Search PubMed⌕ Search

Biomedical subjects

M J Halsey

Publications and source records attributed to M J Halsey.

At least 19 recordsLinked to original sources
PubMed1992

Interactions of the beta carboline abecarnil with the high pressure neurological syndrome in a primate model.

The neurophysiological interactions between the high pressure neurological syndrome (HPNS) and a new beta carboline, abecarnil, were studied in the non-human primate Papio anubis. Abecarnil is a partial agonist at the benzodiazepine site on the GABA/benzodiazepine receptor. Six animals were exposed on two occasions to pressures of 91 ATA in an environment of helium and oxygen. One exposure was pretreated with a total dose of abecarnil 1.0 mg/kg, the other with an equivalent volume of vehicle. Treatment with abecarnil prevented the severe signs of HPNS occurring between 51 and 91 ATA. Onset pressures of the various signs were unaffected. Some signs, e.g. myoclonus, became more frequent when abecarnil was used. A residual protective effect of abecarnil was present 4 weeks after the dose was given, active at pressures less than 71 ATA. Changes with pressure in the EEG were recorded primarily from the frontal cortex, but were also present in the parietal and occipital areas of the left cortex. Amplitude and frequency spectra were calculated and changes with pressure in the four conventional wavebands, plus two others, analysed. The most striking change was the prevention by abecarnil of the pressure-induced 100% increase in alpha wave amplitude in the frontal region. It is concluded that modulation of GABA transmission is important in controlling the expression of HPNS.

Animals↗
PubMed1992

Molecular interactions of anaesthetics with biological membranes.

1. There is not yet a consensus as to which of the neuronal membranes, which molecular component of any particular membrane or what specific function of the membrane is critical for general anaesthesia. 2. However, when considering anaesthetic effects on different synapses, with neurotransmitter receptors, ion channels etc., the unifying central concept is action at a membrane level. 3. This paper will review the general evidence for this unifying hypothesis, and consider the apparent exceptions and limitations. 4. The membrane hypothesis is usually stated in the form of the Meyer and Overton "rule" relating anaesthetic potency to hydrophobic solubility. 5. The relationship applies to inhaled anaesthetics with potencies over a 100,000-fold range and has been described as one of the most powerful correlations in biology. 6. Finding additional compounds that confirm this correlation is not likely to elucidate further the anaesthetic mode of action, and concentrating on the apparent exceptions to the hypothesis may prove to be a better approach. 7. The apparent exceptions to the membrane hypothesis include some of the physiological and convulsant gases as well as higher members of a homologous series of hydrophobic compounds above the so-called "cut-off" effect. 8. The apparent limitations include two of the most widely used clinical agents--enflurane and isoflurane. 9. This paper will include some new data characterizing the anaesthetic site of action using a diverse group of anaesthetics (including some of the exceptions already mentioned). 10. The evidence is against an earlier hypothesis that there is a bimodal distribution of the molecular sites.

Anesthetics↗
PubMed1991

Brain nuclei and neurotransmitters involved in the regulation of the high pressure neurological syndrome in the rat.

The role of glutamatergic (NMDA), cholinergic and purinergic neurotransmission in the pedunculopontine nucleus, red nucleus, ventrolateral thalamic nucleus, entopeduncular nucleus, and the substantia nigra in the development of the high pressure neurological syndrome (HPNS) was investigated in the rat. Focal injection of D-2-amino-7-phosphonoheptanoate (D-APH, 5 nmol per side) into the red nucleus or the pedunculopontine nucleus was protective against HPNS-induced convulsions. Carbachol (10 nmol), injected into the red nucleus, did not influence the severity of the symptoms of HPNS. Injection of carbachol into the pedunculopontine nucleus, significantly lowered the threshold pressure for convulsions and increased the threshold pressure for tremor. 2-Chloroadenosine (5 nmol), injected into the red nucleus, produced a potent antitremorgenic effect and a similar but less pronounced effect when injected into the pedunculopontine nucleus. 2-Chloroadenosine, injected into the substantia nigra (12.5 nmol) or the ventrolateral thalamic nucleus (25 nmol), facilitated the development of tremor and, in the entopeduncular nucleus (25 nmol), facilitated the occurrence of convulsions. These results show the complexity of neurotransmitter interactions in different regions of the brain, under high pressure. They also indicate that the biochemical and anatomical substrates, involved in the convulsions produced by HPNS, differ substantially from those in other experimental models of epilepsy.

2-Amino-5-phosphonovalerate↗
PubMed1991

The effects of the competitive NMDA receptor antagonist CPP on the high pressure neurological syndrome in a primate model.

Neurophysiological interactions between the competitive N-methyl-D-aspartate (NMDA) preferring receptor antagonist, CPP (3-((+-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonate) and the high pressure neurological syndrome (HPNS) have been investigated in the non-human primate Papio anubis. Eight animals were exposed on two occasions to environmental pressures of 81 atmospheres absolute (ATA) in a hyperbaric chamber, using helium and oxygen. One exposure followed pretreatment with CPP (either 5 or 10 mg/kg i.v. plus 5 mg/kg/hr infusion), the other a saline control. Pretreatment with CPP delayed moderate signs of face tremor and myoclonus and abolished severe signs of whole body tremor and seizure activity. By 81 ATA, scores representing severity of HPNS were significantly reduced by CPP to a mean score, reflecting a level of just mild to moderate limb tremoring (P less than 0.001). Changes in the EEG were observed in channels associated with the frontal, parietal and occipital regions of the left cortex. Amplitude and frequency spectra were calculated and changes with pressure in the 4 conventional wavebands were analysed. The most striking change was the complete prevention by CPP of the 100% increase in the amplitude of alpha waves at 81 ATA in the frontal region (P less than 0.001). It is concluded that NMDA transmission has a major role in the expression of HPNS.

Animals↗
PubMed1991

Occupational health and pollution from anaesthetics. A report of a seminar.

The Control of Substances Hazardous to Health Regulations require employers in the United Kingdom to evaluate and control the risks to health for all their employees from exposure to hazardous substances at work. This applies to those working in hospital operating theatres who may be exposed to anaesthetic gas pollution. These legal requirements coupled with continuing concern about the effective localised control of anaesthetic pollution, the potential chemical interactions in the upper atmosphere, as well as the analysis of the prospective study in the United Kingdom on the health of women doctors, have prompted a reassessment of the topic. Some of the original fears are without foundation but the overall conclusion is that we can still not regard anaesthetic pollution as a problem solved.

Air Pollutants, Occupational↗
PubMed1991

Effect of exposure to high pressure on subsequent spatial learning and memory in rats.

The effects of high helium pressure on the subsequent acquisition of spatial memory were studied in male rats. Thirty-two rats were exposed to 65 ATA helium-oxygen pressure for 4.2 days, decompressed (total time in chamber 5 days), and then tested in an eight-arm radial maze. Thirty-two control rats were exposed in the chamber to 1 ATA air. Each rat had 20 sessions in the maze (2 sessions/day for 10 days), and the number of correct (visiting an arm not previously visited to obtain the reward pellet) and incorrect choices (visiting a previously visited arm) were recorded. Statistical analysis showed that the rats exposed to 65 ATA performed significantly better than 1-ATA controls during the first 8 of 20 sessions. This effect was most pronounced in sessions 5-8. Results for sessions 9-20 showed that the pressure-treated rats still made more correct choices but to an extent that did not always reach statistical significance. Possible explanations include the pressure-treated rats performing better because of hunger after a lower food consumption at pressure. Alternatively, pressure itself may enhance proposed mechanisms of spatial memory such as long-term potentiation.

Animals↗
PubMed1991

What solvent best represents the site of action of inhaled anesthetics in humans, rats, and dogs?

The correlation between the potency of inhaled anesthetics and their solubility in a hydrophobic phase provides an opportunity to define better the characteristics of the anesthetic site of action. The correlation implies that inhaled anesthetics act in a hydrophobic site and that the solvent used has properties representative of the true site of anesthetic action. We sought to characterize this site more accurately by testing for the solvent that provided the best correlation for a diverse group of anesthetics. We determined the solubility of halothane, enflurane, cyclopropane, fluroxene, isoflurane, sevoflurane, and desflurane in benzene, olive oil, Intralipid, n-octanol, and lecithin. We used established MAC values for rats, dogs, and humans for all but sevoflurane and desflurane, for which we determined MAC in rats to be 2.80% +/- 0.24% (mean +/- standard deviation) and 7.71% +/- 0.65%, respectively. Lecithin gave the lowest coefficient of variation for the product of potency (MAC) x solubility, but the difference was statistically significant only for a comparison of the products for lecithin and olive oil. The values for lecithin were within the range of values produced by biological variation. More important, the correlation of log MAC and log solubility had an average slope of unity (-1.04 +/- 0.07) for lecithin, but a slope differing from unity for benzene (-0.82 +/- 0.05) and olive oil (-0.87 +/- 0.05). We conclude that lecithin is probably more representative of the site of action of these anesthetics than the other solvents.

Anesthesia, Inhalation↗
PubMed1991

A chamber system for maintaining a hyperbaric environment for long-term animal studies.

An experimental hyperbaric chamber system is described whereby animals, including nonhuman primates, can be cared for under altered environmental conditions for periods in excess of 1 wk. The chamber itself is capable of a working pressure of 200 atm abs, used with various mixtures of gases which can be varied independently. The novel approach of vertical mounting enables cages to be lowered into position, and food and water can be supplied from above while excreta can be removed from below, irrespective of the internal pressure. The chamber has an integrated life support system such that temperature, both of the chamber and of the mass of gas inside, humidity, oxygen, carbon dioxide, and noise levels can be accurately and finely controlled, all within a pathogen-free environment.

Animals↗
PubMed1990

Effect of NMDA and 2-amino-7-phosphonoheptanoate focal injection into the ventrolateral thalamic nucleus on the high pressure neurological syndrome in the rat.

We report the effect of focal injections of N-methyl-D-aspartate (NMDA, 5 nmol) and 2-amino-7-phosphonoheptanoate (APH, 5 and 10 nmol) into the ventrolateral thalamic nucleus on behavioural symptoms of the high pressure neurological syndrome in rats. The injection of NMDA significantly lowers the threshold pressure for tremor and increases its intensity. The injection of APH significantly increases the threshold pressure for tremor and decreases its intensity. APH, 10 nmol, significantly increases the threshold pressure for myoclonus and convulsions. These protective effects are, however, less pronounced than those produced by either systemic injection of APH or its focal infusion into the basal ganglia output system.

2-Amino-5-phosphonovalerate↗
PubMed1990

The effects of MK801 on the high pressure neurological syndrome in the baboon (Papio anubis).

The in vivo neurophysiological interactions of the non-competitive NMDA receptor antagonist MK801 with the High Pressure Neurological Syndrome have been investigated in the primate Papio anubis. A hyperbaric chamber was used to achieve environmental pressures of 61 ATA (atmospheres absolute) over a period of 5 hr. Eight animals underwent 2 compressions each, one following pretreatment with 0.03 mg/kg (i.v.) MK801, the other a control. Half of the animals received MK801 on their first exposure. Mild signs of the high pressure neurological syndrome, e.g. paw and limb tremor were first observed between 10 and 20 ATA and more severe signs, e.g. whole body tremor, myoclonus and vomiting, appeared after 50 ATA. The onset pressures for the various signs were increased by 10-17 ATA when the animals received MK801 (P = 0.06) and the severity of the signs, over the whole range of pressures at which they appeared, was significantly reduced (P less than 0.001). Additional experiments showed that MK801 afforded considerable protection, at pressures up to 81 ATA, but doses larger than those used for the main experiment produced signs of tranquilisation and sedation. Changes in the EEG were observed in channels associated with the frontal, parietal and occipital regions. Amplitude and frequency spectra were calculated and trends with pressure in the 4 conventional wavebands were analysed. The most striking change was a decrease in amplitude of delta waves (P less than 0.001), which was ameliorated by MK801 (P less than 0.001).

Animals↗
PubMed1989

Studies on the role of the NMDA receptor in the substantia nigra pars reticulata and entopeduncular nucleus in the development of the high pressure neurological syndrome in rats.

The effect of the focal injection of N-methyl-D-aspartate (NMDA) and 2-amino-7-phosphonoheptanoate (APH) into the substantia nigra pars reticulata (SNR) and entopeduncular nucleus (EP) on behavioural signs of the high pressure neurological syndrome (HPNS) in rats was studied. Doses of 1, 5 and 10 nmoles of NMDA or APH were injected into the SNR or EP, 10-30 min prior to the exposure of animals to a high pressure. Injection of NMDA into either SNR or EP results in a lowering of the threshold pressure for tremor by about 30%. Injection of NMDA into the SNR has no significant effect on clonic seizures whereas its injection into the EP results in a decrease of threshold pressure for clonic seizures. NMDA also facilitates the occurrence of forelimb clonus when injected into the EP. Injection of the NMDA antagonist, APH, into the SNR or EP significantly increases the threshold pressure of tremor (32.8 and 48.2% respectively). Seizure threshold is also increased by the injection of APH into either area, but nigral injections (especially the higher doses) are more protective against seizures than the EP injections. Comparing the two sites blockade of NMDA receptors within the EP is more protective against tremor, whereas in the SNR NMDA blockade is more protective against seizures.

2-Amino-5-phosphonovalerate↗
PubMed1989

The effects of kynurenic acid, quinolinic acid and other metabolites of tryptophan on the development of the high pressure neurological syndrome in the rat.

The effects of some biologically active metabolites of tryptophan on the high pressure neurological syndrome (HPNS) were studied. Kynurenic acid, quinolinic acid, 5-hydroxytryptophan, kynurenine and 3-hydroxyanthranilic acid, at doses within the physiological range, were administered exogenously to rats prior to exposure to increased pressure and any effects on the tremor, myoclonus and convulsion end points of the high pressure neurological syndrome were observed. Quinolinic acid (25 and 50 mg/kg) and kynurenine (50 mg/kg) reduced the onset pressure for tremor, but not myoclonus or convulsions. Kynurenic acid (100 mg/kg) increased tremor onset pressure; 5-hydroxytryptophan (20 mg/kg) slightly increased onset pressure for tremor but decreased that for myoclonus. 3-Hydroxyanthranilic acid (20 mg/kg) had no significant effect on any of the motor signs of the syndrome. These data provide further support for the idea that the motor events seen in the high pressure neurological syndrome are not produced by a single mechanism. Differences between the responses to related metabolites suggest that the precise balance between compounds such as kynurenic acid and quinolinic acid may be important in the appearance of the high pressure neurological syndrome.

Animals↗
PubMed1989

Systemically administered glycine protects against strychnine convulsions, but not the behavioural effects of high pressure, in mice.

1. The effects of intraperitoneal administration of glycine were studied on the behavioural effects of raised ambient pressure in mice, compared with the effects of such administration on the actions of chemical convulsants. 2. Glycine did not alter the onset pressures for the occurrence of tremor, myoclonic jerks or clonic convulsions, when the ambient pressure was raised using helium. 3. Glycine showed a protective action against the convulsant effects of strychnine. 4. No protective action of glycine was found against the convulsant actions of pentylenetetrazol or bicuculline. 5. It is suggested that the results provide evidence that the high pressure neurological syndrome and strychnine convulsions have different neurophysiological origins.

Animals↗
PubMed1989

A method of remote physiological monitoring of a fully mobile primate in a single animal cage.

A system was designed to allow the physiological monitoring of a fully mobile, unstressed baboon (Papio anubis) in a single animal cage for the purpose of measuring the changes occurring in a hyperbaric environment. It was required to operate for at least three months, both inside a pressure chamber and outside, and to measure the following parameters: electroencephalogram (EEG, three channels), electrooculogram (EOG), electromyelogram (EMG, two channels), electrocardiogram (ECG), arterial blood pressure, respiration and body temperature. Also in the system were catheters through which blood samples could be taken and intravenous drugs given. The overall system consisted of a harness and jacket, an umbilical and back pack, a combined electrical and fluid transmission swivel and a monitoring implant and catheters.

Animal Welfare↗
PubMed1989

Sodium valproate interactions with the HPNS: EEG and behavioral observations.

A new baboon model was used to investigate the therapuetic effect of sodium valproate on the high pressure neurologic syndrome (HPNS). A hyperbaric chamber was used to achieve environmental pressures of 61 ATA, over a 5-h period. Eight animals underwent two compressions, a control and a valproate-treated compression (half the animals had valproate on the first compression). Mild signs of HPNS (e.g., paw and limb tremor) were first observed at approximately 20 ATA. More severe signs (e.g., whole body tremor, myoclonus, and vomiting) were observed above 40 ATA. Sodium valproate was administered during the compression phase and for 2 wk previously. It was effective at the higher pressures above 41 ATA in reducing the severity of the signs of HPNS. The major effect of pressure on the EEG was to increase alpha and theta wave amplitude in a linear manner. Alpha wave amplitude was reduced by sodium valproate.

Animals↗
PubMed1989

Cochlear degeneration in minipigs after repeated hyperbaric exposures.

Auditory function and cochlear pathology were investigated in 4 minipigs subjected to compression to 4 ATA, held for 1 h, and decompressed using a standard schedule (Blackpool Tables) on 21 occasions. Three minipigs were used as controls. Brainstem auditory evoked response testing was carried out after the last hyperbaric exposure and showed no response bilaterally in 3 and unilaterally in 1 of the test animals. Light microscopy demonstrated a loss of hair cells throughout the cochlea in all the compressed animals; in one the tectorial membrane was detached and adherent to Reissner's membrane. Vestibular changes were confined to the saccule. Hemorrhage was not a prominent feature. On scanning electron microscopy the pathologic changes included missing hair cells and fused and giant stereocilia. Possible causes of the pathology include barotrauma or direct effects of repeated compression and decompression on the inner ear, or both. The compression-decompression profile used was one that is thought to be safe for compressed air workers who are repeatedly exposed to hyperbaric conditions.

Animals↗
PubMed1988

Anticonvulsant profile of the dihydropyridine calcium channel antagonists, nitrendipine and nimodipine.

The effects of the dihydropyridine calcium channel antagonists, nitrendipine and nimodipine, on convulsions produced by different mechanisms have been studied in rats. Nitrendipine and nimodipine significantly raised the thresholds to pentylenetetrazol for up to six hours after their injection. The calcium channel agonist, BAY K 8644, lowered the convulsion threshold to pentylenetetrazol and antagonised the effects of nitrendipine. In contrast, the severity of seizures produced by N-methyl-dl-aspartate (NMA) was increased by nitrendipine. BAY K 8644 also slightly increased the effects of NMA. Nimodipine and nitrendipine caused small, but significant, increases in the threshold pressures for the convulsions caused by raising the atmospheric pressure with helium gas. The compounds had no effect on strychnine convulsions. The conclusion is that the calcium channel antagonists are anticonvulsant against only certain types of convulsions, such as pentylenetetrazol and high pressure (and ethanol withdrawal, reported previously). Others may be increased, such as NMA seizures, or unaffected, such as strychnine-induced convulsions.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗