Cardioprotective Effects Of Glucose-insulin-potassium On Dogs With Acute Myocardial Ischemia/reperfusion

Objective: In recent years, there have been several landmark studies showing that glucose-insulin-potassium (GIK) significantly reduced the mortality of patients with acute myocardial infarction (AMI). However, the GIK-induced actions on the ischemic heart and the underlying mechanisms by which GIK exerts its cardioprotection remain unclear. Previous evidence from our laboratory and others has showed that GIK exerts cardioprotective effect on a rat model of myocardial ischemia during ischemia and reperfusion (MI/R). However, to date, whether GIK may improve cardiac functional recovery and reducing myocardial injury in a canine model with severe ischemia and reperfusion are not clear. In addition, the effect of GIK on myocardial oxygen consumption (MVO2) remains unknown. Therefore, the objectives of the present study were to (1) determine the effects of GIK on postischemicmyocardial injury, coronary blood flow (CBF), cardiac functional recovery and MVO2 during MI/R; (2) investigate the role of insulin in the aforementioned actions of GIK.Methods: In anesthetized open-chest dogs, the left anterior descending coronary artery (LAD) was partially occluded (80% reduction in its blood flow) for 50 min and reperfused for 4 h. Dogs were randomly divided into three groups and subjected the following treatments: 1) GIK (glucose: 250 g.L-1, insulin: 60 U.L-1, potassium: 80 mmol.L-1) 2) GK (glucose: 250 g.L-1, potassium: 80 mmol.L-1) 3) Saline (0.9% NaCl, as Vehicle). All treatments were given by intravenous infusion at 2 ml.kg-1.h-1 beginning at 5 min before reperfusion and continuing through the 4-h reperfusion period. Arterial blood pressure, ECG, CBF and left ventricular pressure were monitored. The activities of Creatine kinase (CK) and Lactate dehydrogenase (LDH) were assayed spectrophotometrically. Myocardial infarction was determined by Evans blue-TTC double staining and myocardial apoptosis was determined by TUNEL at the end of reperfusion. MVO2, glucose uptake, plasma FFA were determined.Results:1. Regional myocardial blood flowCBF_lad showed no significant difference among the three groups before ischemia. CBF_Lad was regulated to maintain an 80% reduction from baseline during ischemia. Treatment with GIK was associated with a significant increase in CBFlad compared with vehicle and GK during reperfusion respectively (P<0.05).2. Cardiac functionThere were no differences for any of the hemodynamic parameters among the three groups before and during ischemia. GIK improved cardiac functional recovery during reperfusion period. Treatment with GIK increased +LVdP/dt_max and -LVdP/dt_max by 23.0% (P<0.05) and 23.9% (P<0.05) respectively compared with Vehicle at 4 h after reperfusion, while GK had no these effects.3. Effects of GIK on myocardial reperfusion injuryGIK exerted cardioprotection against MI/R as evidenced by significant decreases of serum CK and LDH. At the end of 4-h reperfusion, serum CK and LDH of the GIK-treated group decreased by 57% (PO.05) and 21.3% (PO.05) compared with Vehicle. Moreover GIK reduced myocardial infarction (6.2±1.5% vs. 9.4±1.9% of Vehicle, P<0.05), while GK failed to show any significant cardioprotection against MI/R injury. In addition, administration of GIK exerted a significant anti-apoptotic effect, as evidenced by reducing TUNEL-positive staining (8.2±2.5% vs. 12.6±2.7% of vehicle, P<0.05).4. Effects of GIK on MVO₂, glucose uptake and plasma FFABefore and during ischemia, there were no differences among groups for MVO₂, glucose uptake and plasma FFA. MVO2 was elevated substantially after reperfusion in all the three groups. MVO2 was slightly higher in GIK-treated group than GK or vehicle-treated group during reperfusion, but had no statistical difference. GK markedly increased blood glucose by 89.6% (P<0.01) at the end of 4-h reperfusion compared with Vehicle. It is also...