Long-Term Chronic Intermittent Hypobaric Hypoxia in Rats Causes an Imbalance in the Asymmetric Dimethylarginine/Nitric Oxide Pathway and ROS Activity: A Possible Synergistic Mechanism for Altitude Pulmonary Hypertension?

Nicole Lüneburg,Patricia Siques,Julio Brito,Karem Arriaza,Eduardo Pena,Hans Klose,Rainer H Böger,Fabiola Leon-Velarde

doi:10.1155/2016/6578578

Abstract

Chronic intermittent hypoxia (CIH) and chronic hypoxia (CH) are associated with high-altitude pulmonary hypertension (HAPH). Asymmetric dimethylarginine (ADMA), a NO synthase (NOS) inhibitor, may contribute to HAPH. This study assessed changes in the ADMA/NO pathway and the underlying mechanisms in rat lungs following exposure to CIH or CH simulated in a hypobaric chamber at 428 Torr. Twenty-four adult Wistar rats were randomly assigned to three groups: CIH2x2 (2 days of hypoxia/2 days of normoxia), CH, and NX (permanent normoxia), for 30 days. All analyses were performed in whole lung tissue. L-Arginine and ADMA were analyzed using LC-MS/MS. Under both hypoxic conditions right ventricular hypertrophy was observed (p < 0.01) and endothelial NOS mRNA increased (p < 0.001), but the phosphorylated/nonphosphorylated vasodilator-stimulated phosphoprotein (VASP) ratio was unchanged. ADMA increased (p < 0.001), whereas dimethylarginine dimethylaminohydrolase (DDAH) activity decreased only under CH (p < 0.05). Although arginase activity increased (p < 0.001) and L-arginine exhibited no changes, the L-arginine/ADMA ratio decreased significantly (p < 0.001). Moreover, NOX4 expression increased only under CH (p < 0.01), but malondialdehyde (MDA) increased (up to 2-fold) equally in CIH2x2 and CH (p < 0.001). Our results suggest that ADMA and oxidative stress likely reduce NO bioavailability under altitude hypoxia, which implies greater pulmonary vascular reactivity and tone, despite the more subdued effects observed under CIH.

Highlights

Working at high altitude and resting at sea level for many years expose humans to an unusual labor-related condition called long-term chronic intermittent hypobaric hypoxia (CIH) [1]
In order to gain a broader view of the changes in the Asymmetric dimethylarginine (ADMA)/nitric oxide (NO) pathway during long-term CIH compared with chronic hypoxia (CH), this study aimed to assess the changes in the ADMA/NO pathway, the underlying pulmonary molecular mechanisms involved, and the potential interaction with other molecules, such as ROS, in lung tissue as a possible explanation for hypoxia-induced pulmonary hypertension
(4) ADMA concentrations in the lung increased in the longterm CIH2x2 and CH due to a hypoxia-induced reduction of dimethylarginine dimethylaminohydrolase (DDAH) activity in CH. (5) ADMA concentrations were positively correlated with systolic blood pressure in longterm CH. (6) Both hypoxic conditions led to a strong increase in biomarkers for oxidative stress

Summary

Introduction

Working at high altitude and resting at sea level for many years expose humans to an unusual labor-related condition called long-term chronic intermittent hypobaric hypoxia (CIH) [1]. Exposure to high altitude causes reduced arterial oxygen saturation that, in turn, may elicit various pathophysiological sequelae depending on whether this exposure is acute or chronic. Both acute and chronic exposure cause pulmonary arterial hypertension and an increase in blood hemoglobin levels [2]. Hypobaric hypoxia-induced pulmonary arterial hypertension (HAPH) is a relevant problem that affects populations living and working at high altitudes, such as those in the Andean region and on the Himalayan plateau, with a prevalence varying between 10 and 15% [3]. A prevalence of pulmonary arterial hypertension up to 4% has been reported among subjects exposed to long-term CIH [5]

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