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Therapeutic hypercapnia prevents inhaled nitric oxide-induced right-ventricular systolic dysfunction in juvenile rats
Kristyn Dunlop1, Kiranjot Gosal2, Crystal Kantores1
1Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1X8.
Insights
Therapeutic hypercapnia (inhaled CO2) protects against inhaled nitric oxide (iNO)-induced right-ventricular dysfunction in neonatal rats. This protective effect is mediated by reducing inflammation and oxidative stress, preserving heart function.
Area of Science:
- Neonatal physiology and pathology
- Cardiovascular research
- Pulmonary hypertension treatment
Background:
- Chronic pulmonary hypertension in neonates often leads to right-ventricular (RV) failure.
- Inhaled nitric oxide (iNO) is used to reduce RV afterload but can cause RV systolic dysfunction with prolonged use.
- Oxidative stress and cytokine expression are implicated in iNO-induced RV dysfunction.
Purpose of the Study:
- To investigate if therapeutic hypercapnia (inhaled CO2) can prevent RV systolic dysfunction caused by prolonged iNO exposure in a neonatal rat model.
- To determine if therapeutic hypercapnia attenuates cytokine-mediated nitric oxide synthase (NOS) upregulation and subsequent peroxynitrite generation.
Main Methods:
- Neonatal Sprague-Dawley rats were exposed to chronic hypoxia (13% O2) and treated with iNO (20 ppm) from day 14 to 21.
- Some animals received therapeutic hypercapnia (10% CO2) concurrently with iNO.
- RV function, hypertrophy, vascular remodeling, peroxynitrite levels, apoptosis, and cytokine/NOS expression were assessed. Specific inhibitors/blockers for NOS-2, IL-1, and TNF-α were used.
Main Results:
- Therapeutic hypercapnia completely normalized RV systolic function, hypertrophy, and pulmonary artery remodeling in iNO-exposed rats.
- Hypercapnia attenuated iNO-induced increases in RV peroxynitrite, apoptosis, and levels of TNF-α, IL-1α, and NOS-2.
- Inhibition of NOS-2 or blockade of IL-1 receptor signaling mimicked hypercapnia's protective effects, while TNF-α blockade did not.
Conclusions:
- Therapeutic hypercapnia prevents adverse effects of sustained iNO on RV systolic function by limiting IL-1-mediated NOS-2 upregulation and nitration.
- Hypercapnia acts synergistically with iNO to normalize RV hypertrophy, vascular remodeling, and pulmonary vascular resistance in chronic hypoxia.
- This suggests a potential therapeutic strategy for managing neonatal pulmonary hypertension and RV failure.
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.
