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Biochemical consequences of electrical pacing in ischemic-reperfused isolated rat hearts
Full text linkIt is still unclear if performance recovery in postischemic hearts is related to their tissue level of high-energy phosphates before reflow. To test the existence of this link, we monitored performance, metabolism and histological damage in isolated, crystalloid-perfused rat hearts during 20 min of low-flow ischemia (90% coronary flow reduction) and reflow. To prevent interference from different ischemia times and perfusing media compositions, the ischemic ATP level was varied by changing energy demand (electrical pacing at 330 min-1). Under full coronary flow conditions, work output, as well as ATP and phosphocreatine contents were the same in control, spontaneously contracting (n = 23) and paced (n = 21) hearts. During low-flow ischemia, the higher work output (p < 0.0001) in paced hearts decreased their tissue content of ATP, phosphocreatine and total adenylates and purines (p < 0.05), as opposed to maintained values in control hearts. During reflow, the recovery of mechanical performance and O2 uptake was 94 ± 5% and 110 ± 9% (p = NS vs. baseline) in controls, vs. 71 ± 5% and 74 ± 6% in paced hearts (p < 0.004 vs. baseline). The levels of ATP and total adenylates and purines remained constant in control, but were markedly depressed (p < 0.05 vs. baseline) in paced hearts. Phosphocreatine+creatine was the same in both groups. These data, together with the observed lack of creatine kinase leakage and of structural damage, indicate that myocardial recovery during reflow reflects the tissue level of ATP, phosphocreatine and total adenylates and purines during ischemia, regardless of physical cell damage
Effects of energy demand in ischemic and in hypoxemic isolated rat hearts
No full textAim of this study was to assess the role of O2, lactate and energy demand in the regulation of myocardial work during severe dysoxia. For this purpose, we measured function and metabolism in isolated Langendorff-perfused rat hearts exposed to either ischemia or hypoxemia (matched for the O2 supply, 10% of baseline) with/out electrical stimulation. When hearts could adjust their HR, hypoxemia demanded more energy than ischemia (p<0.05) despite same O2 supply. Venous PO2 was 12±2 or 139±20 mmHg (p<0.0001), respectively, but VO2 was the same. After 10 min at HR=300 min-1, myocardial performance increased in ischemic but not in hypoxemic hearts P(v)O2 and were not affected by pacing. In contrast, both venous [lactate] and lactate production rate increased, but in ischemic hearts only. We conclude that ischemic hearts were downregulated while hypoxemic hearts were not. Likely, depressed washout of lactate during ischemia could offset the effects of O2 in severely dysoxic hearts. Anaerobic glycolysis provided the energy necessary to meet increased energy demand in ischemic hearts, but could not exploit this action in hypoxemic hearts probably because in these hearts it was already working near maximum
HUMAN RED-BLOOD-CELL AGING AT 5,050-M ALTITUDE - A ROLE DURING ADAPTATION TO HYPOXIA
Full text linkTo 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 ± 0.03 (mol/mol) at SL and increased to 1.08 ± 0.03 (P = 0.002) and 1.28 ± 0.05 (P < 0.0001) at 1WK and 5WK, respectively. The average red blood cell density (D50), 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 ± 0.0007 g/ml at SL and decreased to 1.1046 ± 0.0008 g/ml (NS) and 1.1018 ± 0.0008 g/ml (P < 0.0001) at 1WK and 5WK, respectively. D50 was correlated with 2,3-DPG/Hb at SL (P = 0.004), only weakly at 5WK (P = 0.1), but not at all at 1WK. The arterial O2 saturation was correlated with the change of 2,3-DPG/Hb in 1WK (P = 0.02) and that of D50 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
REGULATION OF BIOENERGETICS IN O-2-LIMITED ISOLATED RAT HEARTS
Full text linkAssessing the role of O2 supply in the regulation of cardiac function in O2-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 PO2 in the perfusing medium) with matched O2 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 PO2 was 12 ± 2 and 120 ± 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 ± 0.9 vs. 1.4 ± 0.2 μmol/min, respectively; P < 0.0001). Electrical stimulation (300 min-1; to increase energy demand) increased performance in ischemic (P < 0.005) but not in hypoxemic hearts without changes in venous PO2 or O2 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+
High-energy phosphates metabolism and recovery in reperfused ischaemic hearts
Full text linkBackground. The aim of this study was to assess how coronary flow, oxygen supply and energy demand affect myocardial ATP, phosphocreatine and their metabolites during oxygen shortage and recovery. Methods. Isolated rat hearts were exposed for 20 min to either low-flow ischaemia or hypoxaemia at the same oxygen supply, followed by return to baseline conditions (20 min). Seventy-three hearts were divided into four groups: ischaemic or hypoxaemic, spontaneously beating or paced to increase energy demand. Results. During O2 shortage, myocardial performance was less in ischaemic, spontaneously beating hearts (SpIs), than in the other groups (14 ± 1% of baseline vs. 25-48%). Consequently, the tissue levels of ATP, total adenylates and phosphocreatine were maintained in SpIs, in contrast to marked decreases in the other groups. Upon reflow, the recovery of performance and of myocardial ATP was 94 ± 5% in SpIs (P = NS vs. baseline) compared with 64-85% (P < 0.05 vs. baseline) in the other groups. The degree of recovery was positively related to the ischaemic contents of ATP (P = 0.03) and adenylates (P = 0.001), but nor to that of phosphocreatine (P = NS). Conclusion. The maintenance of the ATP pool under low oxygen supply conditions is essential for good recovery. The most important factors that determine the ATP pool size are the energy demand, which increases the formation of diffusible ATP catabolites, and the coronary flow, which removes these catabolites, rather than the oxygen supply per se
[Thrombolysis & arrhythmias]
No full textIn this study, we assessed one particular aspect of the arrhythmogenic phenomena that occur during reperfusion secondary to thrombolysis, that is the therein involved metabolic mechanisms. The employed experimental model (isolated Langendorff-perfused rat heart) allowed us to distinguish which factor involved during ischemia, low coronary flow or low oxygen tension, is primarily involved during arrhythmogenesis. This was made possible by comparing two settings characterized by the same oxygen supply, but with different coronary flows and PO2 values, i.e., ischemia and hypoxemia. As expected, the contractile dysfunction was higher during reoxygenation at the end of hypoxemia than during reperfusion at the end of ischemia (p < 0.05). However, the incidence of arrhythmias was similar in both cases. Therefore, whereas the contractile dysfunction appears to be more sensitive to coronary flow, the incidence of arrhythmias appears to be more sensitive to the total oxygen supply to the heart. This implies that the mechanisms underlying the development of contractile dysfunction and arrhythmogenesis follow different paths
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