The purpose of this study was to evaluate the effects of
dichloroacetate sodium (DCA), a
drug that inactivates
pyruvate dehydrogenase kinase (PDH-K), on
pyruvate dehydrogenase (PDH) activity,
lactate level, and function of skeletal muscle in an experimental model of acute limb
ischemia. Thirty-two male Sprague-Dawley rats underwent right iliac artery
ligation to produce hindlimb
ischemia. After 2 hours of
ischemia, 16 animals received intravenous DCA (15 mg/100 g
body weight) and 16 control animals received an equivalent volume of
normal saline. After an additional 1 hour of
ischemia (total 3 hours) tibialis anterior muscle from the ischemic limb and contralateral nonischemic limb was excised, rapidly freeze-clamped with Wallenberg tongs cooled in liquid
nitrogen, and stored at -70 degrees C. Muscles specimens were subsequently assayed for PDH activity and
lactate level by use of spectrophotometric techniques. An additional 16 animals (DCA-treated, n = 8; control, n = 8) underwent ex-vivo gastrocnemius muscle
fatigue testing with
a 10 g tension preload after 3 hours of limb
ischemia. In ischemic hind limbs, DCA treatment significantly (p = 0.025) increased PDH activity (19.6 +/-1.6 micromol/min/g dry weight) compared to controls (13.1 +/-1.3 micromol/min/g dry weight). DCA treatment did not increase (p = 0.13) skeletal muscle PDH activity in the nonischemic limbs (9.6 +/-1.1 micromol/min/g dry weight, controls; 13.2 +/-1.3 micromol/min/g dry weight, DCA group). In DCA-treated animals, hind limb
ischemia resulted in no significant increase in muscle
lactate levels compared to the nonischemic limb, while control animals demonstrated a significant (p = 0.005) elevation in
lactate level in ischemic limbs compared to contralateral nonischemic limb.
Ischemia induced a significant decrease in time to muscle fatigue in both DCA-treated and control animals (p = 0.002 and 0.001, respectively). Time to muscle fatigue in DCA-treated animals was increased compared to controls (2.6 +/-0.3 versus 2 +/-0.6 minutes; p < 0.05)in ischemic limbs but was not significantly different in nonischemic limbs (DCA = 3.3 +/-0.5 minutes; control = 3.1 +/-0.6 minutes). Treatment with DCA during acute limb
ischemia reduced the depression of PDH activity and
lactate level of skeletal muscle. Ischemic muscle function was also improved by DCA treatment. Further investigation of the potential beneficial effects of DCA treatment on muscle injury during
ischemia and reperfusion is warranted.