Hyperthermia induces injury to the intestinal mucosa in the mouse: evidence for an oxidative stress mechanism.

Loss of the intestinal barrier is critical to the clinical course of heat illness, but the underlying mechanisms are still poorly understood. We tested the hypothesis that conditions characteristic of mild heatstroke in mice are associated with injury to the epithelial lining of the intestinal tract and comprise a critical component of barrier dysfunction. Anesthetized mice were gavaged with 4 kDa FITC-dextran (FD-4) and exposed to increasing core temperatures, briefly reaching 42.4°C, followed by 30 min recovery. Arterial samples were collected to measure FD-4 concentration in plasma (in vivo gastrointestinal permeability). The small intestines were then removed to measure histological evidence of injury. Hyperthermia resulted in a ≈2.5-fold elevation in plasma FD-4 and was always associated with significant histological evidence of injury to the epithelial lining compared with matched controls, particularly in the duodenum. When isolated intestinal segments from control animals were exposed to ≥41.5°C, marked increases in permeability were observed within 60 min. These changes were associated with release of lactate dehydrogenase, evidence of protein oxidation via carbonyl formation and histological damage. Coincubation with N-acetylcysteine protected in vitro permeability during hyperthermia and reduced histological damage and protein oxidation. Chelation of intracellular Ca(2+) to block tight junction opening during 41.5°C exposure failed to reduce the permeability of in vitro segments. The results demonstrate that hyperthermia exposure in mouse intestine, at temperatures at or below those necessary to induce mild heatstroke, cause rapid and substantial injury to the intestinal lining that may be attributed, in part, to oxidative stress.

Hydrothermal synthesis and characterization of a layered cobalt phenylphosphonate, Co(PhPO3)(H2O).

We report the hydrothermal synthesis and characterization of a layered cobalt phenylphosphonate. Unlike most metal phosphonates reported to date, the structure was solved by single crystal X-ray diffraction (SC-XRD). Co(ii) centres are hexa-coordinated by oxygen and the octahedra corner-share into a layer. The layers are capped by phenylphosphonate groups, where the phenyl groups define a hydrophobic bilayer region. The material was also characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA) and SQUID (superconducting quantum interference device) magnetometry. The material undergoes an antiferromagnetic transition at a relatively low Néel temperature of 4.0 K, while the Curie-Weiss temperature of -76.5 K reflects the low-dimensionality of the magnetic structure. The effective magnetic moment of 5.01 micro(B) per Co(2+) verifies a high-spin configuration and an octahedral coordination of the metal centres. This layered material was correctly predicted in the literature from powder data, adds to the structural diversity of the cobalt phosphonates, and may be useful as an intercalation or exfoliation compound.

A layered tin(II) phosphonate, [Sn(C6H5O3P)]n.

Poly[tin(II)-mu-phenylphosphonato], [Sn(C(6)H(5)O(3)P)](n), was synthesized solvothermally at 423 K and crystallized in the monoclinic system, space group Cc. The inorganic layers consist of alternating pyramidal Sn and tetrahedral P centers, joined by doubly bridging O atoms. The corner-sharing SnO(3) and PO(3)C(6)H(5) polyhedra define a corrugated layer of six-membered rings. The layers are connected along the unique b axis by interdigitated phenyl rings of the phenylphosphonate groups.

Ambulatory estimates of maximal aerobic power from foot -ground contact times and heart rates in running humans.

Seeking to develop a simple ambulatory test of maximal aerobic power (VO(2 max)), we hypothesized that the ratio of inverse foot-ground contact time (1/t(c)) to heart rate (HR) during steady-speed running would accurately predict VO(2 max). Given the direct relationship between 1/t(c) and mass-specific O(2) uptake during running, the ratio 1/t(c). HR should reflect mass-specific O(2) pulse and, in turn, aerobic power. We divided 36 volunteers into matched experimental and validation groups. VO(2 max) was determined by a treadmill test to volitional fatigue. Ambulatory monitors on the shoe and chest recorded foot-ground contact time (t(c)) and steady-state HR, respectively, at a series of submaximal running speeds. In the experimental group, aerobic fitness index (1/t(c). HR) was nearly constant across running speed and correlated with VO(2 max) (r = 0.90). The regression equation derived from data from the experimental group predicted VO(2 max) from the 1/t(c). HR values in the validation group within 8.3% and 4.7 ml O(2) x kg(-1) x min(-1) (r = 0.84) of measured values. We conclude that simultaneous measurements of foot-ground constant times and heart rates during level running at a freely chosen constant speed can provide accurate estimates of maximal aerobic power.

Influence of moderate haemodilution with fluosol or normal saline on carbaryl disposition in Sprague-Dawley rats.

In rats carbaryl undergoes extensive biotransformation involving both albumin-mediated hydrolysis and cytochrome P-450-mediated metabolism; studies have suggested that approximately one-half of a carbaryl dose is hydrolysed and one-half is metabolized. Fluosol is known to be an inducer of cytochrome P-450, and Fluosol haemodilution reduces plasma albumin concentrations. The disposition of carbaryl was, therefore, determined in rats for 72 h after 40 mL kg-1 haemodilution with Fluosol or normal saline (0.9% NaCl). Volumes of distribution were significantly reduced after saline haemodilution for 72 h but only at 48 h after Fluosol haemodilution. Fluosol and saline haemodilution had little influence on carbaryl total body clearance (CL). These results indicate that both hepatic and non-hepatic clearance pathways were not influenced by the haemodiluents or the haemodilution procedure.

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The effect of moderate hemodilution with Fluosol on cytochrome P4502D6 activity in the rat.

Desmethylimipramine (desipramine, DMI) is predominantly 2-hydroxylated to 2-hydroxydesipramine, and the remainder is N-demethylated to didesmethylimipramine (DDMI) in both rats and man. DMI 2-hydroxylation is mediated by the same cytochrome P-450 isoenzyme (P4502D6) in rats and man. Fluosol hemodilution has previously been shown to influence the activity of P4502B1 and P4502B2, the cytochrome P-450 isoenzymes induced by phenobarbital in rats. In this study, DMI was used as a model substrate to investigate the influence of moderate Fluosol hemodilution on P4502D6 activity in rats. DMI total body clearance was not influenced by Fluosol hemodilution. This was an anticipated outcome since phenobarbital had a negligible effect on DMI metabolism, and Fluosol and phenobarbital affect the same isoenzymes. DMI Vdss was increased at 0.5 hour after hemodilution, but decreased from 24-72 hours. The decreased Vdss is most likely due to increased concentrations of alpha-1-acid-glycoprotein. Thus, Fluosol hemodilution is not expected to influence the hepatic P4502D6 activity in man. However, Fluosol may have marked influences on the apparent volumes of distribution of basic drugs that bind to alpha-1-acid-glycoprotein.

The effect of varying extents of Fluosol-DA or normal saline haemodilution on the dose dependent kinetics of phenytoin in the rat.

Phenytoin kinetics were determined in rats in which the blood was moderately haemodiluted with 20 or 40 mL kg-1 of Fluosol-DA or normal saline. Rats received one of three intravenous phenytoin doses (10, 40, 50 mg kg-1) 0.5, 24, 48, or 72 h after haemodilution and were compared with non-exchanged controls. Haemodilution with either 20 or 40 mL kg-1 of Fluosol or saline had no influence on the dose-dependent kinetics of phenytoin. Haemodilution with 40 mL kg-1 of Fluosol decreased the half-life of phenytoin's major metabolite, HPPH, after a 50 mg kg-1 dose. Neither Fluosol nor saline haemodilution affected the normal delay in biliary cycling of HPPH.

The effect of moderately severe hemodilution with Fluosol-DA on cytochrome P-450 mediated antipyrine metabolism.

Antipyrine metabolism was determined in conscious, unrestrained rats after isovolemic hemodilution with FluosolR-DA. Rats received an intravenous antipyrine dose (20 mg/kg) 0.5, 24, 48, or 72 hours after hemodilution and the pharmacokinetic parameters were compared to non-exchanged control (CONT) animals. Antipyrine clearance (Cl) was significantly decreased at 0.5 and 72 hours after hemodilution. Hemodilution did not significantly alter the antipyrine apparent volume of distribution (Vd) for 48 hours; however, Vd was significantly decreased by 60% at 72 hours. The cytochrome P-450 mediated formation of 3OHME and 4OH was significantly increased at 48 and 72 hours due to an increased metabolite formation rate constant (kf) and not an enhanced metabolic clearance (Clm).

The effect of varying percentages of haemodilution with fluosol-DA or normal saline on antipyrine metabolism in the rat.

Antipyrine disposition and metabolism in conscious, unrestrained rats after 25 or 50% haemodilution with Fluosol or normal (0.9% NaCl) saline is reported. Rats received an intravenous antipyrine dose (20 mg kg-1) 0.5, 24, 48, or 72 h after haemodilution and its pharmacokinetic parameters have been compared with non-exchanged control animals. Haemodilution 25% with Fluosol initially depressed antipyrine metabolism for 24 h by decreasing the antipyrine urinary excretion rate constant and the formation rate constants of 4-hydroxyantipyrine (4-OH) and 3-hydroxymethylantipyrine (3-OHME). Metabolism was then increased for 48 and 72 h with a slight increase in all rate constants. Haemodilution 50% with Fluosol produced a similar pattern but with significant increases in the 3-OHME formation rate constant found at 48 and 72 h. Haemodilution 25% with saline reduced 4-OH formation for 48 h. Haemodilution 50% with saline significantly reduced antipyrine urinary excretion at all times. After a significant increase in the 4-OH and 3-OHME formation rate constants at 24 h following 50% haemodilution with saline, the rate constants were significantly decreased at 48 and 72 h. Haemodilution 25% with Flusol significantly reduced the antipyrine Vd at 0.5 and 72 h. After haemodilution 50% with Fluosol, the Vd alternated between values greater and less than control throughout the 72 h. Haemodilution 25 or 50% with saline had little influence on Vd.

Effect of moderate haemodilution with Fluosol-DA or normal saline on indocyanine green and (+)-propranolol kinetics.

Indocyanine green (ICG) and (+)-propranolol kinetics were determined in the rat following moderate (50%) blood exchange with either Fluosol-DA or 0.9% NaCl (saline). Rats received an intravenous ICG dose (5 mg kg-1) before an intravenous dose of (+)-propranolol (2.5 mg kg-1) 0.5, 24, 48 or 72 h after haemodilution and were compared with non-exchanged controls. Haemodilution with Fluosol-DA reduced the ICG elimination rate constant during the first 24 h while a significant reduction was seen 48 h after normal saline exchange. ICG clearances tended to be less than the control value, and were significantly reduced only at 24 h after Fluosol-DA exchange due to a reduced Varea. (+)-Propranolol half-life was significantly increased 48 and 72 h after saline exchange; (+)-propranolol clearance was also significantly reduced 72 h after Fluosol-DA exchange. ICG clearance may be reflecting a hypovolaemic change which occurs after haemodilution, which would reduce the hepatic blood flow. However, (+)-propranolol clearance was not altered, suggesting that the hepatic blood flow is not changed. It is possible that ICG clearance is changed due to alterations in its extraction ratio instead of hepatic blood flow changes.

Effect of moderate haemodilution with Fluosol-DA or normal saline on low-dose phenytoin and (+/-)-5-(4-hydroxyphenyl)-5-phenylhydantoin kinetics.

Phenytoin kinetics were determined in the rat following moderate (50%) blood exchange with either Fluosol-DA or normal saline. Rats received an intravenous phenytoin dose (10 mg kg-1) 0.5, 24, 48, or 72 h after exchange and were compared with non-exchanged controls. Phenytoin t 1/2 was not altered by exchange with either fluid. Its Cl and Vd were decreased and AUC increased 24, 48, and 72 h after saline exchange and 24 h after Fluosol-DA exchange. (+/-)-5-(4-Hydroxyphenyl)-5-phenylhydantoin (HPPH), a major metabolite of phenytoin, showed a decreased t1/2 and VHPPH 24, 48, and 72 h after exchange with either fluid; t1/2 was also reduced 0.5 h after Fluosol-DA exchange. The decreased Vd and VHPPH may result from changes in cardiac output secondary to haemodilution, or may represent a redistribution in the microcirculation. Fluosol-DA appears to enhance phenytoin and HPPH metabolism 48 and 72 h after exchange.