This work tested the hypotheses that splanchnic oxidant generation is important in determining heat tolerance and that inappropriate.NO production may be involved in circulatory dysfunction with heat stroke. We monitored colonic temperature (T(c)), 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 T(c) 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-.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-.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-.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.NO may contribute to the nonprogrammed splanchnic dilation that precedes vascular collapse with heat stroke.
Superoxide dismutases (SOD) are considered to be antioxidant enzymes. This view came about because its substrate, superoxide, is a free radical; in the era of their discovery, 1960’s – 1970’s, the general mindset was that free radicals in biology must be damaging. Indeed SOD blunts the cascade of oxidations initiated by superoxide. However in the late 1970’s it was observed that cancer cells that have low activity of the mitochondrial form of SOD, MnSOD, grow faster than those with higher activities of MnSOD. These observations indicated that SOD, superoxide, and hydrogen peroxide affected the basic biology of cells and tissues, not just via damaging oxidation reactions. It is now realized that superoxide and hydrogen peroxide are essential for normal cellular and organism function. MnSOD appears to be a central player in the redox biology of cells and tissues.
Previous experiments from our laboratory have demonstrated that severe hyperthermia results in a selective loss of splanchnic vasoconstriction. Using electron paramagnetic resonance spectroscopy to scan whole blood samples collected in vivo from the portal vein and femoral artery of conscious unrestrained rats, we observed an increase in the concentration of spectroscopy-detectable species in portal venous blood of all heat-stressed animals. These spectra consisted of at least three distinct species: one with a broad feature having an effective g factor for the unpaired electron (g) of 2.06 assigned to the copper-binding acute phase protein ceruloplasmin, and two with narrower features that evolved at core temperatures > 39 degrees C representing a semiquinone radical and .NO-heme. This heat-induced signal displays the classic nitrogen triplet hyperfine structure (nitrogen hyperfine splitting constant = 17.5 gauss, centered at g = 2.012) that is consistent with a five-coordinate heme complex and is characteristic of an unpaired electron coupled to nitrogen in the ferrous .NO-heme adduct [(alpha 2+NO) beta 3+]2. The intensity of this signal increased approximately twofold as core temperature rose to > 39 degrees C, peaking 1 h post-heat exposure at greater than threefold basal concentration. This species was not seen in corresponding arterial blood samples. This is the first demonstration that whole body hyperthermia produces increased concentrations of radicals and metal binding proteins in the venous blood of the rat and suggests that severe hyperthermia stimulates an enhanced local release of .NO within the splanchnic circulation.
Previously, we demonstrated by electron paramagnetic resonance (EPR) spectroscopy that ultraviolet radiation induces free-radical formation in Skh-1 hairless mouse skin. Because free-radical oxidative stress is thought to play a principal role in skin photoaging and cancer, oxidative stress and subsequent photodamage should be decreased by supplementation of skin with antioxidants. Using both the ascorbate free radical and an EPR spin-trapping system to detect short-lived radicals, we evaluated the effect of the topically applied antioxidants tocopherol sorbate, alpha-tocopherol, and tocopherol acetate on ultraviolet radiation-induced free-radical formation. We show that tocopherol sorbate significantly decreases the ultraviolet radiation-induced radical flux in skin. With our chronically exposed mouse model, tocopherol sorbate was also found to be significantly more protective against skin photoaging than alpha-tocopherol and tocopherol acetate. These results extend our previous observations of ultraviolet radiation-induced free-radical generation in skin and indicate the utility of tocopherol sorbate as an antioxidant in providing significant protection against ultraviolet radiation-induced oxidative damage.
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