REGULATION OF ENERGY-METABOLISM OF THE HEART DURING ACUTE INCREASE INHEART WORK

We determined the contribution of all major energy substrates (glucose , glycogen, lactate, oleate, and triglycerides) during an acute increa se in heart work (1 mu M epinephrine, afterload increased by 40%) and the involvement of key regulatory enzymes, using isolated working rat hearts exhibiting physiologic values for contractile performance and o xygen consumption. We accounted for oxygen consumption quantitatively from the rates of substrate oxidation, measured on a minute-to-minute basis. Total beta-oxidation (but not exogenous oleate oxidation) was i ncreased by the work jump, consistent with a decrease in the level of malonyl-CoA. Glycogen and lactate were important buffers for carbon su bstrate when heart work was acutely increased. Three mechanisms contri buted to high respiration from glycogen: 1) carbohydrate oxidation was increased selectively; 2) stimulation of glucose oxidation was delaye d at glucose uptake; and 3) glycogen-derived pyruvate behaved differen tly from pyruvate derived from extracellular glucose. Despite delayed activation of pyruvate dehydrogenase relative to phosphorylase, glycog en-derived pyruvate was more tightly coupled to oxidation. Also, glyco gen-derived lactate plus pyruvate contributed to an increase in the re lative efflux of lactate versus pyruvate, thereby regulating the redox . Glycogen synthesis resulted from activation of glycogen synthase lat e in the protocol but was timed to minimize futile cycling, since phos phorylase a became inhibited by high intracellular glucose.