Effects of ethyl pyruvate and other α-keto carboxylic acid derivatives in a rat model of multivisceral ischemia and reperfusion.
BACKGROUND
Ethyl pyruvate (EP) has been shown to ameliorate hepatic, renal, and intestinal mucosal injury and down-regulate expression of several pro-inflammatory mediators in a wide variety of preclinical models of critical illnesses, such as sepsis, burn injury, acute pancreatitis, stroke, and hemorrhagic shock. The molecular mechanisms responsible for the therapeutic effects of EP remain poorly understood, but might be related to the compound's structure as the ester of an α-keto carboxylic acid. Herein, we tested the hypothesis that EP and other α-keto carboxylic acid derivatives can modulate organ injury after lower torso ischemia/reperfusion (I/R).


METHODS
Rats were subjected to 50 min of supraceliac aortic occlusion. Over a 20-min period, starting 2 min before the release of the aortic clamp, the animals received 2 μL/g of Ringer's lactate solution (RL, n = 5) or an equivalent volume of a solution containing EP (n = 5), benzoyl formate (BF, n = 5), parahydroxyphenyl pyruvate (PHPP, n = 5) or sodium pyruvate (NaPyr, n = 5). The total dose of each compound was 0.86 mMol/kg. After 1h of reperfusion, we measured ileal mucosal permeability to fluorescein-labeled dextran (mw 4000 Da), liver malondialdehyde (MDA) content, and plasma levels of alanine aminotransferase (ALT) and TNF. Rats in the control group (CT, n = 4) were subjected to laparotomy and surgical isolation of the supraceliac aorta, but not visceral I/R.


RESULTS
Ileal mucosal permeability, plasma levels of ALT and TNF, and hepatic MDA content increased significantly in the RL group relative to the CT group. Both EP and BF significantly ameliorated the development of systemic arterial hypotension, mucosal hyperpermeability, and significantly decreased plasma levels of TNF. MDA content was significantly decreased by EP, PHPP, BF, and NaPyr.


CONCLUSIONS
In general, EP is more efficacious in this model than is NaPyr. Although more remains to be learned about the pharmacologic differences between EP and pyruvate, one important factor may the greater lipophilicity of the former compound. This insight may permit the development of even more effective cytoprotective and anti-inflammatory agents based on the pyruvoyl moiety.
Cruz
Ruy J
RJ
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. ruycruzjunior@yahoo.com.br
Harada
Tomoyuki
T
Sasatomi
Eizaburo
E
Fink
Mitchell P
MP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D005440:Fluid Therapy; D006038:Glyoxylates / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology*; D010539:Permeability; D010667:Phenylpyruvic Acids / Q000494:pharmacology*; D011773:Pyruvates / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000893:Anti-Inflammatory Agents; D006038:Glyoxylates; D008333:Mandelic Acids; D010667:Phenylpyruvic Acids; D011773:Pyruvates; D014409:Tumor Necrosis Factor-alpha; C046522:ethyl pyruvate; C010590:4-hydroxyphenylpyruvic acid; C012482:phenylglyoxylic acid