Acadesine and intestinal barrier function after hemorrhagic shock and resuscitation

Objective: To determine actions of the prototype adenosine-regulating agent , acadesine (5-amino-1-[beta -D-ribofuranosyl]imidazole-4-carboxamideribosi de; AlCAR), on intestinal barrier function after hemorrhagic shock and flui d resuscitation, three series of experiments were performed to measure func tional (series 1: intestinal permeability and intramural blood flow), struc tural (series 2: histology), and biochemical (series 3: tissue concentratio ns of adenine nucleotides and metabolites) changes. Design: Prospective, controlled animal study. Setting/Subjects: University laboratory; juvenile crossbred pigs of either gender. Interventions: Either AICAR or its saline vehicle were intravenously admini stered 30 mins before 40% hemorrhage. After 1 hr shack, shed blood plus cry stalloid was administered for resuscitation. Data were collected for 1 hr t hereafter. Measurements and Main Results: In series 1, permeability of the ileum was m easured by assaying the portal venous concentration of fluorescein-labeled dextran after placement of this tracer in the lumen. In addition, serosal a nd mucosal blood flaw were monitored with laser-Doppler probes. With vehicl e, hemorrhage and resuscitation increased the dextran concentration three-f ord and decreased blood flow 50% of the baseline values (both p < .05). AIC AR attenuated the permeability increase (p < .05) and attenuated mucosa, bu t not serosal, ischemia (p <.05). Similar effects were observed with a stru cturally dissimilar com pound-4-amina-1-(5-amino-5-deoxy-1-<beta>-D-ribofur anosyl)-3-bromo-pyrazolo [3,4-d] pyrimidine, a specific adenosine kinase in hibitor-as well as continuous intra-arterial infusion of adenosine. In seri es 2, AICAR ameliorated the mucosal damage caused by shock/resuscitation (p <.05). In series 3, AICAR increased ileal tissue adenine nucleotides and m etabolites during the shock period (p <.05). Conclusions: AICAR attenuated gut permeability changes, increased mucosal p erfusion, and increased tissue adenine nucleotides, which is consistent wit h preserved intestinal barrier function after hemorrhage and fluid resuscit ation. In context with previous studies from this laboratory, these results provide further evidence for a role far adenosine as an endogenous antiinf lammatory autacoid after shock and trauma. Further study is needed to deter mine the therapeutic potential of adenosine-regulating agents in resuscitat ion fluids.