CYCLIC-AMP SUPPRESSES THE INHIBITION OF GLYCOLYSIS BY ALTERNATIVE OXIDIZABLE SUBSTRATES IN THE HEART

In normoxic conditions, myocardial glucose utilization is inhibited wh en alternative oxidizable substrates are available. In this work we sh ow that this inhibition is relieved in the presence of cAMP, and we st udied the mechanism of this effect. Working rat hearts were perfused w ith 5.5 mM glucose alone (controls) or together with 5 mM lactate, 5 m M beta-hydroxybutyrate, or 1 mM palmitate. The effects of 0.1 mM chlor ophenylthio-cAMP (CPT-cAMP), a cAMP analogue, were studied in each gro up. Glucose uptake, flux through 6-phosphofructo-1-kinase, and pyruvat e dehydrogenase activity were inhibited in hearts perfused with altern ative substrates, and addition of CPT-cAMP completely relieved the inh ibition. The mechanism by which CPT-cAMP induced a preferential utiliz ation of glucose was related to an increased glucose uptake and glycol ysis, and to an activation of phosphorylase, pyruvate dehydrogenase, a nd 6-phosphofructo-2-kinase, the enzyme responsible for the synthesis of fructose 2,6-bisphosphate, the well-known stimulator of 6-phosphofr ucto-1-kinase. In vitro phosphorylation of 6-phosphofructo-2-kinase by cAMP-dependent protein kinase increased the V-max of the enzyme and d ecreased its sensitivity to the inhibitor citrate. Therefore, in heart s perfused with various oxidizable substrates, cAMP induces a preferen tial utilization of glucose by a concerted stimulation of glucose tran sport, glycolysis, glycogen breakdown, and glucose oxidation.