Dose-dependent effects of ethyl pyruvate in mice subjected to mesenteric ischemia and reperfusion.
OBJECTIVE
We previously showed that infusing rats with a solution of ethyl pyruvate ameliorates intestinal mucosal injury after mesenteric ischemia and reperfusion. Ethyl pyruvate also has been shown to inhibit the expression of various pro-inflammatory cytokines in several animal models of critical illness, but dose-response relationships have not been investigated.


METHODS
Anesthetized C57BL/6 mice were subjected to 60 min of mesenteric ischemia followed by 60 min of reperfusion. After 55 min of ischemia, groups of mice were treated with normal saline or graded bolus doses of ethyl pyruvate dissolved in a calcium-containing balanced salt solution. Some animals (i.e., those in the sham group) were subjected to the anesthetic, but not mesenteric ischemia/reperfusion. Gut mucosal permeability was assessed using an everted gut sac technique.


METHODS
University research laboratory.


RESULTS
Mesenteric ischemia/reperfusion significantly increased ileal mucosal permeability to the hydrophilic macromolecule, fluorescein isothiocyanate dextran (molecular mass 4,000 Da). Whereas the lowest dose of ethyl pyruvate evaluated (17 mg/kg) had no effect on gut mucosal permeability, the two highest doses tested (50 and 150 mg/kg) significantly ameliorated the development of ischemia/reperfusion-induced mucosal hyperpermeability to about the same extent. The two highest doses of ethyl pyruvate also significantly ameliorated deficits in ileal serosal and mucosal and hepatic surface microvascular perfusion induced by mesenteric ischemia/reperfusion. Ethyl pyruvate inhibited post-ischemia/reperfusion hepatic NF-kappaB activation and TNF mRNA expression in a dose-dependent fashion.


CONCLUSIONS
Doses of ethyl pyruvate equal to or greater than 50 mg/kg ameliorate inflammation, microvascular hypoperfusion and gut mucosal damage induced by mesenteric ischemia/reperfusion in mice.
Uchiyama
Takashi
T
Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Delude
Russell L
RL
Fink
Mitchell P
MP
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D007082:Ileum / Q000098:blood supply / Q000187:drug effects; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects; D007511:Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D017078:Laser-Doppler Flowmetry; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D008641:Mesenteric Vascular Occlusion; D008643:Mesentery / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000032:analysis / Q000187:drug effects; D011773:Pyruvates / Q000494:pharmacology / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000187:drug effects
D016166:Free Radical Scavengers; D016328:NF-kappa B; D011773:Pyruvates; D014409:Tumor Necrosis Factor-alpha; C046522:ethyl pyruvate