Abstract 19253: Chronic Hypobaric Hypoxia and Chronic Intermittent Hypobaric Hypoxia in Rats Leads to a Mismatch in the ADMA-NO Pathway

Abstract

Introduction: Chronic Hypoxia (CH) as well as chronic intermittent hypoxia (CIH) are associated with pathophysiological conditions like acute/chronic mountain sickness and pulmonary hypertension. In the manifestation of these diseases the endothelium and the L-arginine/NO pathway plays a crucial role. Asymmetric dimethylarginine (ADMA) is an endogenous formed NO synthase (NOS) inhibitor and well known as a risk factor for respiratory diseases associated with an endothelial dysfunction in the pulmonary circulation. ADMA is metabolized by dimethylarginine dimethylaminohydrolases (DDAH). In order to have a broader view of the involvement and behavior of ADMA and DDAH under CH as well as CIH our study was aimed to assess the changes in ADMA levels and the underlying molecular mechanisms. Methods: Wistar rats were maintained under conditions of CIH (2 days of hypobaric hypoxia followed by 2 days of normoxia (NX) for 30 days (428 torr), CH (30 days, 428 torr) and a control group maintained under NX (n=8 within each group). Systemic blood pressure (SBP) was measured by tail cuff plethysmography. ADMA concentration and DDAH activity were measured in lung tissue by a LC-MS/MS assay. Vascular oxidative stress response was determined by expression of Nox4 and the formation of malondialdehyde. Results: Hemodynamic measurements showed an increase in SBP in CH compared to NX (171.9±1.2 mmHg vs 176.7±4.6 mmHg; p=0.037). CH and CIH led to the development of a moderate right ventricular hypertrophy. ADMA concentrations in the lung were increased under hypoxia (P(NX vs CIH)=0.01 (85.3±66.3 nM vs 140.3±46.7 nM); P(NX vs CH)=0.007 (85.3±66.3 nM vs 197.1±56.0 nM) although it was more pronounced in CH (P=0.04). Hypoxia increased oxidative stress in the lung in combination with a reduced DDAH activity, more pronounced in CH. Expression of the endothelial NOS was increased but NO bioavailability was reduced in CH and CIH. Conclusion: The increase of ADMA might be one reason for impaired NO bioavailability in CH and CIH, resulting in an endothelial dysfunction. Likewise, oxidative stress seems to be another main cause of the mismatch in the ADMA-NO pathway.