Effects of co-administration of the nitric oxide donor ISMN and melatonin in the NO system in a model of hypobaric hypoxia

Abstract

Nitric oxide (NO) is a molecule that depending both on its concentration and tissue redox status, can develop a dual neuroprotective/neurotoxic function. In this sense, it has been demonstrated: (1) that NO plays a crucial role in hypoxic situations and, (2) that antioxidants can exert neuroprotective effects by alleviating the negative consequences derived from the reactive oxygen species (ROS) generated in the hypobaric process, and related to NO as well. Nevertheless, only few studies have analyzed the effect of co-administration of NO donors and antioxidants on brain hypoxia. Thus, we have optimized an experimental model of hypobaric hypoxia (HH) that resembles high altitude environmental conditions in order to study the NO system response to this situation. In this study we analyze the localization and activity of iNOS and eNOS, and protein nitration in the brain of rats submitted to the above mentioned model after two reoxygenation periods (0 and 2 h). Moreover, we studied the effect of co-administration of NO donor isosorbide mononitrate (ISMN) and the neurohormone melatonin in this hypoxic model. Our results show that the co-administration of ISMN and melatonin does not influence iNOS in situ expression, but decreases eNOS after the 2 reoxygenation periods, as well as NO activity (measured as NADPH-diaphorase staining). On the other hand, protein nitration-related damage at 2 reoxygenation times is decreased when both drugs are supplied. In summary, the co-administration of ISMN and melatonin in our model of hypoxia seems to modulate the NO system response. Supported by MICINN (SAF2008-03938).