Mechanisms of circulatory and intestinal barrier dysfunction during whole body hyperthermia

This work tested the hypotheses that splanchnic oxidant generation is impor tant in determining heat tolerance and that inappropriate . NO production m ay be involved in circulatory dysfunction with heat stroke. We monitored co lonic temperature (Tc), heart rate, mean arterial pressure, and splanchnic blood flow (SBF) in anesthetized rats exposed to 40 degreesC ambient temper ature. Heating rate, heating time, and thermal load determined heat toleran ce. Portal blood was regularly collected for determination of radical and e ndotoxin content. Elevating Tc from 37 to 41.5 degreesC reduced SBF by 40% and stimulated production of the radicals ceruloplasmin, semiquinone, and p enta-coordinate iron(II) nitrosyl-heme (heme-. NO). Portal endotoxin concen tration rose from 28 to 59 pg/ml (P< 0.05). Compared with heat stress alone , heat plus treatment with the nitric oxide synthase (NOS) antagonist N-<om ega>-nitro-L-arginine methyl ester (L-NAME) dose dependently depressed heme -. NO production and increased ceruloplasmin and semiquinone levels. L-NAME also significantly reduced lowered SBF, increased portal endotoxin concent ration, and reduced heat tolerance (P< 0.05). The NOS II and diamine oxidas e antagonist aminoguanidine, the superoxide anion scavenger superoxide dism utase, and the xanthine oxidase antagonist allopurinol slowed the rates of heme-<bullet>NO production, decreased ceruloplasmin and semiquinone levels, and preserved SBF. However, only aminoguanidine and allopurinol improved h eat tolerance, and only allpourinol eliminated the rise in portal endotoxin content. We conclude that hyperthermia stimulates xanthine oxidase product ion of reactive oxygen species that activate metals and limit heat toleranc e by promoting circulatory and intestinal barrier dysfunction. In addition, intact NOS activity is required for normal stress tolerance, whereas overp roduction of . NO may contribute to the non-programmed splanchnic dilation that precedes vascular collapse with heat stroke.