Nitric oxide production by the intestinal mucosa during hypoperfusion

Sammanfattning: The present thesis is based on the concept that gastrointestinal blood hypoperfusion is a common phenomenon associated with critical illness. Furthermore, the development of the multiple organ dysfunction syndrome (MODS) is proposed to be initiated by gastrointestinal mucosal barrier dysfunction, allowing intestinal luminal contents to penetrate into the tissue and activate a systemic inflammatory response. As nitric oxide (NO) influences several aspects of the barrier properties, it was considered of interest to elucidate intestinal NO formation during conditions with splanchnic blood hypoperfusion. The general aims of the investigations were to develop a technique for NO measurement in the gut, define the NO source(s) detected by the technique and relate the NO synthesis to conditions typical of critical illness.Experiments were performed on anaesthetised pigs. Isoforms of nitric oxide synthase (NOS) were located in the gut wall using immunohistochemistry. The pigs were instrumented to allow for recordings of global hemodynamics, mesenteric blood perfusion and blood sampling to calculate systemic and regional oxygen-kinetics. Gut mucosal blood perfusion was recorded by use of laser Doppler flowmetry. A tonometric approach was developed for the assessment of intestinal NO-formation and the technique was evaluated bench-side and in-situ. Gut blood hypoperfusion was induced by challenging cardiac performance using graded haemorrhage, cardiac tamponade or live E. coli-sepsis. Confirmatory studies were performed in healthy volunteers where hypovolemia was mimicked by lower body negative pressure. The results showed that luminal NO tonometry is an accurate and rather easily handled technique that reflects enzymatic NO formation by the intestinal mucosal surface epithelium. Plasma level of the endogenous NOS-inhibitor asymmetric di-methylarginine (ADMA) increases and the mucosal NO decreases during severe circulatory stress induced by hypovolaemia or cardiac tamponade. Mucosal hypoperfusion and dysoxia, rather than lack of the substrate L-Arginine or the increased concentration of ADMA, explain the decreased NO signal following circulatory stress. Sepsis is associated with maintained intestinal NO formation despite a concomitant mesenteric hypoperfusion. Intestinal NO formation in man varies in relation with the interdigestive motility pattern. LBNP-induced hypotension in man is associated with markedly decreased mucosal perfusion and decreased mucosal NO formation.