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-carboxamideriboside; AICAR), on intestinal barrier function after hemorrhagic shock and fluid resuscitation, three series of experiments were performed to measure functional (series 1: intestinal permeability and intramural blood flow), structural (series 2: histology), and biochemical (series 3: tissue concentrations of adenine nucleotides and metabolites) changes.


METHODS
Prospective, controlled animal study.


METHODS
University laboratory; juvenile crossbred pigs of either gender.


METHODS
Either AICAR or its saline vehicle were intravenously administered 30 mins before 40% hemorrhage. After 1 hr shock, shed blood plus crystalloid was administered for resuscitation. Data were collected for 1 hr thereafter.


RESULTS
In series 1, permeability of the ileum was measured by assaying the portal venous concentration of fluorescein-labeled dextran after placement of this tracer in the lumen. In addition, serosal and mucosal blood flow were monitored with laser-Doppler probes. With vehicle, hemorrhage and resuscitation increased the dextran concentration three-fold and decreased blood flow 50% of the baseline values (both p < .05). AICAR attenuated the permeability increase (p < .05) and attenuated mucosa, but not serosal, ischemia (p < .05). Similar effects were observed with a structurally dissimilar compound-- 4-amino-1-(5-amino-5-deoxy-1-beta-D-ribofuranosyl)-3-bromo-pyrazolo [3,4-d] pyrimidine, a specific adenosine kinase inhibitor-as well as continuous intra-arterial infusion of adenosine. In series 2, AICAR ameliorated the mucosal damage caused by shock/resuscitation (p < .05). In series 3, AICAR increased ileal tissue adenine nucleotides and metabolites during the shock period (p < .05).


CONCLUSIONS
AICAR attenuated gut permeability changes, increased mucosal perfusion, and increased tissue adenine nucleotides, which is consistent with preserved intestinal barrier function after hemorrhage and fluid resuscitation. In context with previous studies from this laboratory, these results provide further evidence for a role for adenosine as an endogenous anti-inflammatory autacoid after shock and trauma. Further study is needed to determine the therapeutic potential of adenosine-regulating agents in resuscitation fluids.
Ragsdale
D N
DN
Department of Physiology, University of Tennessee, Memphis, USA.
Proctor
K G
KG
D000241:Adenosine / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001783:Blood Flow Velocity; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D005440:Fluid Therapy; D005573:Formycins / Q000494:pharmacology / Q000627:therapeutic use; D007082:Ileum; D007413:Intestinal Mucosa / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology*; D007511:Ischemia / Q000209:etiology* / Q000378:metabolism*; D017078:Laser-Doppler Flowmetry; D008297:Male; D012151:Resuscitation; D012263:Ribonucleosides / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use*; D012771:Shock, Hemorrhagic / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D013552:Swine
D005573:Formycins; C417047:GP 515; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D000248:Adenosine Kinase; D000241:Adenosine