Regulation of bioenergetics in O2-limited isolated rat hearts

Abstract

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 ...

Low-flow Ischemia and Hypoxia Stimulate Apoptosis in Perfused Hearts Independently of Reperfusion

“…Despite matched O 2 supply, heart rate and H + release were higher in H than LFI hearts. This is consistent with previous observations indicating myocardial down-regulation during LFI but not during H, perhaps for the low coronary flow that decreases the washout of membrane-diffusible factors, including lactate, which depresses cardiac function [32]. Myocardial down-regulation during LFI implies preservation of highenergy phosphates [33], improved recovery [34] and greater tolerance to sustained O 2 supply reduction [35].…”

Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine

“…The fall of that ratio at the end of low-flow ischemia is a consequence of increased substrate-level phosphorylation, as it is evident from the increased venous [lactate]. It is well known that ATP generated from glycolysis represents a substantial portion of total energy production under low-flow ischemia (5,16); this feature was also verified in the same experimental model as that used in this study (45). However, the O 2 uptake-to-LVDP ⅐ HR ratio returned to near-normal values at the end of reperfusion except for the TG 4,000 group.…”

“…The TG4,000 ϩ TMZ (n ϭ 5) group was similar to TG 4,000 group, but with 10 Ϫ6 M freshly prepared TMZ (Servier Laboratories; Courbevoie, France). The medium was equilibrated at PO 2 ϭ 670 Ϯ 6 mmHg (means Ϯ SE) and PCO 2 ϭ 36 Ϯ 1 mmHg in membrane oxygenators (45). The resulting pH was 7.38 Ϯ 0.01 at 37°C.…”

Effects of broad band electromagnetic fields on HSP70 expression and ischemia-reperfusion in rat hearts

“…The perfusion apparatus is described elsewhere (Samaja et al, 1994). The medium, a KrebsHenseleit buffer containing 2 mM free Ca 2+ , 11 mM glucose, 10 mM HEPES, pH 7.4 at 378C, was forced through the aorta (retrograde perfusion) at fixed flows (either 15 or 1.5 ml/min).…”