Stephen G. Jenkinson

Effect of Nitric Oxide Synthase Inhibitor on Diaphragmatic Function after Resistive Loading

We studied the effect of a nitric oxide synthase inhibitor, Nomega-Nitro-L-arginine-methyl-ester (L-NAME), on in vitro diphragmatic function both at rest (control) or after inspiratory resistive loading (IRL). Sprague-Dawley rats were anesthetized, instrumented, and then the following experimental groups: (1) controls; (2) L-NAME (100 mg/kg/body weight intravenously alone); (3) IRL alone; and (4) L-NAME + IRL. The IRL protocol consisted of applying a variable resistor to the inspiratory limb of a two-way valve at 70% of maximal airway pressure until apnea. After the experiment, the animals were sacrificed and diaphragmatic strips were obtained for activity of constitutive nitric oxide synthase (cNOS) and measurements of in vitro contractile properties: tetanic (Po) and twitch tensions (Pt). cNOS activity was significantly decreased in the L-NAME and L-NAME + IRL groups (P < or = 0.05) as compared with control and IRL groups. L-NAME alone did not affect Po or Pt. However, in both IRL groups, with and without was a significant decrease in Po and Pt. This reduction was comparable in both groups. In summary, our data showed that L-NAME resulted in a significant decrease cNOS activity, but in vitro contractility was impaired.

Effects of Age on Rat Glutathione Metabolism

The authors hypothesized that rat plasma or tissue glutathione metabolism could change with age due to possible decreases in glutathione-related enzyme activities. To test this hypothesis, the authors measured plasma and tissue concentrations of glutathione and glutathione-related enzymes. Animals were 3 months, 12 months, or 24 months old at the time of experiments. Plasma glutathione was found to be significantly increased in both the 12-month-old and 24-month-old groups compared to the 3-month-old rats. Tissue enzyme measurements showed no significant differences between the groups in lung or liver glutathione peroxidase or glutathione S-transferase. gamma-Glutamyl transpeptidase activity was significantly decreased in kidney and lung with aging. Decreases in tissue gamma-glutamyl transpeptidase activity occur with age; this may contribute to increases in plasma glutathione concentrations.

Analytic Reviews : Oxygen Toxicity

Oxygen therapy is administered to patients to decrease tissue hypoxia and to relieve arterial hypoxemia. High concentrations of oxygen often are used for short pe riods of time in patients with acute respiratory illnesses, and concentrations only slightly higher than ambient levels are administered for much longer time periods to patients with chronic respiratory diseases. Supplying oxygen to plants, animals, or bacteria has long been known to produce varying amounts of tissue damage; toxicity increases as concentrations of oxygen or the pressure used during exposure increases. End-organ damage from hyperoxia depends on both the concentra tion of oxygen administered and the pressure during the exposure. Prolonged exposure to hyperbaric oxygen (> 2.5 atmosphere of pressure) causes both central nervous system and pulmonary toxicity that results in atelectasis, pulmonary edema, and seizures. Lung dam age as a result of normobaric hyperoxia is the predomi nant manifestation of toxicity. A severe retinopathy (re trolental fibroplasia) also can occur in neonates during oxygen exposures at ambient pressure, and cases have been reported to occur with only modest increases in inspired oxygen concentrations. For these reasons, the lowest possible concentration of oxygen that relieves tissue hypoxia is administered to patients, and the oxy gen concentration is stabilized when the desired thera peutic goals are accomplished.

Lack of enhancement of bleomycin lung injury in vitamin E-deficient rats

Abstract DNA breakage caused by bleomycin may be due to the formation of bleomycin-ferrous complexes, which activate molecular oxygen to form activated oxygen species or free radicals. If bleomycin administration results in intracellular free radical formation, then peroxidation of cellular membranes may be a prominent mechanism in producing bleomycin lung toxicity. In order to explore this hypothesis, we performed experiments instilling bleomycin intratracheally into vitamin E-deficient and control rats. Exhaled ethane production and formation of lung tissue malonaldehyde were measured as indices of lipid peroxidation. Mortality and serial changes in lung collagen content were also measured to assess increases in lung injury in the vitamin E-deficient rats. No increases in ethane exhalation occurred in the groups receiving bleomycin as compared to the matched controls receiving saline. Lung malonaldehyde was found to increase at 96 hours following bleomycin instillation. No increases in mortality or the formation of lung collagen occurred in vitamin E-deficient rats treated with bleomycin as compared to control rats given bleomycin. These results suggest that vitamin E-deficient rats do not have enhanced lung toxicity following bleomycin instillation and that although free radical activation may be occurring, lipid peroxidation does not appear to be a prominent mechanism in producing bleomycininduced pulmonary toxicity.

Inability of niacin to protect from in vivo hyperoxia or in vitro microsomal lipid peroxidation

The efficacy of niacin in protecting rats from normobaric hyperoxia was evaluated in vivo by exposing niacin treated animals and controls to greater than 95% O2 for 96 hours. The vitamin was also evaluated as a possible free radical scavenger in vitro using an Fe-ascorbate initiated microsomal lipid peroxidation system. No protective effects were observed in vivo either in mortality or in differences in lung wet and dry weights of the niacin treated rats when compared to controls. Niacin in varying concentrations also did not decrease lipid peroxidation in the microsomal systems. Although this vitamin has been reported to protect animals from paraquat toxicity when given intraperitoneally once daily, niacin administered in similar doses does not appear to protect rats from hyperoxia.