Mechanisms of circulatory and intestinal barrier dysfunction during whole body hyperthermia
Mechanisms of circulatory and intestinal barrier dysfunction during whole body hyperthermia
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DOI：
10.1152/ajpheart.2001.280.2.h509
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发表时间：
2001-02-01
影响因子：
4.8
通讯作者：
Gisolfi, CV
中科院分区：
文献类型：
--
作者：
Hall, DM;Buettner, GR;Gisolfi, CV
这项工作验证了内脏氧化剂的产生在决定耐热性中很重要的假设，以及不适当的中心点NO的产生可能与中暑的循环功能障碍有关。我们监测了暴露在40℃环境温度下麻醉大鼠的结肠温度（Tc）、心率、平均动脉压和内脏血流量（SBF）。加热速率、加热时间和热负荷决定了耐热性。定期采集门静脉血，测定自由基和内毒素含量。将Tc从37℃升高到41.5℃，可使SBF降低40%，并刺激自由基铜蓝蛋白、半醌和五配位铁（II）亚硝基血红素（血红素中心点NO）的产生。门静脉内毒素浓度由28 pg/ml升高至59 pg/ml （P< 0.05）。与单纯热应激相比，一氧化氮合酶（NOS）拮抗剂n -omega-硝基- l -精氨酸甲酯（L-NAME）热加处理剂量依赖性地抑制血红素中心点NO的生成，增加铜蓝蛋白和半醌水平。L-NAME还显著降低了SBF降低、门脉内毒素浓度升高和耐热性降低（P < 0.05）。NOS II和二胺氧化酶拮抗剂氨基胍、超氧化物阴离子清除剂超氧化物歧化酶、黄嘌呤氧化酶拮抗剂别嘌呤醇减缓血红素中心点NO的生成速度，降低铜蓝蛋白和半醌水平，保存SBF。然而，只有氨基胍和别嘌呤醇提高了耐热性，只有别嘌呤醇消除了门静脉内毒素含量的上升。我们得出结论，热疗刺激黄嘌呤氧化酶产生活性氧，激活金属，并通过促进循环和肠道屏障功能障碍限制耐热性。此外，正常的抗逆性需要完整的NOS活性，而中心点NO的过量产生可能导致非程序性内脏扩张，导致血管塌陷伴中暑。
This work tested the hypotheses that splanchnic oxidant generation is important in determining heat tolerance and that inappropriate center dot NO production may be involved in circulatory dysfunction with heat stroke. We monitored colonic temperature (Tc), heart rate, mean arterial pressure, and splanchnic blood flow (SBF) in anesthetized rats exposed to 40 degrees C ambient temperature. Heating rate, heating time, and thermal load determined heat tolerance. Portal blood was regularly collected for determination of radical and endotoxin content. Elevating Tc from 37 to 41.5 degrees C reduced SBF by 40% and stimulated production of the radicals ceruloplasmin, semiquinone, and penta-coordinate iron(II) nitrosyl-heme (heme-center dot NO). Portal endotoxin concentration 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-omega-nitro-L-arginine methyl ester (L-NAME) dose dependently depressed heme-center dot NO production and increased ceruloplasmin and semiquinone levels. L-NAME also significantly reduced lowered SBF, increased portal endotoxin concentration, and reduced heat tolerance (P < 0.05). The NOS II and diamine oxidase antagonist aminoguanidine, the superoxide anion scavenger superoxide dismutase, and the xanthine oxidase antagonist allopurinol slowed the rates of heme-center dot NO production, decreased ceruloplasmin and semiquinone levels, and preserved SBF. However, only aminoguanidine and allopurinol improved heat tolerance, and only allpourinol eliminated the rise in portal endotoxin content. We conclude that hyperthermia stimulates xanthine oxidase production of reactive oxygen species that activate metals and limit heat tolerance by promoting circulatory and intestinal barrier dysfunction. In addition, intact NOS activity is required for normal stress tolerance, whereas overproduction of center dot NO may contribute to the non-programmed splanchnic dilation that precedes vascular collapse with heat stroke.