PREVENTIVE EFFECTS OF INDOMETHACIN ON DIAPHRAGMATIC CONTRACTILE ALTERATIONS IN ENDOTOXEMIC RATS

We evaluated the effects of a sublethal Escherichia coli endotoxemia with and without concomitant administration of indomethacin on diaphragmatic strength in an in vivo rat model. Ninety-six rats were inoculated subcutaneously on two successive days with 0.3 and 0.6 mg/100 g body weight of E. coli lipopolysaccharide, respectively (E animals, n = 64), or saline (C group, n = 32). E animals were divided into two groups based on subcutaneous administration of endotoxin alone (E group, n = 32) or endotoxin plus indomethacin (2.5 mg/kg body weight/day) (EI group, n = 32). Diaphragmatic strength was evaluated in 14 animals from each group 2 days after the first endotoxin or saline administration. Diaphragmatic strength was assessed by measuring the transdiaphragmatic pressure (Pdi) during electrical stimulation of the phrenic nerves at different frequencies (0.5, 10, 20, 30, 50, and 100 Hz). Lung histologic examination and measurements of lung weights were performed 1 and 2 days after the first endotoxin or saline administration in nine animals of each group each day. A slight increase in the number of neutrophils without alveolar septal thickening and alveolar edema was observed in the lungs of endotoxin-inoculated animals. No differences in the lung weight to body weight ratio nor in the dry to wet weight ratio of the lungs were noted between C, E, and EI groups. Diaphragmatic weight was not different in the three groups, whereas the weights of the extensor digitorium longus, tibialis anterior, and soleus muscles were significantly reduced in E compared with C and EI animals. Diaphragmatic strength was reduced in Group E when compared with group C as defined by reduction in Pdi for 50 and 100 Hz. Reduced diaphragmatic strength in E animals was associated with an increase in the rate of relaxation of the twitch Pdi (τ) when compared with C animals (E: 18.08 ± 1.02 ms; C: 14.41 ± 0.81 ms; p<0.05). Indomethacin administration during endotoxemia prevented both the reduction in Pdi at 50 and 100 Hz and prolongation in τ (EI: 15.35 ± 0.7 ms; p<0.05 compared with E). We conclude that (1) sublethal endotoxemia in rats produces a decrease in tetanic diaphragmatic strength secondary to an impaired contractility, and (2) prevention of this phenomenon by indomethacin administration suggests that it could be mediated by products of the arachidonic acid prostaglandin system.