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The Organs Responsible for Increased Nitric Oxide Production After Trauma-Hemorrhage and Resuscitation

Nadia Smail, MD; Robert A. Catania, MD; Ping Wang, MD; William G. Cioffi, MD; Kirby I. Bland, MD; Irshad H. Chaudry, PhD

Arch Surg. 1998;133:399-405.

Objective  To determine which organs produce the increased levels of nitric oxide (NO) seen after hemorrhage and resuscitation.

Animals and Interventions  Adult male rats underwent laparotomy (ie, trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximum bleedout volume was returned in the form of Ringer lactate. The rats were then resuscitated with Ringer lactate, 4 times the maximum bleedout volume for 1 hour. Sham-operated animals underwent only the surgical procedure.

Main Outcome Measures  Plasma levels of nitrate/nitrite (NO₃^-/NO₂^-, stable products of NO) were measured by colorimetric assay at the maximum bleedout volume; at the end of hemorrhage; at the end of resuscitation; and 1.5, 4, 8, and 24 hours after resuscitation. In additional rats, the heart, liver, small intestine, kidneys, and spleen were harvested 4 hours after resuscitation for the measurement of NO₃^-/NO₂^- levels. Moreover, tissue perfusion was determined in the above-mentioned organs by radioactive microspheres 4 hours after resuscitation in other groups of animals.

Results  Plasma levels of NO₃^-/NO₂^- were similar to those of sham-operated animals during hemorrhage and at the end of resuscitation. One and a half hours after the end of resuscitation, however, NO production increased significantly. The peak levels of plasma NO₃^-/NO₂^- occurred at 4 hours, and the levels remained elevated even 24 hours after resuscitation. Tissue NO₃^-/NO₂^- levels were significantly increased in the liver, small intestine, and spleen 4 hours after resuscitation. In contrast, the levels of NO₃^-/NO₂^- were similar to those of sham-operated animals in the heart and kidneys at all times. Blood flow in the heart was maintained after hemorrhage, whereas hepatic, intestinal, splenic, and renal perfusion decreased significantly.

Conclusions  The gut and liver seem to be the sites responsible for the increased NO production seen after trauma and hemorrhage. The overproduction of NO is most likely caused by up-regulation of inducible NO synthase. Thus, attempts to reduce NO production using specific inhibitors for inducible NO synthase might be helpful for improving hepatic and intestinal functions after trauma and hemorrhagic shock.

From the Center for Surgical Research and the Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence.

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