Acadesine and intestinal barrier function after hemorrhagic shock and resuscitation

D. N. Ragsdale, Kenneth G Proctor

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Objective: To determine actions of the prototype adenosine-regulating agent, acadesine (5-amino-1-[β-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. Design: Prospective, controlled animal study. Setting/Subjects: University laboratory; juvenile crossbred pigs of either gender. Interventions: 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. Measurements and Main 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) and 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-β-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.

Original languageEnglish
Pages (from-to)3876-3884
Number of pages9
JournalCritical Care Medicine
Volume28
Issue number12
StatePublished - Dec 1 2000
Externally publishedYes

Fingerprint

Hemorrhagic Shock
Resuscitation
Adenosine
Adenine Nucleotides
Shock
Permeability
pyrazolo(3,4-d)pyrimidine
Hemorrhage
Autacoids
Adenosine Kinase
Intra Arterial Infusions
Dextrans
Ileum
acadesine
Histology
Mucous Membrane
Lasers
Anti-Inflammatory Agents
Swine
Ischemia

Keywords

  • Adenosine
  • Blood flow
  • Dextrans
  • High-pressure liquid chromatography
  • Histology
  • Ileum
  • Laser Doppler
  • Mucosa
  • Trauma

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Acadesine and intestinal barrier function after hemorrhagic shock and resuscitation. / Ragsdale, D. N.; Proctor, Kenneth G.

In: Critical Care Medicine, Vol. 28, No. 12, 01.12.2000, p. 3876-3884.

Research output: Contribution to journalArticle

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abstract = "Objective: To determine actions of the prototype adenosine-regulating agent, acadesine (5-amino-1-[β-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. Design: Prospective, controlled animal study. Setting/Subjects: University laboratory; juvenile crossbred pigs of either gender. Interventions: 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. Measurements and Main 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) and 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-β-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.",
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