Metabolic and ionic response of skeletal muscle to ischemia and reperfusion: Extracellular calcium ion and muscle injury

This thesis investigated the metabolic and ionic response of skeletal muscle to prolonged periods of ischemia and reperfusion. Using the isolated perfused rat hindlimb preparation, metabolic (i.e. O{dollar}sb2{dollar} consumption, lactate and glucose flux, ATP, total adenine nucleotides (TAN), phosphocreatine, glycogen) and ionic (i.e. intracellular sodium (Na{dollar}sp+rbracksb{lcub}rm i{rcub}{dollar}, potassium (K{dollar}sp+rbracksb{lcub}rm i{rcub}{dollar}, chloride (Cl{dollar}sp-rbracksb{lcub}rm i{rcub}{dollar}, lactate (Lac{dollar}sp-rbracksb{lcub}rm i{rcub}{dollar} and calcium (Ca{dollar}sp{lcub}2+{rcub}rbracksb{lcub}rm i{rcub}{dollar} contents) measures were determined during 40 min of ischemic stimulation (1 Hz twitch) followed by 2C min of reperfusion stimulation. Twitch stimulation was used to rapidly induce ischemia/reperfusion injury by increasing metabolic demand. Findings reveal that glycogenolysis was activated during the initial 5 min of ischemic stimulation. Increasing the ischemic duration (5-40 min) inactivated glycogenolysis and enhanced TAN degradation. Glycogenolytic inactivation and TAN degradation was partially attributed to the increase in intramuscular hydrogen ion (H{dollar}sp+rbracksb{lcub}rm m{rcub}{dollar}, previously shown to limit PHOS and/or PFK activity and activate AMP deaminase. Reperfusing skeletal muscle following 40 min of ischemic stimulation resulted in a partial resynthesis of ATP, TAN, phosphocreatine and glycogen which was proportionally greater in the slow oxidative soleus (Sol) than the fast glycolytic white gastrocnemius (WG) and fast oxidative/glycolytic plantaris (Pl). In reference to ion regulation, 40 min of ischemic stimulation initiated a large increase in (Lac{dollar}sp-rbracksb{lcub}rm i{rcub}{dollar}, however, (Na{dollar}sp+rbracksb{lcub}rm i{rcub}{dollar}, (K{dollar}sp+rbracksb{lcub}rm i{rcub}{dollar}, (Cl{dollar}sp-rbracksb{lcub}rm i{rcub}{dollar} and (Ca{dollar}sp{lcub}2+{rcub}rbracksb{lcub}rm i{rcub}{dollar} remained constant. The maintenance of ion balance during ischemic stimulation was attributed to the reduction in blood flow which limits interactions between the ICF and ECF. In contrast, reperfusing skeletal muscle following 40 min of ischemic stimulation initiated an increase in (Na{dollar}sp+rbracksb{lcub}rm i{rcub}{dollar}, (Cl{dollar}sp-rbracksb{lcub}rm i{rcub}{dollar}, and (Ca{dollar}sp{lcub}2+{rcub}rbracksb{lcub}rm i{rcub}{dollar} and reduced (K{dollar}sp+rbracksb{lcub}rm i{rcub}{dollar} and (Lac{dollar}sp-rbracksb{lcub}rm i{rcub}{dollar}. The increase in (Ca{dollar}sp{lcub}2+{rcub}rbracksb{lcub}rm i{rcub}{dollar} during reperfusion was greater in WG and Pl compared to Sol. The differential effect of reperfusion on Ca{dollar}sp{lcub}2+{rcub}{dollar} accumulation and energy metabolism in Sol, WG and Pl supports the view that fast glycolytic and fast oxidative muscles are more susceptible to ischemic injury than slow oxidative muscles. The increased Ca{dollar}sp{lcub}2+{rcub}{dollar} accumulation during reperfusion can be ascribed to the activation of the Na{dollar}sp+{dollar}/Ca{dollar}sp{lcub}2+{rcub}{dollar} exchange and to the L-type Ca{dollar}sp{lcub}2+{rcub}{dollar} channel. Blocking Ca{dollar}sp{lcub}2+{rcub}{dollar} flux with pharmacological agents specific to these Ca{dollar}sp{lcub}2+{rcub}{dollar} transport proteins enhanced the metabolic and contractile recovery of skeletal muscle.