The adenosine deaminase inhibitor erythro-9-[2-hydroxyl-3-nonyl]-adenine decreases intestinal permeability and protects against experimental sepsis: a prospective, randomised laboratory investigation.
BACKGROUND
The treatment of septic conditions in critically ill patients is still one of medicine's major challenges. Cyclic nucleotides, adenosine and its receptors play a pivotal role in the regulation of inflammatory responses and in limiting inflammatory tissue destruction. The aim of this study was to verify the hypothesis that adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibition by erythro-9-[2-hydroxyl-3-nonyl]-adenine could be beneficial in experimental endotoxicosis/sepsis.


METHODS
We used two established animal models for endotoxicosis and sepsis. Twenty-four male Wistar rats that had been given intravenous endotoxin (Escherichia coli lipopolysaccharide) were treated with either erythro-9-[2-hydroxyl-3-nonyl]-adenine infusion or 0.9% saline during a study length of 120 minutes. Sepsis in 84 female C57BL/6 mice was induced by caecal ligation and puncture. Animals were treated with repeated erythro-9-[2-hydroxyl-3-nonyl]-adenine injections after 0, 12 and 24 hours or 4, 12 and 24 hours for delayed treatment.


RESULTS
In endotoxaemic rats, intestinal production of hypoxanthine increased from 9.8 +/- 90.2 micromol/l at baseline to 411.4 +/- 124.6 micromol/l and uric acid formation increased from 1.5 +/- 2.3 mmol/l to 13.1 +/- 2.7 mmol/l after 120 minutes. In endotoxaemic animals treated with erythro-9-[2-hydroxyl-3-nonyl]-adenine, we found no elevation of adenosine metabolites. The lactulose/L-rhamnose ratio (14.3 versus 4.2 in control animals; p = 2.5 x 10(-7)) reflects a highly permeable small intestine and through the application of erythro-9-[2-hydroxyl-3-nonyl]-adenine, intestinal permeability could be re-established. The lipopolysaccharide animals had decreased L-rhamnose/3-O-methyl-D-glucose urine excretion ratios. Erythro-9-[2-hydroxyl-3-nonyl]-adenine reduced this effect. The mucosa damage score of the septic animals was higher compared with control and therapy animals (p < 0.05). Septic shock induction by caecal ligation and puncture resulted in a 160-hour survival rate of about 25%. In contrast, direct adenosine deaminase-1 inhibition resulted in a survival rate of about 75% (p = 0.0018). A protective effect was still present when erythro-9-[2-hydroxyl-3-nonyl]-adenine treatment was delayed for four hours (55%, p = 0.029).


CONCLUSIONS
We present further evidence of the beneficial effects achieved by administering erythro-9-[2-hydroxyl-3-nonyl]-adenine, an adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibitor, in an endotoxicosis and sepsis animal model. This suggests a potential therapeutic option in the treatment of septic conditions.
Kayhan
Nalan
N
Department of Thoracic and Cardiovascular Surgery, University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Funke
Benjamin
B
Conzelmann
Lars Oliver
LO
Winkler
Harald
H
Hofer
Stefan
S
Steppan
Jochen
J
Schmidt
Heinfried
H
Bardenheuer
Hubert
H
Vahl
Christian-Friedrich
CF
Weigand
Markus A
MA
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D005260:Female; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D010539:Permeability / Q000187:drug effects; D011446:Prospective Studies; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*
D058892:Adenosine Deaminase Inhibitors; D008070:Lipopolysaccharides; C010192:9-(2-hydroxy-3-nonyl)adenine; D000243:Adenosine Deaminase; D000225:Adenine