Background <p>Inhaled nitric oxide (iNO) is a commonly used pulmonary vasodilator in neonates, but its effects on intestinal perfusion remain unclear. This study assessed the impact of iNO on splanchnic tissue oxygenation as a surrogate for intestinal perfusion using near infrared spectroscopy (NIRS), with NG-nitro-L-arginine methyl ester (L-NAME) used to inhibit endogenous nitric oxide synthase (NOS) and isolate the effect of exogenous NO.</p> Methods <p>Seventeen piglets (7–10 days old) were anesthetized and ventilated with NIRS probes placed on the forehead and abdomen. Piglets were allocated to group 1 (<i>n</i> = 4) receiving iNO only, group 2 (<i>n</i> = 6) receiving iNO then L-NAME, and group 3 (<i>n</i> = 7) receiving L-NAME then iNO. Serum nitrate/nitrite and endothelin-1 expression were assessed via colorimetric assay and ELISA.</p> Results <p>iNO increased splanchnic oxygenation, significantly reducing the difference between cerebral and abdominal NIRS. This effect was blunted by L-NAME pre-treatment (<i>p</i> = 0.02 at 0 and 60 ppm). Serum nitrate/nitrite and endothelin-1 levels did not differ significantly between groups, nor did mean arterial pressure.</p> Conclusion <p>iNO enhances splanchnic tissue oxygenation to near cerebral levels. Pretreatment with L-NAME eliminates this effect, suggesting a role for endogenous NOS in this process. These findings suggest a potential protective role of iNO against intestinal ischemia and merit further investigation.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>As shown in previous studies, there are extrapulmonary effects of inhaled nitric oxide (iNO) on tissue perfusion; this study specifically validates this by evaluating oxygenation of the gut.</p> </ItemContent> <ItemContent> <p>iNO increases splanchnic tissue oxygenation to cerebral levels.</p> </ItemContent> <ItemContent> <p>This preclinical research establishes improvement in intestinal oxygenation with iNO use in contrast to other studies proposing iNO as a potential contributor to the development of NEC in the setting of cardiac defects.</p> </ItemContent> <ItemContent> <p>This study suggests that iNO could be a potential therapeutic agent in ischemic intestinal conditions.</p> </ItemContent> </UnorderedList></p>