Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock

Abstract

1 The present investigation compares the effects of intravenous infusion of the NO synthase inhibitor NG-monomethyl-L-argiine (L-NMMA) with that of an inhalation with NO gas in a porcine model of endotoxin (lipopolysaccharide, LPS) shock. In addition, the effects of the combination of these two treatments were also investigated. 2 Male pigs were anaesthetized and instrumented for the measurement of haemodynamic parameters. Blood samples were withdrawn at different time intervals for determination of blood gases, pH, and plasma levels of nitrite/nitrate and tumour necrosis factor. 3 Endotoxin infusion (15 tLg kg-' h-' for 3 h) caused a progressive fall in mean arterial blood pressure (MABP) and cardiac output (CO) and a biphasic increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistence (PVR). A continuous infusion of L-NMMA (0.1 mg kg' min-') significantly attenuated the fall in MABP, but did not affect MPAP, CO and PVR. NO-inhalation (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-' min-') with NO-inhalation (50 p.p.m.) completely prevented the fall in MABP, significantly improved CO, and attenuated the biphasic increase in MPAP and 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 combined administration of L-NMMA infusion and NO-inhalation completely prevented the fall in Pao2 and significantly protected against the increase in Paco2. 5 Infusion of endotoxin for 180 min resulted in a mortality of 58%, which was not affected by L-NMMA (63%). In contrast, treatment of LPS-animals with either NO-inhalation alone or NOinhalation plus L-NMMA completely prevented mortality. 6 This investigation demonstrates that treatment with NO-inhalation, in order to prevent the dramatic increase in MPAP, PVR and the alterations in peripheral blood gases combined with systemic L-NMMA to improve systemic MABP and thus organ perfusion, may be a new therapeutic regimen in the treatment of septic shock.

Nitric oxide inhalation and nitric oxide synthase inhibitor supplement for endotoxin‐induced hypotension

“…In contrast, in the L‐NNA group there was a selective, significant decrease in pulmonary arterial pressure with no effect on the systemic arterial pressure. While Offner et al have reported similar results, the present study demonstrated the effectiveness of a combined therapy of NO inhalation and NOS inhibitors, even in neonatal animals on day 0 23,25,26 . Furthermore, it was suggested that in cases of endotoxin‐induced hypotension complicated with pulmonary hypertension, NO inhalation carries the risk of aggravating the hypotension.…”

“…Our approach, therefore, is to use a treatment strategy that targets the pulmonary hypertension in addition to the systemic hypotension. Recently, relatively good results have been reported from studies of combined therapy employing NO synthetic inhibitors to treat hypotension and NO inhalation for pulmonary hypertension 23,25,26 . However, most cases of sepsis treated by neonatologists occur within 72 h of birth, when respiratory and circulatory dynamics are adapting to the extra‐uterine environment.…”

“…It has been reported both that cardiac output increases 14 and decreases 26,29 due to endotoxins. In the present study cardiac output declined, and it is likely that in this condition there are diastolic disturbances in the left ventricle as a result of decreased blood flow from the right ventricle caused by an elevation in the pulmonary arterial pressure, resulting in reduced output from the left ventricle.…”

“…In the present study, L‐NNA not only inhibited the fall of blood pressure in endotoxin‐induced hypotension in neonatal animals, it even caused blood pressure to return to pre‐experimental levels. Reports show that the administration of NOS inhibitors before the administration of endotoxins prevents shock or inhibits the decrease in blood pressure 21,23,26 . There are few reports of successful treatment after the subjects had fallen into a state of hypotensive shock 25 .…”

Animal Models as the Basis of Pharmacologic Intervention in Trauma and Sepsis Patients

“…Nitric Oxide. Currently there is controversy about whether nitric oxide (NO) suppression with nonselective or selective agents [52], supplementation [53], neither, or both [54] is an adequate measure to deal with NO in trauma and sepsis. There are positive examples of NO synthase blockade in trauma [55,56] and sepsis [57], but there are also studies showing deleterious effects [58,59].…”