The importance of maintaining GI perfusion and function during sepsis has become recognized, especially in light of recent studies regarding the translocation of intestinal bacteria, and observed beneficial effects of enteral versus parenteral feeding. our laboratory is interested in improving gastrointestinal perfusion and function during sepsis. The opioid system figures prominently in achieving this goal. Naloxone has the potential to improve gastrointestinal (GI) problems associated with sepsis and septic shock. Studies from our laboratories indicate that naloxone can improve small bowel perfusion in an animal model of septic shock, independent of blood pressure or cardiac output changes. We need to determine the mechanisms and pathways involved in this phenomenon before it can be properly and safely exploited for the benefit of septic patients in whom GI involvement is a problem. In this proposal we will determine the involvement of 1) peripheral vs. central opioid mediated splanchnic perfusion changes, 2) vagally mediated effects, 3) alpha2 adrenergic mediated effects, and 4) the relationship between increased small bowel motility and perfusion. This information will allow later studies aimed at exploiting this physiologic system to improve intestinal perfusion and function during sepsis. Rats will be anesthetized and nichrome plate electrodes will be affixed to the antrum of the stomach, duodenal bulb, and segment of jejunum to allow for bipolar myoelectric recordings. In separate groups of animals, the vagus nerve tracts on the ventral and posterior sides of the esophagus will then be isolated and a one cm. section removed from both tracts. Seven days later, catheters will be placed to monitor blood pressures, and for injection of radiolabelled microspheres to measure splanchnic perfusion. Peripheral vs. central opioid pathways will be examined by comparing the effects of naloxone with a quaternary derivative of naloxone (does not cross the bloodbrain barrier). The role of the vagus will be determined by comparing the effects of these compounds in vagal-intact and vagotomized rats. The effect of alpha2 adrenergic receptor mediation will be studied using yohimbine as an alpha2 antagonist. Correlations between intestinal myoelectric activity and intestinal perfusion will be made in all groups. Future studies will use this information to determine how best to improve intestinal absorption, and reduce intestinal translocation of bacteria during septic shock.
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