24423485
- NLM abbreviation
- Free Radic Biol Med
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Grant note
- MOP93596 / Canadian Institutes of Health Research
- Language
- English
- Date published
- 04/2014
- Academic Unit
- Stead Family Department of Pediatrics; Neonatology; Internal Medicine
- Record Identifier
- 9984093491202771
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