Relation of myocardial oxygen consumption and function to high energy phosphate utilization during graded hypoxia and reoxygenation in sheep in vivo.

Abstract

IntroductionThis study investigates the relation between myocardial oxygen consumption (MV 02), function, and high energy phos- Severe hypoxia ultimately leads to contractile failure, which is attributed to an imbalance between myocardial oxygen supply and demand (1)(2)(3)(4). Sudden extreme oxygen deprivation causes rapid depletion of energy stores in the form of the high energy phosphates, phosphocreatine, and ATP, as well as accumulation of ATP hydrolysis products. In isolated myocytes (5) and buffer-perfused hearts (5, 6) anoxia or hypoxia results in a reduced oxidative phosphorylation rate. Myocardial respiration wanes despite increasing ADP and intracellular phosphate (Pi),' which both stimulate mitochondrial ATP production under aerobic conditions. The intact animal generally maintains or increases myocardial oxygen consumption during early or moderate hypoxia (7-9). Small decreases in myocardial phosphocreatine content with no depletion of the cytosolic ATP pool have been documented during moderate hypoxic conditions (10, 11). However, myocardial oxygen consumption rates have not been directly measured during periods of rapid high energy phosphate depletion and repletion in the intact animal. The purpose of this study was to examine the relation between myocardial oxygen consumption, function, and high energy phosphates during severe hypoxia and reoxygenation in vivo. Additionally, rephosphorylation parameters were measured to determine if evidence of respiratory uncoupling or mitochondrial damage occurs during reoxygenation in vivo. Graded hypoxia was performed in an effort to gradually reduce arterial oxygen tension to attain the P02 at which high energy phosphate stores rapidly decreased. Highly time-resolved 31P nuclear magnetic resonance (NMR) spectroscopy enabled monitoring of myocardial phosphates throughout hypoxia and recovery with simultaneous measurement of oxygen consumption. Consequently, these measurements enhanced analysis of mitochondrial function in vivo during reoxygenation. MethodsAnimal preparation. Animals used in this study were handled in accordance with institutional and National Institutes of Health animal care and use guideline. Sheep between 30 and 70 d old (mean 47 d±6.8) were sedated with an intramuscular injection of 10 mg/kg ketamine, and 0.2-0.4 mg/kg xylazine, intubated, and then ventilated (C-900 pediatric ventilator; Siemens Corp., Schaumberg, IL) with room air and oxygen, followed by an intravenous dose of alpha-chloralose (40 mg/ kg). Femoral arterial cannulation was performed for monitoring systemic blood pressure and sampling blood. Arterial pH was maintained between 7.35 and 7.45 by adjustment of ventilatory tidal volume and 1. Abbreviations used in this paper: FIo2, fractional inspiratory oxygen

Mitochondrial protein and HSP70 signaling after ischemia in hypothermic-adapted hearts augmented with glucose

“…Anaerobic ATP production can maintain cytosolic ATP levels until more prolonged ischemia depletes cardiac glycogen stores. Although phosphocreatine is rapidly restored, ATP depletion persists after reperfusion or reoxygenation (16,20). This persistence is generally attributed to purine loss and degradation.…”

Temperature Threshold and Preservation of Signaling for Mitochondrial Membrane Proteins during Ischemia in Rabbit Heart

“…These levels cannot be considered indices of mitochondrial function or damage, as they are dependent on the balance between energy production and utilization during ischemia, as well as the status of the purine salvage pathways (30). Reductions in ATP utilization caused by temperatures below the threshold preserve ATP stores during ischemia and prevent nucleotide loss through purine degradation pathways (27).…”

“…These pathways might include those responsible for mitochon- drial repair as mitochondrial dysfunction and damage occur during hypoxia/ischemia and reoxygenation or reperfusion (30). This dysfunction has been linked to reductions in activities of both the adenine nucleotide translocator and the mitochondrial ATPase (8,14).…”

Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice

“…Interestingly, despite use of a no-flow ischemia model, which is more susceptible to lactic acid accumulation from anaerobic glycolysis (60,61), Myc-activated hearts demonstrated greater tolerance to I/R injury. In fact, it should be noted that creatine rephosphorylation rate, which is an in vivo assessment of mitochondrial function after ischemia (62), was superior in Myc-activated hearts. This is in contrast to previous studies wherein hypertrophied hearts were more sensitive to ischemic injury and more dependent on glycolytic substrates than nonhypertrophied hearts (63)(64)(65)(66)(67).…”