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Biomedical subjects

R Vink

Publications and source records attributed to R Vink.

At least 19 recordsLinked to original sources
PubMed1992

Nuclear magnetic resonance spectroscopy and the study of tissue oxygen metabolism: a review.

Nuclear magnetic resonance (NMR) techniques are being increasingly utilised as an in vivo method to monitor tissue oxygen concentration in various organs. In muscle and heart, proton NMR spectroscopy of myoglobin has been used to calculate local oxygen tension through the oxygen sensitivity of the histidine group signal intensity. Similarly, spin lattice relaxation times of perfluorocarbon emulsions are oxygen sensitive, and this property has been taken advantage of to produce oxygen maps of brain by fluorine NMR imaging. Phosphorus NMR spectroscopy has also been extensively used to monitor bioenergetic state, which under some conditions, is directly related to tissue oxygen tension. This review will focus on these NMR techniques for oxygen determination, and will critically assess their utility for further studies.

Animals↗
PubMed1992

Increased mortality in female rats after brain trauma is associated with lower free Mg2+.

Male and female Sprague-Dawley rat siblings (200-350 g) were monitored by phosphorus magnetic resonance spectroscopy for 4 h after moderate (2.8 atmospheres) fluid-percussion-induced traumatic brain injury. Following injury, two of nine male animals died whereas 100% of all female rats (n = 16) died (p < 0.01). Prior to injury, brain free magnesium concentration in males was 0.58 +/- 0.05 mM and in females 0.41 +/- 0.09. After injury, mean brain free magnesium concentration in males declined to 0.32 +/- 0.06 whereas mean brain free magnesium concentration in ventilated females (n = 6) after injury declined to 0.17 +/- 0.03 (p < 0.05). There were no significant differences between groups with respect to any other measured variables. We conclude that female rats are more susceptible to irreversible injury after brain trauma, and that this increased susceptibility to injury may be related to brain free magnesium levels.

Adenosine Triphosphate↗
PubMed1991

kappa-Opioid antagonist improves cellular bioenergetics and recovery after traumatic brain injury.

Treatment with opioid receptor antagonists improves outcome after experimental brain trauma, although the mechanisms underlying the protective actions of these compounds remain speculative. We have proposed that endogenous opioids contribute to the pathophysiology of traumatic brain injury through actions at kappa-opioid receptors, possibly by affecting cellular bioenergetic state. In the present study, the effects of the kappa-selective opioid-receptor antagonist nor-binaltorphimine (nor-BNI) were examined after fluid percussion brain injury in rats. Metabolic changes were evaluated by 31P magnetic resonance spectroscopy; the same animals were subsequently followed over 2 wk to evaluate neurological recovery. Nor-BNI, administered intravenously as a 10 or 20 mg/kg bolus at 30 min after injury, significantly improved neurological outcome at 2 wk posttrauma compared with controls. Animals treated with nor-BNI showed significantly greater recovery of intracellular free magnesium concentrations and cytosolic phosphorylation potentials during the first 4 h after injury compared with saline-treated controls. The improvement in cytosolic phosphorylation potential was significantly correlated to neurological outcome. These data support the hypothesis that kappa-opioid receptors mediate pathophysiological changes after traumatic brain injury and that the beneficial effects of opioid-receptor antagonist may result from improvement of posttraumatic cellular bioenergetics.

Animals↗
PubMed1990

Mitochondrial metabolism following traumatic brain injury in rats.

Although a number of studies of traumatic brain injury have implicated mitochondrial dysfunction as a cause of altered posttraumatic energy metabolism, no studies to date have isolated mitochondria and measured their respiratory capacity following trauma. The present study sought to determine whether mitochondrial capacity for oxidative phosphorylation is adversely affected by fluid-percussion-induced traumatic brain injury in rats. Prior to brain injury, the mitochondrial respiratory control ratio was 4.3 +/- 0.2 and the ratio of nmoles of ADP phosphorylated per natom oxygen consumed (ADP/O ratio) was 2.66 +/- 0.09. After injury (2.8 atm; t = 4 h), there were slight but not significant alterations in ADP/O ratio (2.41 +/- 0.07) and state 3 respiratory rate (ADP stimulated); however, there were no changes in the respiratory control ratio. These data suggest that traumatic brain injury, unlike ischemia, does not cause uncoupling of ATP synthesis from respiration, and that brain mitochondria are quite resistant to trauma-induced injury.

Adenosine Diphosphate↗
PubMed1990

Effect of noncompetitive blockade of N-methyl-D-aspartate receptors on the neurochemical sequelae of experimental brain injury.

Pharmacological inhibition of excitatory neurotransmission attenuates cell death in models of global and focal ischemia and hypoglycemia, and improves neurological outcome after experimental spinal cord injury. The present study examined the effects of the noncompetitive N-methyl-D-aspartate receptor blocker MK-801 on neurochemical sequelae following experimental fluid-percussion brain injury in the rat. Fifteen minutes after fluid-percussion brain injury (2.8 atmospheres), animals received either MK-801 (1 mg/kg, i.v.) or saline. MK-801 treatment significantly attenuated the development of focal brain edema at the site of injury 48 h after brain injury, significantly reduced the increase in tissue sodium, and prevented the localized decline in total tissue magnesium that was observed in injured tissue of saline-treated animals. Using phosphorus nuclear magnetic resonance spectroscopy, we also observed that MK-801 treatment improved brain metabolic status and promoted a significant recovery of intracellular free magnesium concentrations that fell precipitously after brain injury. These results suggest that excitatory amino acid neurotransmitters may be involved in the pathophysiological sequelae of traumatic brain injury and that noncompetitive N-methyl-D-aspartate receptor antagonists may effectively attenuate some of the potentially deleterious neurochemical sequelae of brain injury.

Adenosine Triphosphate↗
PubMed1990

Effects of TRH-analog treatment on tissue cations, phospholipids and energy metabolism after spinal cord injury.

Effects of thyrotropin-releasing hormone analog CG3703 on biochemical changes following impact spinal cord trauma were investigated by 31P magnetic resonance spectroscopy, atomic absorption spectrophotometry, high-pressure liquid chromatography and radioimmunoassay using parallel injury models in rabbits and rats. Treatment with CG3703 at 45 min after trauma in rabbits significantly attenuated decreases in intracellular pH and reversed increases in phosphodiester to phosphomonoester ratio, as shown by 31P magnetic resonance spectroscopy. The improved phosphodiester/phosphomonoester ratio was correlated with improved ATP status after treatment, although there was no improvement in aerobic bioenergetic capacity as reflected by phosphocreatine to inorganic phosphate ratios. In rats, treatment with CG3703 significantly reduced changes in tissue cations (Na+, K+, Mg2+) and water content following trauma, but did not significantly alter the accumulation of free fatty acids or thromboxane B2. Thus, the beneficial effects of treatment with thyrotropin-releasing hormone or thyrotropin-releasing hormone analogs on outcome following traumatic spinal cord injury may be due, in part, to actions relating to ion homeostasis.

Animals↗
PubMed1990

Pharmacological and physiological effects of magnesium on experimental traumatic brain injury.

It is now generally accepted that in addition to mechanical or primary injury to the central nervous system (CNS) resulting from a traumatic event, much of the irreversible neural injury occurring after CNS trauma is caused by secondary factors. One of the secondary injury factors implicated in the development of irreversible tissue injury, and associated mortality and morbidity after neurotrauma, is magnesium. This review focuses on recent evidence suggesting that magnesium plays a critical role in the injury process, not only by having direct effects on cellular metabolism, but also by regulating other proposed secondary injury factors such as excitatory amino acids, calcium, lipid hydrolysis, opioid peptides, and energy metabolism. Treatments that have a demonstrated neuroprotective effect following neurotrauma are shown to restore brain cellular magnesium homeostasis after injury.

Animals↗
PubMed1990

Opiate antagonist nalmefene improves intracellular free Mg2+, bioenergetic state, and neurologic outcome following traumatic brain injury in rats.

Treatment of CNS trauma with the opiate antagonist naloxone improves outcome, though the mechanisms of action remain speculative. Nalmefene is another opiate-receptor antagonist, but it has substantially greater potency and duration of action than naloxone. It also has increased activity at kappa opiate receptors and has recently been shown to limit histological changes and neurological dysfunction after traumatic spinal cord injury. The present study examined the effects of treatment with nalmefene on outcome after fluid-percussion-induced traumatic brain injury in rats, using magnetic resonance spectroscopy to monitor acute metabolic changes and behavioral tests to determine chronic neurological recovery. Single-dose treatment with nalmefene (100 micrograms/kg, i.v.) at 30 min after trauma significantly improved (p less than 0.05) neurological outcome (up to 4 weeks) as compared to saline-treated controls. Early changes in intracellular free-magnesium concentration, adenosine diphosphate concentration, and cytosolic phosphorylation potential were all significantly improved by nalmefene treatment, reflecting improved bioenergetic state. We suggest that the ability of nalmefene to improve cellular bioenergetics after trauma may in part account for the neuroprotective effects of this and related compounds.

Adenosine Triphosphate↗
PubMed1989

Phospholipase C activity reduces free magnesium concentration.

The events leading to decline of intracellular free magnesium concentration following traumatic brain injury are unknown. One possible mechanism that may lead to such declines is an alteration in the number and nature of magnesium binding sites within cell membranes following a traumatic event. Although both alterations in membrane structure and decrease in free magnesium concentration have been independently demonstrated to occur following brain trauma, no correlations between the two events have been shown. In the present study, rat brain phospholipids were extracted and reconstituted in MgATP containing aqueous solutions. Using 31P magnetic resonance spectroscopy to measure free magnesium concentration, enzymatic hydrolysis of the artificial membrane vesicles by phospholipase C was shown to reduce the free magnesium concentration. Since activation of phospholipase C has been demonstrated to occur following traumatic brain injury, we propose that this event may initiate decline in free magnesium levels in vivo.

Adenosine Triphosphate↗
PubMed1989

Traumatic spinal cord injury in rabbits decreases intracellular free magnesium concentration as measured by 31P MRS.

The mechanisms by which traumatic injury to the central nervous system cause irreversible tissue damage remain speculative. Recent reports suggest that a decrease in tissue total and free Mg2+ concentration may be an important factor in the development of such injury after experimental brain trauma. Although total Mg changes have been reported following spinal cord trauma, no studies have examined spinal cord-free Mg2+. In the present study, we have used phosphorus magnetic resonance spectroscopy to determine intracellular free Mg2+ concentration and atomic absorption spectrophotometry to measure total tissue Mg concentration in rabbit spinal cord prior to and following impact trauma. We report that intracellular free Mg2+ concentration decreases from a pre-injury value of 0.80 +/- 0.12 mM (mean +/- S.E.M.) to 0.31 +/- 0.05 mM at 2 h post-trauma. Following injury there was an associated decrease in total tissue Mg and K concentration, but no alterations in tissue Na or water content.

Animals↗
PubMed1989

The role of excitatory amino acids and NMDA receptors in traumatic brain injury.

Brain injury induced by fluid percussion in rats caused a marked elevation in extracellular glutamate and aspartate adjacent to the trauma site. This increase in excitatory amino acids was related to the severity of the injury and was associated with a reduction in cellular bioenergetic state and intracellular free magnesium. Treatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dextrophan or the competitive antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid limited the resultant neurological dysfunction; dextrorphan treatment also improved the bioenergetic state after trauma and increased the intracellular free magnesium. Thus, excitatory amino acids contribute to delayed tissue damage after brain trauma; NMDA antagonists may be of benefit in treating acute head injury.

Animals↗
PubMed1989

Magnesium protects against neurological deficit after brain injury.

The biochemical factors that mediate secondary or delayed damage to the central nervous system (CNS) remain speculative. We have recently demonstrated that brain injury in rats causes a rapid decline in brain intracellular free magnesium (Mg2+) and total magnesium concentrations that is significantly correlated with the severity of injury. In order to further investigate the relationship between Mg2+ and brain injury, we examined the effect of Mg2+ treatment on posttraumatic neurological outcome following fluid-percussion brain injury (2.0 atm) in rats. Since administration of ATP-MgCl2 has been shown to be beneficial in a variety of models of organ ischemia, we also examined the efficacy of ATP-MgCl2 or ATP alone in the treatment of experimental brain injury. Animals treated with low (12.5 mumol) or high (125 mumol) dose MgCl2 at 30 min postinjury showed a significant dose-dependent improvement in neurological function when compared to saline-treated controls. Treatment with ATP-MgCl2 (12.5 mumol) or ATP alone (12.5 mumol) caused no significant improvement in chronic neurological outcome. MgCl2-treated animals showed no change in postinjury mean arterial blood pressure (MAP), whereas animals treated with either ATP-MgCl2 or ATP alone showed a transient but significant fall in MAP (P less than 0.01) during the drug-infusion period. Our results suggest that postinjury treatment with MgCl2 is effective in limiting the extent of neurological dysfunction following experimental traumatic brain injury in the rat.

Adenosine Triphosphate↗
PubMed1989

Metabolic changes in rabbit spinal cord after trauma: magnetic resonance spectroscopy studies.

Combined phosphorus and proton magnetic resonance spectroscopy (MRS), using double-tuned surface coils, was used to monitor certain metabolic changes in the L-3 spinal segment of anesthetized rabbits prior to and following experimental spinal cord trauma. Following severe trauma, resulting in spastic paraplegia, there was a delayed and progressive accumulation of lactic acid, a decline in intracellular pH, and a loss of high-energy phosphates. Maximal alterations occurred between 2 and 3 hours after the trauma, with little further change by 4 hours. Histological examination 2 weeks after trauma showed tissue necrosis and cavitation. These findings support the concept of secondary tissue injury after spinal cord trauma and suggest that early changes in metabolism, as shown by MRS, may predict irreversible tissue damage.

Adenosine Triphosphate↗
PubMed1989

Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model.

Experimental fluid-percussion models produce brain injury by rapidly injecting saline into the closed cranium. In the present study we characterize the physiological, histopathological and neurological responses to mechanical brain injury in the rat produced by lateral fluid-percussion injury of graded severity. Physiological experiments (n = 105) demonstrated that all levels of injury produced an acute and transient systemic hypertension and bradycardia. Acute hypertension followed by significant hypotension occurred at higher magnitudes of injury. Post-injury suppression of electroencephalographic amplitude was related to the severity of injury. An increase in slow wave (delta/theta) electroencephalographic activity with a concomitant decrease in alpha/beta electroencephalographic activity were observed only at moderate and high magnitude of injury and were correlated with a worsened neurological outcome (r = 0.84; P less than 0.05) and increased mortality (r = 0.66; P less than 0.05). Alterations in brainstem auditory-evoked potentials were also observed only at the higher levels of injury. Histopathological analysis revealed that the extent of post-injury hemorrhage, cavitation and vascular disruption (as measured by extravasation of Evans Blue dye) was greater at the higher magnitudes of injury. Neurological scoring performed over a 4-week post-injury period demonstrated that lateral fluid-percussion brain injury produces a chronic neurological deficit that is directly related to the severity of injury. Survival was also significantly reduced at the higher magnitudes of injury. These data demonstrate that the lateral model of fluid-percussion injury in the rat reproduces many of the features of head injury observed in other models and species and may therefore be a useful experimental model for the study of the pathophysiology of traumatic brain injury.

Animals↗
PubMed1989

Effects of the N-methyl-D-aspartate receptor blocker MK-801 on neurologic function after experimental brain injury.

Pharmacologic inhibition of excitatory amino acid (EAA) neurotransmission attenuates cell death in models of global and focal ischemia and hypoglycemia and improves neurologic outcome after experimental traumatic spinal cord injury. The present study examined the effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor blocker MK-801 on cardiovascular and neurologic function after experimental fluid-percussion (FP) brain injury in the rat. Animals received either an intravenous bolus of MK-801 (1 mg/kg) or saline (equal volume) 15 min prior to FP brain injury or 15 min following FP brain injury. MK-801 pretreatment significantly improved postinjury cardiovascular variables and attenuated postinjury neurologic dysfunction. Postinjury treatment with MK-801 also significantly improved cardiovascular variables, but had little effect on postinjury neurologic scores. These results suggest that EAA neurotransmitters may be involved in the pathophysiological sequelae of traumatic brain injury and that noncompetitive blockade of the NMDA receptor prior to brain injury may reduce EAA-induced damage and limit neurologic dysfunction.

Amino Acids↗
PubMed1989

Thyrotropin-releasing hormone and central nervous system trauma.

TRH and TRH analogues improve physiological function, survival, and neurological outcome in a variety of models of CNS trauma, including impact spinal cord injury in cats and rats, fluid-percussion-induced brain injury in rats, and compression-induced brain injury in cats. The mechanism by which TRH improves such functions may relate to its ability to improve blood flow and metabolism in the region of injury. Beneficial effects on blood flow may possibly relate to antagonism of the physiological effects of endogenous opioids, leukotrienes, or platelet-activating factor.

Animals↗
PubMed1988

Treatment with the thyrotropin-releasing hormone analog CG3703 restores magnesium homeostasis following traumatic brain injury in rats.

Treatment with thyrotropin-releasing hormone (TRH) analogs following traumatic injury to the central nervous system (CNS) improves neurological outcome through mechanisms that remain unclear. Previous studies have shown that traumatic brain injury is associated with a profound decline in intracellular free magnesium (Mgf) and in total tissue magnesium (Mgt), the extent of Mgf decline being linearly correlated to the severity of injury and resultant neurological deficit. We have used 31P magnetic resonance spectroscopy and atomic absorption spectrophotometry, respectively, to measure cerebral Mgf concentration and Mgf content in rats following fluid percussion brain trauma and treatment with the TRH analog, CG3703. Treatment at 30 min postinjury with CG3703 significantly improved Mgf when compared to saline-treated controls. There were no significant changes in Mgt, Na+, K+ or water content following CG3703 treatment. Since a decline in intracellular free magnesium may affect cellular bioenergetic status, calcium flux, activity of excitatory amino acids, opiate receptors, and the release of eicosanoids, these results suggest that the beneficial effects of treatment with TRH analogs after CNS trauma may be mediated through magnesium-dependent mechanisms.

Animals↗