The effects of dichloroacetate in a rabbit model of acute hind-limb ischemia and reperfusion.
BACKGROUND
Dichloroacetate (DCA) is a drug that allows pyruvate dehydrogenase to remain active under anaerobic conditions by inhibiting the inactivating enzyme, pyruvate dehydrogenase kinase. We hypothesize that the administration of DCA during acute limb ischemia may have a beneficial effect by reducing the severity of anaerobic metabolism and lessening the irreversible injury.


METHODS
We studied a rabbit model using unilateral ligation of the iliac artery or femoral artery to evaluate two degrees of ischemia. After 2 hours of hind-limb ischemia, the animals were administered IV DCA (15 mg/kg) or an equivalent volume of saline.


RESULTS
Higher serum lactate levels were seen after high compared to low ligation in control animals consistent with more severe ischemia. DCA treatment significantly reduced serum lactate levels after both high and low ligation. Similarly, the rise in percentage end-tidal CO(2) after reperfusion was less after DCA. All animals regained hind-limb function after the procedure, but ischemia or reperfusion resulted in appreciable muscle necrosis (> 10% area) in 50% of high- and 22% of low-ligation control animals. DCA treatment eliminated significant muscle necrosis in 100% of high-ligation animals. Muscle histology was similar in control and DCA-treated low-ligation animals.


CONCLUSIONS
Treatment with DCA during acute arterial occlusion did significantly lower markers of anaerobic metabolism and reduced muscle necrosis in a rabbit model of acute hind-limb ischemia. DCA delivery through collateral blood flow may prolong the ischemia time interval before the onset of irreversible muscle injury and potential limb loss.
Wilson
Jeffrey S
JS
Division of Vascular and Endovascular Surgery, University of South Florida College of Medicine, Tampa, FL, USA.
Rushing
Greg
G
Johnson
Brad L
BL
Kline
Jeffrey A
JA
Parker
Jaime L
JL
Bowser
Andrew
A
Bandyk
Dennis F
DF
Back
Martin R
MR
D000818:Animals; D003999:Dichloroacetic Acid / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism*; D019344:Lactic Acid / Q000097:blood; D018482:Muscle, Skeletal / Q000473:pathology; D009336:Necrosis; D010100:Oxygen / Q000097:blood; D011817:Rabbits; D012039:Regional Blood Flow; D015424:Reperfusion
D019344:Lactic Acid; D003999:Dichloroacetic Acid; D010100:Oxygen