EFFECTS OF NITRIC-OXIDE SYNTHASE INHIBITION COMBINED WITH NITRIC-OXIDE INHALATION IN A PORCINE MODEL OF ENDOTOXIN-SHOCK

1 The present investigation compares the effects of intravenous infusi on of the NO synthase inhibitor N-G-monomethyl-L-arginine (L-NMMA) wit h that of an inhalation with NO gas in a porcine model of endotoxin (l ipopolysaccharide, LPS) shock. In addition, the effects of the combina tion of these two treatments were also investigated. 2 Male pigs were anaesthetized and instrumented for the measurement of haemodynamic par ameters. Blood samples were withdrawn at different time intervals for determination of blood gases, pH, and plasma levels of nitrite/nitrate and tumour necrosis factor. 3 Endotoxin infusion (15 mu g kg(-1) h(-1 ) for 3 h) caused a progressive fall in mean arterial blood pressure ( MABP) and cardiac output (CO) and a biphasic increase in mean pulmonar y arterial pressure (MPAP) and pulmonary vascular resistence (PVR). A continuous infusion of L-NMMA (0.1 mg kg(-1) min(-1)) significantly at tenuated the fail in MABP, but did not affect MPAP, CO and PVR. NO-inh alation (50 p.p.m.) did not affect MABP, but significantly blunted the biphasic increase in MPAP and PVR and significantly delayed the fall in CO. The combination of L-NMMA infusion (0.1 mg kg(-1) min(-1)) with NO-inhalation (50 p.p.m.) completely prevented the fall in MABP, sign ificantly improved CO, and attenuated the biphasic increase in MPAP an d PVR. 4 Endotoxin also caused a decline in PaO2 and a rise of PaCO2. Infusion of L-NMMA neither affected the fall in PaO2 nor the increase in PaCO2. In contrast, inhalation with NO gas alone as well as the com bined administration of L-NMMA infusion and NO-inhalation completely p revented the fall in PaO2 and significantly protected against the incr ease in PaCO2. 5 Infusion of endotoxin for 180 min resulted in a morta lity of 58%, which was not affected by L-NMMA (63%). In contrast, trea tment of LPS-animals with either NO-inhalation alone or NO-inhalation plus L-NMMA completely prevented mortality. 6 This investigation demon strates that treatment with NO-inhalation, in order to prevent the dra matic increase in MPAP, PVR and the alterations in peripheral blood ga ses combined with systemic L-NMMA to improve systemic MABP and thus or gan perfusion, may be a new therapeutic regimen in the treatment of se ptic shock.