Regulation of bioenergetics in O,-limited isolated rat hearts. J. Appl. Physiot. 77(6): 2530-2536,1994.-Assessing the role of 0, supply in the regulation of cardiac function in O,-limited hearts is crucial to understanding myocardial ischemic preconditioning and adaptation to hypoxia. We exposed isolated Langendorff-perfused rat hearts to either ischemia (low coronary flow) or hypoxemia (low PO, in the perfusing medium) with matched 0, supply (10% of baseline). Myocardial contractile work and ATP turnover were greater in hypoxemic than in ischemic hearts (P < 0.05; n = 12). Thus, the energy demand was higher during hypoxemia than during ischemia, suggesting that ischemic hearts are more downregulated than hypoxemic hearts. Venous PO, was 12 t 2 and 120 t 15 Torr (P < 0.0001) for ischemic and hypoxemic hearts, respectively, but O2 uptake was the same. Lactate release was higher during hypoxemia than during ischemia (9.7 t 0.9 vs. 1.4 ,t 0.2 pmol/min, respectively; P < 0.0001). Electrical stimulation (300 min-'; to increase energy demand) increased performance in ischemic (P < 0.005) but not in hypoxemic hearts without changes in venous PO, or 0, uptake. However, venous lactate concentration and lactate release increased in ischemic (P < 0.002) but not in hypoxemic hearts, suggesting that anaerobic glycolysis provides the energy necessary to meet the increased energy demand in ischemic hearts only. We conclude that high intracellular lactate or H+ concentration during ischemia plays a major role as a downregulating factor. Downregulation disappears in hypoxemic hearts secondary to enhanced washout of lactate or H+.hypoxemia; ischemia; lactate; oxygen uptake; oxygen supply; energy demand IN THE MAMMAL MYOCARDIUM, high-energy phosphates are utilized at high rates with respect to their steadystate intracellular concentration (21). Therefore, the myocardial contractile system is critically dependent on energy-yielding metabolic processes and on the continuous supply of 0, and substrates. If the 0, supply is low with respect to the needs of the system, a potentially lethal condition may be established due to rapid depletion of high-energy phosphates, leading to cell failure and necrosis. Such a situation is referred to here as "dysoxia," i.e., O,-limited cytochrome turnover (10). To prevent the effects of dysoxia, contractile systems may adapt by establishing a new equilibrium between energy supply and demand. For example, the capacity of energyyielding processes may be amplified through increased availability of key enzymes (21). Alternatively, myocardial activity may be downregulated during ischemia (I) to reduce high-energy phosphate utilization (2). The regulators of myocardial activity during dysoxia are not identified, but the 0, supply (Qo,; flow X 0, content) is a major candidate. Stainsby et al. (38) suggested that the mechanical and metabolic responses of skeletal muscle to I[low flow at normal arterial PO, (Pao,)] and hypoxemia (H; low Pzb, at normal flow) are not the same and thus Qo, may not be the only ...

AND PAOLO CERRETELLI. Human red blood cell aging at 5,050-m altitude: a role during adaptation to hypoxia. J. Appl. Physiol. 75(4): 1696 -1701 , 1993 test the hypothesis that the human red blood cell aging process participates actively in the adaptation to hypoxia, we studied some physical and biochemical hematologic variables in 10 volunteers at sea level (SL) and after 1 (1WK) or 5 wk (5WK) of exposure to 5,050-m altitude. The 2,3-diphosphoglycerate-to-hemoglobin ratio (2,3-DPG/ Hb) was 0.88 t 0.03 (mol/mol) at SL and increased to 1.08 t 0.03 (P = 0.002) and 1.28 t 0.05 (P < 0.0001) at 1WK and 5WK, respectively. The average red blood cell density (D&, which is inversely proportional to the fraction of young red blood cells and is therefore an index of the red blood cell aging process, was 1.1053 k 0.0007 g/ml at SL and decreased to 1.1046 t 0.0008 g/ml (NS) and 1.1018 t 0.0008 g/ml (P < 0.0001) at 1WK and 5WK, respectively. D,, was correlated with 2,3-DPG/ Hb at SL (P = 0.004), only weakly at 5WK (P = O.l), but not at all at 1WK. The arterial 0, saturation was correlated with the change of 2,3-DPG/Hb in 1WK (P = 0.02) and that of D,, in 5WK (P = 0.04). It is concluded that short-term (1WK) increase of 2,3-DPG/Hb is not associated with the erythropoietic response but is presumably due to respiratory alkalosis. By contrast, after prolonged hypoxia (5WK), erythropoiesis may provide an efficient way for increasing blood 2,3-DPG through an augmented proportion of young red blood cells. 2,3-diphosphoglycerate; erythropoiesisPRESERVATIONOFADEQUATETISSUE O,supplyisofcritical importance in hypoxia. Circulatory, respiratory, and erythropoietic adjustments are primarily involved in the acclimatization process (2, 19,31,34). An important functional role may also be attributed to the increased affinity for 0, of the red blood cell (RBC) by way of higher 2,3-diphosphoglycerate (2,3-DPG) concentration (l3,14). Hyperventilation-induced alkalosis (21) appears to trigger the initial increase of 2,3-DPG through stimulation of RBC phosphofructokinase (5,8,13). However, the discrepancy in change between blood pH, which returns to near normal values in a few days (16) [although never completely (18)], and [2,3-DPG], which remains high, suggests alternative mechanisms regulating [ 2, in sojourners and altitude natives.The mature RBC is unable to perform certain functions that normally occur in most aerobic cells, including the synthesis of proteins and the generation of energy from oxidative processes requiring 0,. The inability to repair extensive damage, such as unbalanced metabolism or altered ion homeostasis, confers on the human RBC the unique characteristics of a limited 120-day life span, as assessed by 5gFe tagging (1, 6) and carbon monoxide rebreathing (29) techniques. This imposes the set point between the production of new RBCs by the bone marrow and their removal from the circulation by the reticuloendothelial system. The latter process occurs at random in some animal species but is selective for aging RBCs in humans (...

. We tested the hypothesis that residual oxygen supply during acute low-flow ischaemia or hypoxemia is a major regulator of myocardial performance, metabolism and recovery. Rat hearts were exposed for 20 min to either ischemia (coronary flow reduced to 10% of baseline), hypoxemia (oxygen content reduced to 10% baseline) or a "mixed" condition (combined ischaemia and hypoxemia). The oxygen supply (coronary flow x oxygen content) was matched in all groups (n = 16 per group). Hypoxemic hearts had the highest performance (systolic and developed pressures, _dP/dtm~ and oxygen uptake) and content of IMP and AMP. Ischaemic hearts had the highest content of ATE phosphocreatine, adenine nucleotides and purines. As flow and/or oxygenation were restored, post-ischemic hearts showed better functional and metabolic recovery than post-hypoxemic ones. "Mixed" hearts were more similar to hypoxemic ones during oxygen shortage but to ischemic ones during recovery. We conclude that as oxygenation is critically limiting, coronary flow is relatively more important than oxygen supply in determining myocardial function, metabolism and recovery, most likely secondary to changes in the metabolism of diffusible substances.