Abstract 1552
Poster Session II, Sunday, 5/2 (poster 132)
In contrast to ischemia-reperfusion, the effects of systemic hypoxia on leukocyte endothelial interactions have received little attention. The objective of these experiments was to study the effect of systemic hypoxia on leukocyte adherence in the mesenteric venule of the rat and the role of nitric oxide (NO) in mediating this response. Intravital microscopy was used to measure leukocyte adherence to the mesentric venules of anesthetized non-acclimatized rats (NA) and of rats acclimatized (A) to hypobaric hypoxia (PB=370 Torr) for three weeks. Leukocyte adherence and emigration were also measured after 2 h of hypoxia in conscious NA rats. In anesthetized NA rats 10 min of hypoxia (PaO2 = 32±3.9 Torr) markedly increased leukocyte adherence, a response which was substantially attenuated by superfusion of the mesenteric circulation with either the NO donor spermine NONOate, the NO substrate L-arginine, or by systemic administration of the antioxidants catalase plus superoxide dismutase. Conscious NA rats exposed by hypoxia for two h showed leukocyte adherence and emigration which were also attenuated by prior administration of antioxidants. In contrast, A rats showed no evidence of vascular endothelial dysfunction in normoxia, and no increase in leukocyte adherence during 10 min of hypoxia (Pa02=37.6±0.8 Torr). Since NO prevented the leukocyte adherence during hypoxia in NA rats, we reasoned that the protective effect of acclimatization could be related to elevated tissue NO levels due to increased expression of inducible NO synthase (iNOS) during prolonged exposure to hypoxia. This was supported by the observation that administration of the iNOS inhibitor 1,4-PBIT to A rats during hypoxia markedly enhanced adherence. These results support the hypothesis that systemic hypoxia causes microvascular injury in NA rats due to depletion of available NO by reactive oxidants. Acclimatization to hypobaric hypoxia protects the mesenteric venule from the hypoxic insult, probably by upregulating iNOs.