The glucose-insulin-potassium (GIK) regimen in the treatment of myocardial ischemia.

IN 1959 Selyel reported that myocardial resistance to cardiotoxic agents was reduced by intracellu-lar hypokalemia and hypomagnesemia. Resistance was regained when this ionic imbalance was restored. Obstruction of a coronary artery inevitably causes a heterogeneous mixture of normal well-oxygenat-ed, ischemically injured, and dead cells. This zone is biochemically and electrically unstable. Its progressively changing proportions are determined by many factors including the location of the site of vascular insufficiency, the magnitude of the collateral circulation, the condition of the cell prior to injury, the level of endogenous glycogen stores, and possibly by successful therapeutic intervention. Early ischemic changes are potentially reversible. Survival and recovery of normal function has been demonstrated despite total cessation of flow for periods of 20 to 60 min. The metabolic behavior of this zone of ischemia (the sick cell) most often determines the clinical course of the patient. Creatine phosphate (CP) and adenosine triphos-phate (ATP) concentration fall rapidly after the onset of ischemia. There is an increase in intracellu-lar adenosine di and monophosphate and in inorganic phosphate (Pi), the latter diffusing through the plasma membrane. Metabolic feedback controls permit an enhancement of anaerobic glycolysis supported by an increase in glucose transport and phosphorylation and in glycogenoly-sis. Glycogen depletion begins almost immediately. There is a shift of glycolytic intermediates to a reduced redox state, a fall in lactate extraction and an increase in intracellular a-glycero-phosphate and lactate production. The enzymic capacity of the glycolytic pathway in the mammalian heart is theoretically capable of supplying sufficient energy for normal stroke work. It can do so in the reptile but as yet unknown factors restrict mammalian glycolytic energy production to from 12% to 15% of total requirements. Glycolytic activity is near maximal in the ischemic cell during normoglycemia. Near maximal rates have been demonstrated at very low external glucose concentrations and little change in glucose uptake was seen when concentration was increased above 50 mg% in the presence of insulin.2 Thus significant enhancement of energy production by this pathway is probably unresponsive to stimulation by an increase in circulating glucose concentration. Optimal anaerobic energy production cannot meet the ATP requirements of the normally contracting myocardium. Furthermore, anaerobic glycolysis is not an unmixed blessing. The accompanying increase in intracellular lactate and other acidic metabolic end products gradually exceeds the poor intrinsic buffering capacity of the myocardial cell, with a resultant fall in pH. Cellular acidosis progressively inhibits phosphofructokinase (PFK) activity …