INHIBITION OF EXHALED NITRIC-OXIDE PRODUCTION DURING SEPSIS DOES NOT PREVENT LUNG INFLAMMATION

Objectives: Increases in exhaled nitric oxide have been demonstrated t o originate from the lungs of rats after septic lung injury. The aim o f this study was to investigate whether treatment with the nitric oxid e synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) would pr event lipopolysaccharide (LPS) induced increases in exhaled nitric oxi de and whether this would have an effect on septic lung inflammation. Design: Prospective, randomized, placebo-controlled animal laboratory investigation. Setting: University laboratory Subjects: Male, anesthet ized, paralyzed, and mechanically ventilated Sprague-Dawley rats (n = 27). Interventions: Rats were mechanically ventilated with air filtere d to remove nitric oxide (espiratory rate 40 breaths/min, tidal volume 3 mt, positive end expiratory pressure 0, FIO2 0.21). They were then randomized to receive intravenous injections of either L-NAME (25 mg/k g/hr x 4 hrs) (n = 11) or saline (n = 10). Both groups were again rand omized to receive either LPS (Salmonella typhosa: 20 mg/kg iv x 1 dose ) or an equal volume of saline 5 mins later. Thereafter, exhaled gas w as collected in polyethylene bags for measurements of nitric oxide con centration. After 4 hrs, the rats were killed and the lungs were prese rved and examined histologically. To examine the effect of L-NAME and LPS on mean arterial blood pressure, six additional rats underwent the same ventilation protocol with cannulation of the right internal caro tid artery so that systemic arterial pressures could be measured. Meas urements and Main Results: Exhaled gas was collected and measurements of NO concentrations were made using chemiluminescence every 20 mins f or 240 mins during ventilation. A total lung injury score was calculat ed by determining the extent of cellular infiltrate, exudate and hemor rhage. Mean arterial pressure was recorded every 5 mins for 20 mins an d then at 20-min periods for 120 mins. Exhaled nitric oxide concentrat ions increased in all the LPS-treated rats that did not receive L-NAME by 120 mins; a plateau was reached by 190 mins that was similar to 4 times greater than control rats not treated with LPS (p<.001). In cont rast, rats treated with L-NAME and LPS did not show an increase in exh aled NO. Administration of L-NAME induced a 10-min nonsustained increa se in mean arterial pressure in two rats treated with L-NAME followed by LPS. This increase in mean arterial pressure was not seen in two pl acebo and two LPS-treated rats that did not receive L-NAME. Lung infla mmation was significantly worse in the two groups of rats which receiv ed LPS compared with the two that did not. L-NAME did not cause lung i nflammation in rats that did not receive LPS; however, LPS-treated rat s that received L-NAME had more inflammatory interstitial infiltrate ( p<.05) and a trend toward worse lung injury than did LPS-treated rats that did not receive L-NAME. Conclusion: We conclude that L-NAME can i nhibit the increase in exhaled NO from the lungs of septic rats, but t hat this inhibition does not reduce lung inflammation, and may worsen it.