Chronic and chronic intermittent hypobaric hypoxia in rats leads to a mismatch in the endothelial ADMA/NO pathway

Introduction: Hypoxia, either from altitude or clinical ailments is associated with pathophysiological conditions like mountain sickness and/or hypoxia-induced pulmonary hypertension. An endothelial dysfunction plays a crucial role in the manifestation of these diseases. 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. ADMA is metabolized by dimethylarginine dimethylaminohydrolases (DDAH). Our study was aimed to assess the molecular involvement and behavior of the ADMA/NO pathway during chronic hypoxia (CH) and intermittent hypoxia (CIH).

Methods: Male Wistar rats were put under CIH (2 days of hypobaric hypoxia, 2 days of normoxia for 30 days (428 torr), CH (30 days, 428 torr) and a control group maintained under normoxia (NX) (n = 8 within each group). Systemic blood pressure (SBP) was measured by tail cuff plethysmography. ADMA concentrations and DDAH activity in the lung were measured by a validated LC-MS/MS assay. Vascular oxidative stress response was determined by expression of Nox4 and the formation of malondialdehyd.

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 led to increased oxidative stress in the lung in combination with a reduced DDAH activity. Expression of the endothelial NOS was increased but the NO bioavailability was reduced.

Conclusion: The increase of ADMA could be one reason for an 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.