Magnetization transfer as a technique for in vivo assessment of altered energy transfer in cardiac hypertrophy.
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Adenosine Triphosphate↗
Biomedical subjects
E D Lewandowski
Publications and source records attributed to E D Lewandowski.
Nuclear magnetic resonance evaluation of metabolic and respiratory support of work load in intact rabbit hearts.
Pre-steady-state 13C nuclear magnetic resonance (NMR) spectra can provide a nondestructive probe of metabolic events associated with the physiology of intact organs. Therefore, the relation between phosphorylation state and intermediary metabolism in rabbit hearts, oxidizing [2-13C]acetate, was examined with a combination of 31P and 13C NMR. Multiple enrichment of the tissue glutamate pool with 13C as an index of metabolic turnover within the tricarboxylic acid cycle was readily observed as a function of work load. Dynamic changes in pre-steady-state 13C spectra evolved according to work load and correlated closely to respiratory rate in rabbit hearts perfused 1) under normal conditions (n = 7), 2) at basal metabolic rates (20 mM KCl arrest, n = 5), 3) and at heightened contractile state (10(-7) M isoproterenol, n = 7). The ratio of signal intensity arising from the secondary labeling sites within glutamate (C-2 and C-3) to that of the initial labeling site (C-4) reached steady state within 8.5 minutes in isoproterenol-treated hearts versus 18.5 minutes in control hearts. Work load did not affect glutamate concentration or fractional enrichment at the C-4 position, although an unlabeled fraction of glutamate persisted. Arrested hearts displayed slowed evolution of steady-state 13C enrichment with increased contributions from anaplerotic sources for tricarboxylic acid intermediate formation (32%) as compared with control (9%). Thus, the response of mitochondrial dehydrogenase activity to the demands of cardiac performance is likely to influence the recruitment of anabolic sources supplying the tricarboxylic acid cycle.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetates↗
Dynamic changes in 13C NMR spectra of intact hearts under conditions of varied metabolite enrichment.
Dynamic changes in 13C NMR signal from enriched glutamate pools within hearts have been examined under varied conditions of metabolite pool size and fractional enrichment. Relative signal intensities of 13C-enriched glutamate isotope isomers were similar within spectra from both intact hearts and corresponding in vitro samples. The parameters used to assess metabolic activity with 13C NMR proved independent of fractional enrichment and pool size. The data show the importance of acknowledging unlabeled, 13C NMR invisible metabolites.
Animals↗
Assessment of experimental pericardial effusion using nuclear magnetic resonance imaging techniques.
An experimental canine model of pericardial effusion was designed to validate previous clinical nuclear magnetic resonance imaging (NMR) studies. Saline (n = 7), serum (n = 4), blood (10% hematocrit [n = 5]; 20% hematocrit [n = 5]), and lipid (n = 4) effusions were chosen to resemble: (1) transudative/exudative, (2) nonhemorrhagic/hemorrhagic, and (3) chylous effusions, respectively. There was a linear correlation between the infused volume and the pericardial/epicardial distance measurements on the nuclear magnetic resonance images. Hemorrhagic and nonhemorrhagic exudative effusions were distinguished from transudative effusions by the low signal intensity of transudative effusions images obtained at a TR (repetition time) of 400 and 800 msec. Nonhemorrhagic effusions had significantly lower effusion-to-myocardial signal intensity ratio at TR of 400 msec than did hemorrhagic effusions. Differences in hematocrit were not appreciated qualitatively or quantitatively. Compared with other effusion types, only chylous effusions were hyperintense to myocardium at a TR of 400 msec. Chylous effusions were further uniquely characterized by a decreasing effusion-to-myocardial signal intensity ratio with increasing TR. These experimental findings corroborate the findings of earlier clinical reports and suggest that NMR can provide important assistance in the evaluation of pericardial effusions.
Animals↗
NMR studies of beta-oxidation and short-chain fatty acid metabolism during recovery of reperfused hearts.
The effects of beta-oxidation on the contractile recovery and metabolic activity of postischemic (10 min) rabbit hearts were examined during reperfusion with the short-chain fatty acid butyrate. Hearts received either 13C-enriched butyrate or acetate to evaluate metabolic targeting with 13C nuclear magnetic resonance (NMR) spectroscopy. Acetate and butyrate supported similar contractility (rate of pressure development, dP/dt) and 31P-NMR-detected, high-energy phosphate (HEP) levels during normal perfusion. In postischemic hearts, butyrate sustained a greater percentage of preischemic dP/dt (83 +/- 4%) than did acetate reperfusion (44 +/- 6%, P less than 0.05) with no differences in HEP. The efficiency of oxygen consumption per unit of work was greater in hearts reperfused with butyrate (2.8 +/- 0.2 microM.g-1.mmHg-1) vs. acetate (3.4 +/- 0.1). Inhibition of butyrate oxidation with 4-bromocrotonic acid (4-BCA) during normal perfusion severely reduced dP/dt and HEP. Acetate supported normal dP/dt and HEP levels during perfusion with 4-BCA and butyrate, but contractile recovery during reperfusion with acetate, 4-BCA, and butyrate (46 +/- 6%) was similar to that with acetate alone. With acetate and butyrate combined at reperfusion, acetate accounted for 56% of substrate entering oxidative metabolism at acetyl CoA and delayed contractile recovery (57 +/- 5% at midpoint and 80 +/- 6% at end). Thus improved respiratory efficiency of contraction in reperfused hearts was related to the activity of beta-oxidation.
Acetates↗
Effects of inosine on glycolysis and contracture during myocardial ischemia.
The effects of inosine (INO) on substrate metabolism and rigor formation in ischemic myocardium were examined in isolated rabbit hearts. Metabolite content was assessed in tissue extracts by chemical analysis and in the whole heart by 13C and 31P nuclear magnetic resonance spectroscopy. In ischemic hearts metabolizing either [3-13C]pyruvate or [1-13C]glucose, 1 mM INO increased both total and 13C-labeled alanine content; lactate content was unaffected. At 3 minutes of ischemia, tissue alanine was 1.81 +/- 0.11 microM/g wet wt (mean +/- SEM) in hearts perfused with pyruvate+INO versus 1.23 +/- 0.15 microM/g wet wt in hearts perfused with pyruvate alone (p less than 0.05). INO reduced tissue glycogen during ischemia in pyruvate-perfused hearts. Tissue alanine content in ischemic hearts that were supplied glucose+INO (1.29 +/- 0.13 microM/g wet wt) was greater than in ischemic hearts supplied glucose alone (0.65 +/- 0.14 microM/g wet wt). Alanine was found to originate from pyruvate and was a glycolytic end product in glucose-perfused hearts. INO raised the [3-13C]alanine/[3-13C]lactate ratio in ischemic, intact hearts (glucose = 0.24 +/- 0.07 versus glucose+INO = 0.60 +/- 0.09; pyruvate = 0.49 +/- 0.08 versus pyruvate+INO = 0.89 +/- 0.08). At 7 minutes of ischemia, ATP content fell to 70 +/- 3% with glucose+INO versus 58 +/- 5% with glucose alone. Rigor (stone heart) was delayed from 14.7 +/- 1.3 to 23.2 +/- 1.6 minutes with INO. INO did not change ATP content in ischemic hearts that were supplied pyruvate but delayed rigor (pyruvate = 9.9 +/- 1.2 minutes; pyruvate+INO = 15.6 +/- 1.0 minutes), possibly at the expense of glycogen. Supplemental glucose improved the effectiveness of INO with pyruvate to preserve ATP (pyruvate+glucose = 42 +/- 6%; pyruvate+glucose+INO = 72 +/- 6%) and further delayed rigor (pyruvate+glucose = 13.3 +/- 1.5 minutes; pyruvate+glucose+INO = 20.3 +/- 1.8 minutes). Glucose metabolism supported improved energetic and contractile states in ischemic hearts treated with INO. Thus, cardioprotection of the ischemic heart by INO was associated with preservation of functional integrity and improved energy production due to increased glycolytic activity. Activation of glycolysis in the presence of INO was accommodated by augmented alanine production without the additional accumulation of lactate.
Alanine↗
Fatty acid metabolism and contractile function in the reperfused myocardium. Multinuclear NMR studies of isolated rabbit hearts.
The hypothesis that substrate availability can alter contractile function in reperfused myocardium after global ischemia was investigated in this study. Isolated rabbit hearts were placed in a dual tuned (31P/13C) NMR probe with a 9.4-T magnet and perfused with the following substrates given individually or in combination: 10 mM glucose, 2 mM palmitate, and 2.5 mM [3-13C]pyruvate. Glucose was the sole substrate present for all groups of hearts before the onset of 10 or 20 minutes of zero-flow ischemia. Contractility (dP/dt) was significantly higher in hearts reperfused with glucose compared with hearts reperfused with palmitate or the combination. In addition, myocardial oxygen consumption/unit of work at reperfusion was more efficient with glucose than with palmitate. ATP content during reperfusion was similar with glucose and palmitate and did not account for improved function with glucose. To determine if inhibition of pyruvate metabolism by palmitate might result in altered postischemic function, additional hearts were reperfused with 2.5 mM [3-13C]pyruvate provided alone or in combination with palmitate. Using 13C NMR spectroscopy, it was shown that with the addition of palmitate, pyruvate oxidation was decreased in control and 10-minute ischemic hearts as is consistent with inhibition of pyruvate dehydrogenase by fatty acids. However, palmitate/pyruvate did not worsen postischemic function as compared with palmitate or pyruvate alone. Tricarboxylic acid cycle activity was slowed in reperfused pyruvate hearts, but no further reduction was observed when palmitate was present. In conclusion, palmitate reduces the mechanical function of the reperfused isolated rabbit heart as compared with glucose. This effect of palmitate does not appear to be caused by suppression of pyruvate oxidation or by a change in high energy phosphate content.
Animals↗
Reduced substrate oxidation in postischemic myocardium: 13C and 31P NMR analyses.
13C and 31P nuclear magnetic resonance (NMR) spectra were used to assess substrate oxidation and high-energy phosphates in postischemic (PI) isolated rabbit hearts. Phosphocreatine (PCr) increased in nonischemic controls on switching from glucose perfusion to either 2.5 mM [3-13C]pyruvate (120%, n = 7) or [2-13C]acetate (114%, n = 8, P less than 0.05). ATP content, oxygen consumption (MVO2), and hemodynamics (dP/dt) were not affected by substrate availability in control or PI hearts. dP/dt was 40-60% lower in PI hearts during reperfusion after 10 min ischemia. Hearts reperfused with either pyruvate (n = 11) or acetate (n = 8) regained preischemic PCr levels within 45 s. Steady-state ATP levels were 55-70% of preischemia with pyruvate and 52-60% with acetate. Percent maximum [4-13C]glutamate signal showed reduced conversion of pyruvate to glutamate via the tricarboxylic acid (TCA) cycle at 4-min reperfusion (PI = 24 +/- 4%, means +/- SE; Control = 48 +/- 4%). The increase in 13C signal from the C-4 position of glutamate was similar to control hearts within 10.5 min. The increase in [4-13C]glutamate signal from acetate was not different between PI and control hearts. The ratio of [2-13C]Glu:[4-13C]Glu, reflecting TCA cycle activity, was reduced in PI hearts with acetate for at least 10 min (Control = 0.76 +/- 0.03; PI = 0.51 +/- 0.09) until steady state was reached. Despite rapid recovery of oxidative phosphorylation, contractility remained impaired and substrate oxidation was significantly slowed in postischemic hearts.
Acetates↗
High-energy phosphates and function in isolated, working rabbit hearts.
An isolated, working, rabbit heart has been developed for use with nuclear magnetic resonance (NMR) spectroscopy. This model is functionally stable over a 4-h period and displays classic hemodynamic responses to work-load changes. Control 31P spectra of this preparation (n = 5) were obtained with simultaneous recordings of left ventricular pressure (LVP), LVP differentiated with respect to time (dP/dt), heart rate (HR), and cardiac output (CO). ATP, phosphocreatine (PCr), and hemodynamics remained stable over a 90-min perfusion. Hearts were also subjected to 13.5 min of global ischemia (IS) at 37 degrees C followed by 60 min of reperfusion (RE, n = 7) or 45 min of chronic IS (n = 6). Contraction ceased within 60 s of IS. PCr loss was rapid, reaching undetectable limits by 11 min. ATP loss was gradual and bore no relationship to functional loss. ATP fell to 60 +/- 4% (means +/- SE) of pre-IS levels after 13.5 min of IS. With RE, PCr returned to control levels, whereas ATP values remained depressed for the entire 60 min. Functional activity resumed with RE, but dP/dt did not rise above 85 +/- 7% of preischemic values. No correlation between residual ATP at the end of IS and functional recovery during RE was evident.
Adenosine Triphosphate↗
Inosine preserves ATP during ischemia and enhances recovery during reperfusion.
The effects of exogenous inosine (IN) on high-energy phosphate metabolism and function in isolated, working rabbit hearts were monitored with 31P-nuclear magnetic resonance spectroscopy. Dynamic measurements of ATP and phosphocreatine (PCr) were made along with concomitant functional recordings during normal perfusion, global ischemia (IS), and reperfusion (RE). We found that 0.1 mM IN enhanced the rate of pressure development (dP/dt) within the left ventricle by 10 +/- 5% (n = 7). Although IN levels in treated hearts were elevated during normal perfusion, no effect was observed on ATP or PCr levels. However during IS, pretreatment with IN minimized ATP loss for the first 20 min relative to untreated controls (UNT, P less than 0.05). Both IN and UNT hearts that were ischemic for only 13.5 min regained function during a 60-min RE period. However, at the end of IS, IN hearts (n = 8) displayed 88 +/- 10% of the pre-IS ATP levels, whereas UNT hearts (n = 7) retained only 60 +/- 10%. With RE, ATP in IN hearts remained elevated over that of UNT hearts for the entire 60 min. IN treatment also increased the rate of recovery of dP/dt and maintained improved function over 60 min of RE. No correlation was found between post-IS ATP levels and dP/dt values during RE in either IN or UNT hearts. These data indicate that IN was protective against ATP loss during IS and improved functional recovery on RE.
Adenosine Triphosphate↗