scholarly journals Tirilazad Pretreatment Improves Early Cerebral Metabolic and Blood Flow Recovery from Hyperglycemic Ischemia

1995 ◽  
Vol 15 (1) ◽  
pp. 88-96 ◽  
Author(s):  
Yuichi Maruki ◽  
Raymond C. Koehler ◽  
Jeffrey R. Kirsch ◽  
Kathleen K. Blizzard ◽  
Richard J. Traystman
Keyword(s):  
Lipid Peroxidation ◽  
Blood Flow ◽  
Intracranial Pressure ◽  
Intracellular Ph ◽  
High Energy ◽  
Vehicle Group ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Early Reperfusion ◽  
Tirilazad Mesylate

Acidosis may augment cerebral ischemic injury by promoting lipid peroxidation. We tested the hypothesis that when acidosis is augmented by hyperglycemia, pretreatment with the 21-aminosteroid tirilazad mesylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery. In a randomized, blinded study, anesthetized dogs received either tirilazad mesylate (1 mg/kg plus 0.2 mg/kg/h; n = 8) or vehicle (n = 8). Hyperglycemia (400–500 mg/dl) was produced prior to 30 min of global incomplete cerebral ischemia. Intracellular pH and high energy phosphates were measured by phosphorus magnetic resonance spectroscopy. During ischemia, microsphere-determined CBF decreased to 8 ± 4 ml min−1 100 g−1 and intracellular pH decreased to 5.6 ± 0.2 in both groups. During the first 20 min of reperfusion, ATP partially recovered in the vehicle group to 57 ± 21% of baseline, but then declined progressively in association with elevated intracranial pressure. By 30 min, ATP recovery was greater in the tirilazad group (77 ± 35 vs. 36 ± 19%), although postischemic hyperemia was similar. By 45 min, the tirilazad group had a higher intracellular pH (6.5 ± 0.5 vs. 5.9 ± 0.6) and a lower intracranial pressure (18 ± 6 vs. 52 ± 24 mm Hg). By 180 min, blood flow and ATP were undetectable in seven of eight vehicle-treated dogs, whereas ATP was >67% and pH was >6.7 in six of eight tirilazad-treated dogs. Thus, tirilazad acts during early reperfusion to prevent secondary metabolic decay associated with severe acidotic ischemia. If tirilazad acts by inhibiting lipid peroxidation, then these data are consistent with extreme acidosis limiting recovery by a mechanism involving lipid peroxidation.

Influence of intracellular acidosis on contractile function in the working rat heart

1987 ◽  
Vol 253 (6) ◽  
pp. H1499-H1505 ◽  
Author(s):  
F. M. Jeffrey ◽  
C. R. Malloy ◽  
G. K. Radda
Keyword(s):  
Stroke Volume ◽  
Intracellular Ph ◽  
Rat Heart ◽  
Contractile Function ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Intracellular Acidosis ◽  
Tension Development ◽  
O2 Delivery

The decrease in myocardial contractility during ischemia, hypoxia, and extracellular acidosis has been attributed to intracellular acidosis. Previous studies of the relationship between pH and contractile state have utilized respiratory or metabolic acidosis to alter intracellular pH. We developed a model in the working perfused rat heart to study the effects of intracellular acidosis with normal external pH and optimal O2 delivery. Intracellular pH and high-energy phosphates were monitored by 31P nuclear magnetic resonance spectroscopy. Hearts were perfused to a steady state with a medium containing 10 mM NH4Cl (extracellular pH, 7.4). The subsequent washout of NH3 from the cytosol generated a slight acidosis (from intracellular pH 7.0 to 6.8) which was associated with little change in the determinants of O2 consumption (rate-pressure product) and O2 delivery (coronary flow). Acidosis induced a substantial decrease in aortic flow and stroke volume which was associated with little change in peak systolic pressure. Results were qualitatively similar at different external [Ca2+] (1.75, 2.5, 3.15 mM) and preload (12 or 21 cmH2O) but were most prominent at the lowest external [Ca2+] and left atrial pressure. In contrast to this model of isolated intracellular acidosis, hearts subject to a respiratory (extracellular plus intracellular) acidosis showed a marked reduction in pressure development. It was concluded that 1) for the same intracellular acidosis the influence on tension development was more pronounced with a combined extra- and intracellular acidosis than with an isolated intracellular acidosis, and 2) stroke volume at constant preload was impaired by intracellular acidosis even though changes in developed pressure were minimal. These observations suggest that isolated intracellular acidosis has adverse effects on diastolic compliance and/or relaxation.

Regional blood flow and skeletal muscle energy status in endotoxemic rats

1987 ◽  
Vol 252 (5) ◽  
pp. E581-E587 ◽  
Author(s):  
M. M. Jepson ◽  
M. Cox ◽  
P. C. Bates ◽  
N. J. Rothwell ◽  
M. J. Stock ◽  
...  
Keyword(s):  
Blood Flow ◽  
Protein Synthesis ◽  
Regional Blood Flow ◽  
High Energy ◽  
Whole Body ◽  
Sublethal Dose ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Energy Status ◽  
Brown Adipose

Endotoxins induce muscle wasting in part as a result of depressed protein synthesis. To investigate whether these changes reflect impaired energy transduction, blood flow, O2 extraction, and high-energy phosphates in muscle and whole-body O2 consumption (VO2) have been measured. VO2 was measured for 6h after an initial sublethal dose of endotoxin (Escherichia coli lipopolysaccharide 0.3 mg/100 g body wt sc) or saline and during 6h after a second dose 24 h later. In fed or fasted rats, VO2 was either increased or better maintained after endotoxin. In anesthetized fed rats 3-4 after the second dose of endotoxin VO2 was increased, and this was accompanied by increased blood flow to liver (hepatic arterial supply), kidney, and perirenal brown adipose tissue and a 57 and 64% decrease in flow to back and hindlimb muscle, respectively, with no change in any other organ. Hindlimb arteriovenous O2 was unchanged, indicating markedly decreased aerobic metabolism in muscle, and the contribution of the hindlimb to whole-body VO2 decreased by 46%. Adenosine 5'-triphosphate levels in muscle were unchanged in endotoxin-treated rats, and this was confirmed by topical nuclear magnetic resonance spectroscopy, which also showed muscle pH to be unchanged. These results show that although there is decreased blood flow and aerobic oxidation in muscle, adenosine 5'-triphosphate availability does not appear to be compromised so that the endotoxin-induced muscle catabolism and decreased protein synthesis must reflex some other mechanism.

Noninvasive assessment of pharmaceutical intervention during myocardial ischemia-reperfusion in a canine model using two-dimensional 31P chemical shift imaging

1998 ◽  
Vol 76 (2-3) ◽  
pp. 522-531 ◽  
Author(s):  
Constance M Campbell ◽  
Gerald Wisenberg ◽  
Jane Sykes ◽  
R Terry Thompson
Keyword(s):  
Magnetic Resonance ◽  
Myocardial Ischemia ◽  
Magnetic Resonance Spectroscopy ◽  
Infarct Size ◽  
Inverse Correlation ◽  
High Energy ◽  
Metabolic Effects ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Early Reperfusion

The metabolic effects during myocardial ischemia and sustained reperfusion of the antianginal agents diltiazem (n = 10) and propranolol (n = 10) were monitored with noninvasive phosphorus nuclear magnetic resonance spectroscopy to establish any correlation between metabolic changes and infarct size. Spectroscopy followed changes in high-energy phosphate concentrations and myocardial intracellular pH during 2 h of left anterior descending coronary artery occlusion and 3 subsequent weeks of reperfusion, in a closed chest canine infarct model. Gadolinium-DTPA enhanced magnetic resonance imaging was used to assess the extent of myocardial injury (infarct size). Microspheres were used to document the zone at risk and the success of reperfusion. Whereas diltiazem appeared to reduce the derangement in high-energy phosphates during coronary occlusion, there was no significant change in infarct size when compared with a previously studied control group. Propranolol, which produced a lesser decline in pH during occlusion and smaller pH changes during early reperfusion, was associated with a significant reduction in the degree of tissue necrosis (compared with controls). There was an inverse correlation (r = -0.51) between the change in myocardial pH (occlusion end to immediate reperfusion) and the recovery index (an index of myocardial salvage). By 1 h into reperfusion, there was a stronger inverse correlation between pH and infarct size (r = -0.75), implying a protective effect of delaying pH recovery during early reperfusion and indicating the potential use of this parameter as a predictor of tissue viability.Key words: diltiazem, propranolol, magnetic resonance spectroscopy, myocardial infarction.

The effect of high buffer cardioplegia and secondary cardioplegia on cardiac preservation and postischemic functional recovery: a 31P NMR and functional study in Langendorff perfused pig hearts

1991 ◽  
Vol 69 (11) ◽  
pp. 1760-1768 ◽  
Author(s):  
Ganghong Tian ◽  
Graham W. Mainwood ◽  
George P. Biro ◽  
Karen E. Smith ◽  
Keith W. Butler ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Intracellular Ph ◽  
Functional Recovery ◽  
High Energy ◽  
Functional Study ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Intracellular Acidosis ◽  
Heart Preservation ◽  
Postischemic Recovery

High buffer cardioplegia may provide protection against ischemic damage by reducing the extent of intracellular acidosis. Secondary cardioplegia may improve postischemic recovery by restoration of high energy phosphates, ionic gradients, and intracellular pH. To test these hypotheses, pig hearts were arrested with high buffer (150 mM MOPS) cardioplegia or modified St. Thomas' solution II and then kept ischemic at 12 °C for 8 h. High energy phosphates and intracellular pH were followed during the period of ischemia, using 31P nuclear magnetic resonance spectroscopy, and functional recovery was followed during reperfusion. The hearts arrested by high buffer cardioplegia showed significantly higher intracellular pH than hearts preserved with St. Thomas' solution, but there were no significant differences in high energy phosphates. There were no significant differences in functional recovery. We found, however, that secondary cardioplegia abolished ventricular fibrillation, and resulted in improved functional recovery after 8 h of ischemic preservation compared with the hearts reperfused with Krebs–Henseleit solution alone. Our results suggest that despite attenuating the decreases in intracellular pH, high buffer cardioplegia does not improve recovery following 8 h of preservation at 12 °C. Secondary cardioplegia reduces the incidence of ventricular fibrillation and improves postischemic functional recovery of the myocardium.Key words: cardioplegia, secondary cardioplegia, heart preservation, 31P NMR spectroscopy, reperfusion.

Myocardial oxygenation and high-energy phosphate levels during KATP channel blockade

2003 ◽  
Vol 285 (4) ◽  
pp. H1420-H1427 ◽  
Author(s):  
Jianyi Zhang ◽  
Arthur H. L. From ◽  
Kamil Ugurbil ◽  
Robert J. Bache
Keyword(s):  
Blood Flow ◽  
Myocardial Blood Flow ◽  
High Energy ◽  
Arterial Stenosis ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Channel Blockade ◽  
High Energy Phosphate ◽  
Similar Reduction ◽  
Myocardial Oxygenation

Inhibition of ATP-sensitive K+ (KATP) channel activity has previously been demonstrated to result in coronary vasoconstriction with decreased myocardial blood flow and loss of phosphocreatine (PCr). This study was performed to determine whether the high-energy phosphate abnormality during KATP channel blockade can be ascribed to oxygen insufficiency. Myocardial blood flow and oxygen extraction were measured in open-chest dogs during KATP channel blockade with intracoronary glibenclamide, whereas high-energy phosphates were examined with 31P magnetic resonance spectroscopy (MRS), and myocardial deoxymyoglobin (Mb-δ) was determined with 1H MRS. Glibenclamide resulted in a 20 ± 8% decrease of myocardial blood flow that was associated with a loss of phosphocreatine (PCr) and accumulation of inorganic phosphate. Mb-δ was undetectable during basal conditions but increased to 58 ± 5% of total myoglobin during glibenclamide administration. This degree of myoglobin desaturation during glibenclamide was far greater than we previously observed during a similar reduction of blood flow produced by a coronary stenosis (22% of myoglobin deoxygenated during stenosis). The findings suggest that reduction of coronary blood flow with an arterial stenosis was associated with a decrease of myocardial energy demands and that this response to hypoperfusion was inhibited by KATP channel blockade.

Metabolic and cardiodynamic responses of isolated turtle hearts to ischemia and reperfusion

1992 ◽  
Vol 262 (3) ◽  
pp. R437-R443 ◽  
Author(s):  
J. S. Wasser ◽  
E. A. Meinertz ◽  
S. Y. Chang ◽  
R. G. Lawler ◽  
D. C. Jackson
Keyword(s):  
Heart Rate ◽  
Intracellular Ph ◽  
Time Course ◽  
Lactate Production ◽  
High Energy ◽  
Global Ischemia ◽  
Rate Pressure Product ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Developed Pressure

We used 31P and 1H nuclear magnetic resonance spectroscopy to measure intracellular pH, high energy phosphates, and lactate levels in hearts of turtles (Chrysemys picta bellii) subjected to 1.5 h of global ischemia followed by reperfusion. We simultaneously monitored maximum ventricular developed pressure (Pmax), maximal rate of pressure development (dP/dtmax), rate-pressure product (RPP), cardiac output, and heart rate and also measured lactate efflux from the hearts during reperfusion. Our goal was to test the hypothesis that turtle hearts would prove tolerant of prolonged global ischemia at 20 degrees C and would recover completely on reperfusion without any indication of ischemia-or reperfusion-related injury. The 1.5 h of ischemia resulted in decreases in phosphocreatine and ATP to 31.4 +/- 2.8 and 87.3 +/- 6.3% of control, respectively, while Pi rose to 236.6 +/- 26.3%. Intracellular pH decreased during this period from 7.38 +/- 0.02 to 6.87 +/- 0.04. Most of these changes occurred during the first 30 min. Tissue lactate rose during 1.5 h of ischemia from approximately 1.5 to 22.3 mumol/g wet tissue wt. However, the rate of lactate production was much higher during the first 21 min of ischemia (0.41 mumol.g-1.min-1) than during the remaining 70 min (0.10 mumol.g-1.min-1). With the onset of ischemia, Pmax, dP/dtmax, RPP, and heart rate all decreased dramatically with roughly the same time course as the changes in high-energy phosphates and intracellular pH. On reperfusion, turtle hearts rapidly restored high-energy phosphates, intracellular pH, lactate, and cardiodynamics to control levels, usually within 15-30 min, with no evidence of reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood flow and high-energy phosphates in microregions of left ventricular subendocardium

1981 ◽  
Vol 240 (5) ◽  
pp. H804-H810 ◽  
Author(s):  
H. D. Kleinert ◽  
H. R. Weiss
Keyword(s):  
Blood Flow ◽  
Linear Relationship ◽  
Tissue Perfusion ◽  
High Energy ◽  
Left Ventricular ◽  
Significant Loss ◽  
Tissue Blood Flow ◽  
High Energy Phosphates ◽  
Tissue Samples ◽  
Heterogeneous Distribution

Blood flow and high-energy phosphate (HEP) content were determined simultaneously in multiple microregions of left ventricular subendocardium in 29 normal anesthetized open-chest rabbits by use of a new micromethod to determine whether a direct linear relationship existed between these parameters. Tissue samples weighed 1-2 mg. ATP and creatine phosphate (CP) content were quantitated in quick-frozen hearts by fluorometry at sites where tissue perfusion was measured by H2 clearance by use of bare-tipped platinum electrodes. A series of validation studies were conducted to ensure that 1) no significant damage to the tissue surrounding the electrode occurred during the period of experimentation and 2) no significant loss of biochemical constituents had occurred due to labile processes during freezing or storage of the tissue. Blood flow, ATP, and CP values averaged 79.1 +/- 24.1 (SD) ml.min-1.100 g-1, 4.9 +/- 1.3 mumol/g tissue, and 8.0 +/- 3.0 mumol/g tissue, respectively, and are similar to those reported in studies using larger tissue samples. Correlation between the heterogeneous distribution of tissue perfusion and HEP revealed no direct linear relationship between these parameters in the normal unstressed rabbit subendocardium.

Magnetic resonance spectroscopy of high-energy phosphates and lactate immediately after coronary artery bypass surgery

Perfusion ◽  
1998 ◽  
Vol 13 (5) ◽  
pp. 328-333 ◽  
Author(s):  
D NF Harris ◽  
J A Wilson ◽  
S D Taylor-Robinson ◽  
K M Taylor
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Cerebral Ischaemia ◽  
Artery Bypass ◽  
High Energy ◽  
Jugular Bulb ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Intracellular Acidosis ◽  
High Incidence

Hypothermic cardiopulmonary bypass (CPB) is associated with a high incidence of neuropsychological defects, marked cerebral swelling immediately after surgery and jugular bulb desaturation during rewarming. This suggests cerebral ischaemia may occur, but evidence is indirect. We studied four patients with 31P magnetic resonance spectroscopy (MRS) and four with 1H MRS before and immediately after coronary surgery. There was no visible lactate in 1H MR spectra. In 31P MR spectra, the ratio of phosphocreatine to adenosine triphosphate was maintained (before: 2.13 ± 0.86 vs after: 2.57 ± 1.31; mean ± 1 SD) and there was no intracellular acidosis (intracellular pH: 7.1 ± 0.04 vs 7.16 ± 0.08), while phosphocreatine/inorganic phosphate was increased immediately after the operation (2.92 ± 0.37 vs 6.39 ± 2.67, p = 0.03). This suggests rebound replacement of energy stores following recovery from temporary cerebral ischaemia during CPB: intra-operative studies would be needed to test this hypothesis further.

Muscle metabolic responses to exercise above and below the “critical power” assessed using 31P-MRS

2008 ◽  
Vol 294 (2) ◽  
pp. R585-R593 ◽  
Author(s):  
Andrew M. Jones ◽  
Daryl P. Wilkerson ◽  
Fred DiMenna ◽  
Jonathan Fulford ◽  
David C. Poole
Keyword(s):  
Critical Power ◽  
Quadriceps Muscle ◽  
High Energy ◽  
Knee Extension ◽  
Work Rate ◽  
Metabolic Responses ◽  
Time To Exhaustion ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Constant Work Rate

We tested the hypothesis that the asymptote of the hyperbolic relationship between work rate and time to exhaustion during muscular exercise, the “critical power” (CP), represents the highest constant work rate that can be sustained without a progressive loss of homeostasis [as assessed using 31P magnetic resonance spectroscopy (MRS) measurements of muscle metabolites]. Six healthy male subjects initially completed single-leg knee-extension exercise at three to four different constant work rates to the limit of tolerance (range 3–18 min) for estimation of the CP (mean ± SD, 20 ± 2 W). Subsequently, the subjects exercised at work rates 10% below CP (<CP) for 20 min and 10% above CP (>CP) for as long as possible, while the metabolic responses in the contracting quadriceps muscle, i.e., phosphorylcreatine concentration ([PCr]), Pi concentration ([Pi]), and pH, were estimated using 31P-MRS. All subjects completed 20 min of <CP exercise without duress, whereas the limit of tolerance during >CP exercise was 14.7 ± 7.1 min. During <CP exercise, stable values for [PCr], [Pi], and pH were attained within 3 min after the onset of exercise, and there were no further significant changes in these variables (end-exercise values = 68 ± 11% of baseline [PCr], 314 ± 216% of baseline [Pi], and pH 7.01 ± 0.03). During >CP exercise, however, [PCr] continued to fall to the point of exhaustion and [Pi] and pH changed precipitously to values that are typically observed at the termination of high-intensity exhaustive exercise (end-exercise values = 26 ± 16% of baseline [PCr], 564 ± 167% of baseline [Pi], and pH 6.87 ± 0.10, all P < 0.05 vs. <CP exercise). These data support the hypothesis that the CP represents the highest constant work rate that can be sustained without a progressive depletion of muscle high-energy phosphates and a rapid accumulation of metabolites (i.e., H+ concentration and [Pi]), which have been associated with the fatigue process.

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