Abstract 15500: Increased Dimethylarginines in Rats and Humans Exposed to Chronic Intermittent Hypobaric Hypoxia
Background: Working and living at high altitude above 4000m exposes human beings to labor conditions involving chronic intermittent hypobaric hypoxia (CIHH). Approximately 4% of people exposed to such conditions develop pulmonary hypertension (PH). Dimethylarginines (DMA) have been shown to interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA) and cellular L-arginine uptake (ADMA and symmetric dimethylarginine, SDMA). Data of clinical trials as well as experimental data show that increased concentration of DMA in blood plasma and lung tissue are associated with unfavorable pulmonary hemodynamics and increased mortality in PH. ADMA is degraded enzymatically by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), whilst SDMA was reported to be eliminated almost exclusively by the renal route. We performed a clinical study and an experimental animal approach to clarify the role of DMA in the response of the pulmonary circulation to CIHH and the molecular mechanisms behind.
Methods: About 100 draftees (mean age 18 years) from northern Chile were included into the study and were followed up for 4 months in the status of CIHH (5 days at 3550m altitude, 2 days at sea level). The experimental approach was done with young male Wistar rats in the status of CIHH (2 days hypoxia (hypobaric chamber, 428 torr) followed by 2 days normoxia for a period of 1 month). The determination of plasma and tissue concentrations of DMA and DDAH activity was performed by using a high throughput LC-MS/MS assay.
Results: During 4 months follow up the draftees show a dramatic increase in ADMA plasma concentration (1.57±1.03 μM to 2.25±1.95 μM; p<0.001), whereas the SDMA plasma concentrations did not change. The SDMA (0.35±0.10 μM vs. 0.52±0.07 μM; p=0.006) and ADMA (0.87±0.28 μM vs. 1.49±0.41 μM; p=0.019) concentrations of rats exposed to CIHH were significantly increased concomitantly with reduced DDAH activity in the lungs (0.42±0.13 μM/min vs. 0.30±0.08 μM/min; p=0.08).
Conclusion: The abnormal regulation of DDAH in CIHH leading to increased ADMA concentrations may result in a decreased NO availability. This could be one molecular mechanism for hypoxia-induced pulmonary hypertension.
- © 2010 by American Heart Association, Inc.