Involvement of adenosine in the antiinflammatory action of ketamine.
BACKGROUND
Ketamine is an anesthetic drug. Subanesthetic doses of ketamine have been shown to reduce interleukin-6 concentrations after surgery and to reduce mortality and the production of tumor necrosis factor alpha and interleukin 6 in septic animals. Similarly, adenosine was shown to reduce tumor necrosis factor alpha and mortality of septic animals. The aim of this study was to determine whether adenosine mediates the antiinflammatory effects of ketamine.


METHODS
Sepsis was induced in mice by lipopolysaccharide or Escherichia coli inoculation. Leukocyte recruitment and cytokine concentrations were used as inflammation markers. Adenosine concentrations were assayed by high-performance liquid chromatography, and the involvement of adenosine in the effects of ketamine was demonstrated by adenosine receptor agonists and antagonists.


RESULTS
Ketamine markedly reduced mortality from sepsis, leukocyte recruitment, and tumor necrosis factor-alpha and interleukin-6 concentrations. Ketamine administration in mice and rats was associated with a surge at 20-35 min of adenosine in serum (up to 5 microm) and peritoneal fluid. The adenosine A2A receptor agonist CGS-21680 mimicked the effect of ketamine in peritonitis, whereas the A2A receptor antagonists DMPX and ZM 241385 blocked its antiinflammatory effects. In contrast, A1 and A3 receptor antagonists had no effect. ZM 241385 reversed the beneficial effect of ketamine on survival from bacterial sepsis.


CONCLUSIONS
The current data suggest that the sepsis-protective antiinflammatory effects of ketamine are mediated by the release of adenosine acting through the A2A receptor.
Mazar
Julia
J
Department of Nephrology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel.
Rogachev
Boris
B
Shaked
Gad
G
Ziv
Nadav Y
NY
Czeiger
David
D
Chaimovitz
Cidio
C
Zlotnik
Moshe
M
Mukmenev
Igor
I
Byk
Gerardo
G
Douvdevani
Amos
A
D000241:Adenosine / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D007649:Ketamine / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D043705:Receptor, Adenosine A2A; D007649:Ketamine; D000241:Adenosine