Rates of glycolysis and glycogenolysis during ischemia in glucose-insulin-potassium-treated perfused hearts: A 13C, 31P nuclear magnetic resonance study.

Abstract

The effects of 11.7 mM glucose, insulin, and potassium (GIK) on metabolism during ischemia were investigated in the perfused guinea pig heart using magnetic resonance spectroscopy. Intracellular metabolites, primarily glycogen and glutamate, were labeled with I3 C by addition of [l-13 C]glucose to the perfusate during a normoxk, preischemic period. 13C and 31 P NMR spectroscopy was used to observe the metabolism of "C-labeled metabolites simultaneously with high-energy phosphorus metabolites and pH. The extent of acidosis and the rate and amount of labeled lactate accumulation during ischemia were the same in control (3 mM glucose + insulin) and GIK-treated hearts. In contrast, the rate of labeled glycogen mobilization during ischemia in GIK-treated hearts was one third the rate observed in control hearts. These observations suggest that GIK decreased the rate of glycogenolysis during ischemia without affecting the rate of glycolysis. We propose that glucose contributed as a glycolytic substrate to a greater extent during ischemia in GIK-treated hearts than in hearts perfused with 3 mM glucose and insulin. The glycogen-sparing effect of GIK demonstrated in these studies could delay the onset of ischemic damage in a clinical setting by prolonging the availability of glycolytic substrate necessary for production of high-energy phosphate. (Circulation Research 1988;62:1065-1074 M yocardial ischemia is a common and important clinical problem. Although metabolism of the ischemic myocardium has been an area of active investigation for many years, the metabolic changes resulting from the inadequate oxygen and substrate supply and product removal associated with ischemia are incompletely understood. However, it is clear that one of the important metabolic events leading to cellular damage during ischemia is failure of the rate of energy production to meet the demands for energy utilization.Several therapeutic strategies have been introduced to alter cardiac metabolism during ischemia. A mixture of glucose, insulin, and potassium (GIK) was initially used 25 years ago as a means of eliminating the electrocardiographic abnormalities of myocardial infarction.1 Since that time GIK has been used in numerous studies of coronary artery occlusion in animals and man. Nearly all of the animal studies, using a variety of measures of recovery, have shown reduced infarct size and improved tissue metabolism.2 " 3 Studies in man have been less conclusive. Infusion of GIK in patients Received November 6, 1986; accepted January 6, 1988. with acute myocardial infarction has resulted in improved left ventricular function, 6 improved electrical stability, 7 clinical improvement, 8 and reduced mortality. 9 Other studies have found no reduction in mortality.l 0 " In patients with stable angina pectoris and coronary artery disease, administration of GIK, together with cardiac pacing, was beneficial in some studies 12 and detrimental in others.13M A better understanding of the metabolic action of GDC may explain many of these contradicto...

Hypoxia and glucose independently regulate the beta-adrenergic receptor-adenylate cyclase system in cardiac myocytes.

“…10 Ml of 1251-ICYP (20 pM final concentration) were incubated at 37°C for 30 min in the presence of varying concentrations of (-)-isoproterenol (10 nM to 100MM) after the reaction was initiated by the addition of80…”

“…Subsequent studies into the beneficial mechanism of GIK indicated that glucose reduced the use of free fatty acids thereby decreasing myocardial oxygen consumption and retarding progressive myocardial injury (9). Nuclear magnetic resonance studies suggest that exogenously supplied glucose may supplement endogenous glycogen mobilization, delay glycogen depletion and prolong the production ofhigh energy phosphates required by myocardial cell metabolism (10).…”

Effects of amino acids on substrate selection, anaplerosis, and left ventricular function in the ischemic reperfused rat heart.

“…Both measurements are difficult in reperfused myocardium where isotopic and metabolic steady state are difficult to establish. '3C is a stable isotope that has recently been applied to numerous problems in intermediary metabolism (33)(34)(35). '3C isotopomer analysis offers advantages over other measurements of substrate selection because it is technically simple, and anaplerosis and competition among several substrates can be assessed in a single experiment (36)(37)(38).…”

Improvement of Hypoperfusion with Norepinephrine Injury by Ex Vivo Insulin in Isolated Diabetic Rat Hearts

“…It might be effective if the dosage of insulin was increased or insulin was given for a longer period. Another possible reason is that during the 30-min hypoperfusion with NE, severe changes in the myocardium might occur in our preparations as shown in non diabetic hearts (23) in which the significant decrease in high energy phosphate and the elevation in intracellular pH were observed during 15-min no-flow. Thus, these pos sibilities might injure the activities of enzymes that are associated with energy metabolism and/or myocardial ion homeostasis, resulting in insufficient restoration by post-treated insulin.…”