Biochemical regulation of developed intraventricular systolic pressure.
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Action Potentials↗
Biomedical subjects
T L James
Publications and source records attributed to T L James.
Substrate regulation of the nucleotide pool during regional ischaemia and reperfusion in an isolated rat heart preparation: a phosphorus-31 magnetic resonance spectroscopy analysis.
Isolated rat heart preparations were studied to characterise the alterations in high energy phosphates that occur during reversible regional ischaemia and to determine whether pyruvate, as the sole exogenous energy substrate, would attenuate the ischaemia induced depletion of the nucleotide pool when compared with glucose. Using phosphorus-31 magnetic resonance spectroscopy baseline concentrations of adenosine triphosphate, phosphocreatine, inorganic phosphate, and intracellular pH were compared with values during 30 min of left coronary artery occlusion followed by 30 min of reperfusion. These variables were related to changes in developed pressure, coronary flow, and oxygen consumption. In addition, the total nucleotide pool was evaluated by biochemical analysis of myocardial tissue extracts and coronary effluent. The ischaemic region was characterised by a dye staining technique and cross sectional echocardiographic measurements of regional myocardial wall thinning. In both glucose and pyruvate perfused groups, coronary flow and oxygen consumption decreased to 50-60% of control within 1 min of ischaemia and returned to baseline values with reflow. Developed pressure decreased to 50(9) and 74(8)% (mean(SEM] of control after 30 min of ischaemia in glucose and pyruvate perfused groups respectively. Reperfusion resulted in complete recovery of developed pressure in hearts perfused with pyruvate but not in the glucose group. Glucose perfused hearts had a greater decrease in intracellular pH during ischaemia (7.07(0.01) to 6.36(0.1] than pyruvate perfused hearts (7.06(0.02) to 6.83(0.04]. Reperfusion resulted in a rapid return to baseline intracellular pH in both groups. During ischaemia, adenosine triphosphate values decreased to a greater degree in glucose than in pyruvate perfused hearts (57(4) and 79(5)% of baseline respectively). Thirty minutes of reperfusion did not significantly improve adenosine triphosphate concentrations in either group. Phosphocreatine concentrations decreased to 52(7) and 75(6)% of baseline in glucose and pyruvate perfused groups respectively after the ischaemic period. Reperfusion resulted in normalisation of phosphocreatine values in the pyruvate but not in the glucose perfused group. Biochemical analysis of myocardial tissue extracts confirmed the spectroscopy data and showed that pyruvate inhibits the efflux of adenine nucleotide derivatives. Tissue concentrations of adenosine monophosphate were three times greater and adenosine 50% less after 30 min of ischaemia in the pyruvate perfused group.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Complete and partial ureteral obstruction: evaluation of renal effects with P-31 MR spectroscopy and Tc-DMSA scintigraphy.
Phosphorus-31 magnetic resonance (MR) spectroscopy was used to study the effects of partial and complete ureteral obstruction on the porcine kidney; results were compared with renal tubular function as determined with technetium-99m dimercaptosuccinic acid (DMSA) scintigraphy. Twenty-seven pigs were used: nine as sham-operated controls, six with partial ureteral obstruction, and 12 with complete ureteral obstruction. P-31 MR spectra and Tc-DMSA scintiscans were obtained weekly over 3 weeks. Partial obstruction caused no significant change in P-31 MR spectra, whereas Tc-DMSA scintiscans showed a 74% decrease in tubular function by the end of 3 weeks. Complete obstruction caused a 43% reduction in the mean adenosine triphosphate (ATP) to inorganic phosphate (Pi) ratio, which paralleled the 96% decrease in Tc-DMSA uptake over 3 weeks. The difference in ATP/Pi ratios between control and completely obstructed kidneys was significant (P less than .01) at 2 and 3 weeks after ligation. These results indicate that radionuclide Tc-99m DMSA uptake is very sensitive to the pathophysiologic changes in renal tubular function, while the organ average cellular bioenergetic state (ATP/Pi) is not as strongly affected.
Adenosine Triphosphate↗
Improvement in myocardial performance without a decrease in high-energy phosphate metabolites after isoproterenol in Syrian cardiomyopathic hamsters.
To determine the effect of isoproterenol on cardiac energetics and function in an animal preparation of cardiomyopathy, we studied Langendorff perfused hearts from Syrian cardiomyopathic hamsters. High-energy phosphate metabolites (phosphocreatine [PCr], ATP, inorganic phosphate [Pi]) and intracellular pH (pHi) were measured by 31P nuclear magnetic resonance spectroscopy and correlated with left ventricular developed pressure, coronary flow, and O2 consumption before and during a 10(-6)M infusion of isoproterenol. Total intracellular calcium was also determined by atomic absorption spectroscopy with the use of potassium ethylenediamine tetra-acetate cobaltate as a marker for extracellular space. In cardiomyopathic hamsters, isoproterenol infusion increased mean developed pressure by 300% (p less than .005 compared with control; n = 5), O2 consumption eightfold (p less than .0005), and PCr by 40% (p less than .05). PCr/Pi ratio, which is analogous to phosphorylation potential, improved 100% (p = .05). In normal hamsters, isoproterenol infusion resulted in an 83% increase in developed pressure (p less than .001) and a 25% increase in O2 consumption (NS). However, mean PCr and PCr/Pi decreased by 30% and 50%, respectively (p less than .05 for both), during isoproterenol infusion. pHi decreased in normal animals (p less than .01), but tended to improve in diseased animals (NS) during isoproterenol infusion. Freeze-clamp measurements of phosphate metabolites correlated well with the nuclear magnetic resonance data. Intracellular calcium increased from 0.0102 +/- 0.002 to 0.144 +/- 0.030 mumol/ml heart water in normal hamsters during isoproterenol infusion. Cardiomyopathic hamsters had a markedly elevated baseline calcium content of 60.82 +/- 5.85 mumol/ml heart water due to the presence of dystrophic calcification.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Triphosphate↗
The effects of hypovolemic hypotension on high-energy phosphate metabolism of traumatized brain in rats.
To clarify the effect of hypovolemic hypotension on high-energy phosphate metabolism in head injury, sequential changes in in vivo phosphorus-31 magnetic resonance (31P MR) spectra were compared in 35 rats after impact injury with and without hypotension. Fourteen rats were subjected to hypotension alone (mean arterial blood pressure (MABP) of either 40 or 30 mm Hg for 60 minutes), seven to fluid-percussion impact injury (4 to 5 atm) alone, and 14 to impact injury and hypotension (MABP of 40 to 30 mm Hg). Impact injury alone caused a transient decrease in the phosphocreatine (PCr) level and an increase in the inorganic phosphate (Pi) value. While hypotension alone produced only small changes on 31P MR spectra, impact injury plus hypotension caused pronounced changes. Impact injury and an MABP of 40 mm Hg caused a 50% decrease in PCr concentration and an approximately twofold increase in Pi level, which were significantly greater than values in rats with impact injury alone. Impact injury and an MABP of 30 mm Hg also caused a significant decrease in adenosine triphosphate value, which was not observed in rats with impact injury alone or with an MABP of 30 mm Hg alone. Decreases in intracellular pH were greater in rats with impact injury and hypotension. After traumatic injury, the brain is extremely vulnerable to hypovolemic hypotension, as reflected in the loss of high-energy phosphates in brain.
Animals↗
Solution structure of [d(GGTATACC)]2: wrinkled D structure of the TATA moiety.
Phase-sensitive two-dimensional nuclear Overhauser effect spectra of [d(GGTATACC)]2 in aqueous deuterium oxide solution at four mixing times were quantified to give all nonoverlapping cross-peak intensities. A structural model for [d(GGTATACC)]2 was built in which the GG- and -CC moieties were in the B-DNA form, while the middle -TATA- moiety was in the wrinkled-D form (BDB model). This model was subjected to energy refinement by molecular mechanics calculations with the program AMBER. Counterions (Na+) were added to neutralize the charges, and water molecules were placed bridging across the minor groove. A complete relaxation matrix analysis was used to calculate two-dimensional nuclear Overhauser effect spectra of [d(GGTATACC)]2 from the above models (before and after energy refinement) and from four other [d(GGTATACC)]2 structural models: regular A, crystalline A, regular B, and energy-minimized B. Among them, the energy-minimized BDB model yielded a set of theoretical spectra that gave the best fit to the experimental spectra. It was also the energetically most stable. Therefore, it is a good representation of the ensemble- and time-averaged structure of the octamer in solution. This model has backbone torsion angles similar to those of B-form DNA in the GG- and -CC moieties and torsion angles similar to those of wrinkled D form DNA in the -TATA- moiety. The base stacking and base pairing are not interrupted at the junctions between the two structural moieties. Its minor groove is narrower than that of B DNA, and the solvent-accessible surface of the minor groove forms a closed hydration tunnel in the middle -TATA- segment.
Adenine↗
31P magnetic resonance spectroscopy of mesenteric ischemia.
31P magnetic resonance spectroscopy (MRS) was performed in vivo on normal and ischemic rat intestine. Within 3 min after induction of ischemia, there is a dramatic fall in adenosine triphosphate (ATP) and rise in inorganic phosphate (Pi). Our results suggest that MRS may prove useful in the early detection of mesenteric ischemia.
Adenosine Triphosphate↗
Comparison of lactate concentration determinations in ischemic and hypoxic rat brains by in vivo and in vitro 1H NMR spectroscopy.
An experimental protocol for the quantitation of lactate is demonstrated for in vivo 1H NMR surface coil spectroscopy. The in vivo lactate concentration can be calculated by comparing the in vivo and in vitro ratios of lactate and N-acetylaspartate (NAA) NMR signals. With this protocol, approximately 25% of lactate present in the hypoxic or ischemic rat brain is observed by NMR.
Animals↗
Measurement of lactate accumulation by in vivo proton NMR spectroscopy during global cerebral ischemia in rats.
In vivo 1H NMR spectral editing techniques were used to monitor cerebral lactate production during remotely controlled temporary forebrain ischemia in rats. The lactate/N-acetylaspartate (NAA) ratio correlated with survival after ischemia and subsequent reperfusion. The lactate/NAA ratio that predicted death after ischemia in rats was estimated to be approximately 1.3.
Animals↗
Influence of heart rate on metabolic and hemodynamic parameters in the Syrian hamster cardiomyopathy.
The effect of varying heart rate in 155- to 170-day-old isolated, perfused cardiomyopathic Syrian hamster hearts was evaluated by 31P nuclear magnetic resonance spectroscopy. At a low paced heart rate of 170 bpm, cardiomyopathic hearts did not differ from normal hearts except for a lower developed left ventricular pressure. As pacing rate was increased progressively to 270/min, cardiomyopathic hearts showed prolongation of contraction, which led to a pronounced rise in diastolic pressure as the interstimulus interval shortened. This was accompanied by a marked decrease in energy-rich phosphorus compounds. By contrast, increasing heart rate in normal hearts did not change left ventricular pressure and caused only a mild reduction in energy-rich phosphorus compounds. Intracellular pH of cardiomyopathic animals paced at 270 bpm was significantly lower than in normal animals. Thus, indices reflecting mitochondrial function of 155- to 170-day-old cardiomyopathic hamsters appear adequate at low heart rate. Increasing the heart rate unmasks latent mitochondrial dysfunction.
Adenosine Triphosphate↗
Spin-echo fluorine magnetic resonance imaging at 2 T: in vivo spatial distribution of halothane in the rabbit head.
Spin-echo 19F magnetic resonance imaging was performed at 2.0 T to explore the in vivo spatial distribution of halothane in the rabbit head. Because the halothane concentration is low in vivo, and because the measured relaxation times of the 19F resonance peak for halothane were T1 approximately equal to 1.0 sec and T2 approximately equal to 3.5-65 msec, 1-3-h imaging times were required (TR = 1 sec, TE = 9 msec) in order to obtain adequate images with a 64 X 256 raw data matrix and a 20-mm slice thickness. With this technique, halothane was primarily detected in lipophilic regions of the rabbit head, but little or no halothane was observed in brain tissue. Because T2 was shorter in brain tissue than in surrounding fat, a shorter TE than we could obtain is needed for optimal spin-echo imaging of brain halothane.
Animals↗
Assessment of clinical renal preservation by phosphorus-31 magnetic resonance spectroscopy.
To evaluate the role of magnetic resonance spectroscopy (MRS) and to develop surface coils for assessing cadaveric renal viability during hypothermic storage, we used the monophosphate/inorganic phosphate ratio (MP/Pi) to monitor phosphorous metabolites in intact kidneys during various renal preservation maneuvers. Eighteen canine kidneys and 16 cadaveric kidneys were studied as follows: Group 1 (N = 4) in situ kidneys were monitored by implanted MRS coils; Group 1 (N = 4) ex vivo kidneys were immediately attached to vascular cannulas and monitored by MRS surface coils during normothermic perfusion; Group 3 (N = 4) kidneys were removed, cold-flushed and, after 24 hours of 4C storage, monitored by MRS surface coils before and during four hours of reperfusion via vascular cannulas; Group 4 (N = 6) kidneys were removed, cold-flushed and monitored by surface coils during cold storage up to 72 hours. In addition, 16 cadaveric kidneys were studied while in sterile cold-storage containers. Postoperative renal function was followed in recipient patients. The MP/Pi ratios in Group 1 kidneys correlated with the ability to regenerate adenosine triphosphate (ATP). Groups 2 and 3 showed similar regeneration of ATP and MP/Pi after postischemic reperfusion, and the signal-to-noise ratios of the surface coils were better than those in the implanted coils in Group 1. Surface-coil monitoring in Group 4 kidneys showed predictable decay rates of MP/Pi during one to 72 hours of cold storage; in contrast, simultaneous cortical medullary microcirculation studies with 99mTc-macroaggregated albumin were inconclusive. Human cadaveric kidneys with high MP levels were associated with excellent renal function after transplantation, while those with low MP (less than or equal to 0.50) were associated with nonviability. We conclude that MRS is a practical and safe diagnostic modality for clinical transplantation.
Adenosine Triphosphate↗
An in vivo study of halothane uptake and elimination in the rat brain with fluorine nuclear magnetic resonance spectroscopy.
A recent NMR study reported the elimination of halothane from the brain of rabbits to be ten times slower than expected, based on known anesthetic solubility and cerebral blood flow. The authors conducted a study in five rats using fluorine nuclear magnetic resonance (NMR) spectroscopy to see if major pharmacokinetic discrepancies are associated with the uptake, maintenance, and elimination of halothane from the brain. The rats underwent a 60-min period of halothane anesthesia. They employed a spatially selective NMR spectroscopy technique known as surface coil "depth-pulsing" to assure that the fluorine NMR signals originated in brain tissue, and not in the scalp, muscle, adipose tissue, and bone marrow that surround the brain. After the inspired anesthetic concentration was decreased to zero, the amplitude of the fluorine NMR signal decreased to 40% of its maximum value within 34 +/- 8.0 minutes (n = 5), rather than after 7 h as in the recent study, where the fluorine signal may have contained substantial contributions from metabolites or tissues outside the brain. Fluorine was barely detectable in all of the animals 90 min after stopping the administration of halothane. The authors' results are in agreement with model calculations and several other investigations.
Anesthesia↗
An in vivo 19F nuclear magnetic resonance study of isoflurane elimination from the rabbit brain.
19F nuclear magnetic resonance spectroscopy was performed at 2.0 Tesla to evaluate the washout of isoflurane from the adult rabbit brain after 90 min of anesthesia. This investigation reconciles previous in vivo NMR studies of others, which observed a slow anesthetic washout, with invasive non-NMR studies that found a rapid washout, as predicted by perfusion-limited models of anesthetic uptake and elimination. Two NMR surface coil experiments were performed: in the first, a 1-cm surface coil was placed directly over the exposed dura to be certain that the washout was observed only from the brain; in the second, a 3-cm coil was placed noninvasively over the intact scalp to emulate previous NMR experiments. As in previous NMR experiments, a slow washout of isoflurane was observed with the large coil. The NMR signal that is observed with the large coil cannot be attributed solely to brain tissue. Fat surrounding the brain contributes significantly to the fluorine NMR spectra that are observed with the 3-cm coil, and its contributions lengthen the apparent washout time. A rapid washout of isoflurane from the rabbit brain was observed with the small coil, whose signal unambiguously arises only from brain tissue. The observed rapid washout is consistent with previous invasive biochemical measurements of anesthetic washout from the brain.
Anesthesia↗
In situ brain metabolism.
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Adenosine Diphosphate↗
Assessment of testicular metabolic integrity with P-31 MR spectroscopy.
To evaluate the reliability of phosphorus-31 magnetic resonance (MR) spectroscopy in the assessment of acute testicular ischemia, vascular integrity, and spermatogenesis, the authors studied in vivo canine and primate testicles grouped as follows: group 1 testes (n = 8), in situ canine controls; group 2 (n = 11), canine testes subjected to warm ischemia; group 3, canine (n = 4) and primate (n = 4) testicles from hormone-treated animals. Group 1 control testicles showed high monophosphoester (MP) levels; low levels of inorganic phosphate (Pi), phosphodiester (PD), and phosphocreatine; and high levels of adenosine triphosphate (ATP). Group 2 testes revealed a time-dependent decay of MP/Pi ratios (from 2.1 to 0.70). Regeneration of ATP was noted in the acute reperfusion period. After 6 weeks of pituitary gonadotropin suppression, group 3 testes showed a significant decrease (P less than .05) in MP/PD ratios from a control level of 2.6 +/- 0.3 and a decrease in the MP/beta-ATP ratio from 2.4 +/- 0.1 to 1.8 +/- 0.3. P-31 MR spectroscopy appears to be a potential method for noninvasively assessing testicular ischemic injury and the metabolic integrity of spermatogenesis.
Animals↗
Factors influencing myocardial response to metabolic acidosis in isolated rat hearts.
We assessed the effects of metabolic acidosis in Langendorff rat hearts to identify factors influencing myocardial response to metabolic acidosis. Intracellular pH (pHi), beta-ATP, phosphocreatine, and inorganic phosphate (Pi) content were measured by 31P nuclear magnetic resonance spectroscopy along with simultaneous measurements of coronary flow and developed pressure during 30 min of perfusion at pH = 6.8, followed by 15 min of reequilibration at pH = 7.4. Under high work-load conditions, pHi, high-energy phosphates, coronary flow, and developed pressure were severely reduced during metabolic acidosis. Each of these hearts exhibited a progressive decline in developed pressure and stopped beating during reequilibration. Lowering work load prevented severe biochemical or mechanical deterioration, allowing complete recovery during reequilibration. In the presence of high work load, factors found to improve myocardial tolerance to metabolic acidosis included maintaining base-line or higher levels of coronary flow with vasodilators or substitution of pyruvate for glucose as the energy-producing substrate. Raising perfusate osmolality did not prevent severe decreases in coronary flow and developed pressure during acidosis, but did allow a dramatic recovery during reequilibration. Recovery of biochemical and mechanical performance after 30 min of metabolic acidosis was directly related to 1) ln[ATP]/[ADP]f[Pi] greater than or equal to 4.1, where [ADP]f is the concentration of free ADP; 2) pHi greater than 6.40; and 3) ATP level greater than or equal to 75% of control.
Acidosis↗
Lactic dehydrogenase isozymes, 31P magnetic resonance spectroscopy, and in vitro antimitochondrial tumor toxicity with gossypol and rhodamine-123.
Three compounds that share specific antimitochondrial properties are gossypol, rhodamine-123, and lonidamine. We compare the antiproliferative activities of these drugs against six human cell lines derived from breast (T47-D), pancreas (MiaPaCa, RWP-2), prostate (DU-145), colon (HCT-8), and cervix (HeLa) carcinomas. Tumor cells enriched in cathodal LDH isozymes (LDH4 and LDH5) are significantly more sensitive to gossypol and rhodamine-123. When compared for ability to inhibit growth of human marrow in soft agar, 10 microM gossypol shows little effect on colony formation whereas 10 microM rhodamine-123 completely prevents stem cell growth, suggesting that gossypol may have the most favorable therapeutic index. Within 24 h of drug administration, there is a relative increase in intracellular inorganic phosphate pools and a marked decline in soluble high-energy phosphates in sensitive tumor cells, as measured by 31P magnetic resonance spectroscopy. These studies suggest that specific antimitochondrial agents might be selectively administered on the basis of tumor LDH isozyme content and noninvasively monitored for antiproliferative activity by 31P spectroscopy.
Cell Division↗