Mechanisms of nitric oxide generation from nitroglycerin and endogenous sources during hypoxia in vivo

Nitroglycerin (GTN), often used in conditions of cardiovascular ischaemia, acts through the liberation of nitric oxide (NO) and the local concentration of NO in the tissue is responsible for any biological effect. However, little is known about the way in which the concentration of NO from GTN and other NO-donors is influenced by low oxygen tension in the target tissues. To evaluate the impact of changes in oxygen tension in the metabolism of NO-donors we measured exhaled NO in anaesthetized rabbits in vivo and expired NO and perfusate nitrite (NO2−) in buffer-perfused lungs in situ. The impact of acute hypoxia on NO formation from GTN, isosorbide-5-mononitrate (ISMN), dissolved authentic NO, NO2− and NO generated from endogenous NO-synthase (NOS) was studied in either model. Acute hypoxia drastically increased exhaled NO concentrations from all NO-donors studied, both in vivo and in the perfused lung. During similar conditions endogenous NO generation from NOS was strongly inhibited. The effects were most pronounced at less than 3% inspired oxygen. The mechanisms for the increased NO-formation during hypoxia seems to differ between GTN- and NO2−-derived NO. The former phenomenon is likely due to diminished breakdown of NO. In conclusion, hypoxic conditions preserve very high local NO concentrations generated from organic nitrates in vivo and we suggest that this might benefit preferential vasodilation in ischaemic tissue regions. Our findings point out the necessity to consider the influence of oxygen tension when studying the action of NO-donors. British Journal of Pharmacology (2002) 135, 373–382; doi:10.1038/sj.bjp.0704489