TY - JOUR
T1 - Effects of ethyl pyruvate and other α-keto carboxylic acid derivatives in a rat model of multivisceral ischemia and reperfusion
AU - Cruz, Ruy J.
AU - Harada, Tomoyuki
AU - Sasatomi, Eizaburo
AU - Fink, Mitchell P.
N1 - Funding Information:
The authors acknowledge support for this work by the Defense Advanced Research Projects Administration (DARPA contract W81XWH-05-2-0026) as well as U.S. Public Health Service, National Institutes of Health ( GM067082 ).
PY - 2011/1
Y1 - 2011/1
N2 - 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 50min of supraceliac aortic occlusion. Over a 20-min period, starting 2min before the release of the aortic clamp, the animals received 2μL/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.
AB - 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 50min of supraceliac aortic occlusion. Over a 20-min period, starting 2min before the release of the aortic clamp, the animals received 2μL/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.
KW - Ethyl pyruvate
KW - Intestinal
KW - Ischemia
KW - Permeability
KW - Pyruvate
KW - Reperfusion
KW - Resuscitation
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U2 - 10.1016/j.jss.2009.07.008
DO - 10.1016/j.jss.2009.07.008
M3 - Article
C2 - 19959189
AN - SCOPUS:78649935672
SN - 0022-4804
VL - 165
SP - 151
EP - 157
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -