High Pressure Neurological Syndrome Research Articles

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 (100mg/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.

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.

Investigations into the origin of the high pressure neurological syndrome: the interaction between pressure, strychnine and 1,2-propandiols in the mouse.

1. The effects of a variety of structural isomers of the centrally acting muscle relaxant mephenesin on the high pressure neurological syndrome have been investigated. Threshold pressures for the onset of the behavioural signs, tremors and convulsions, were established. The effects of these compounds on the response to pressure were also compared with their ability to antagonize the convulsive action of strychnine. 2. The dose-response relationships for strychnine and picrotoxin were investigated at fixed pressures. Additionally, the dose-response relationship of strychnine, in the presence of mephenesin, at pressure was investigated. 3. All the isomers of mephenesin protected against the effects of both pressure and strychnine. The relative potency was found to be identical with respect to both. Mephenesin was clearly the most effective; it raised the threshold pressure for tremors by 2.5 times, that for convulsions elicited by pressure by 1.5 and the ED50 for strychnine convulsions by 1.6 times. Strychnine was found to be strictly additive with pressure whereas picrotoxin exhibited gross deviations from additivity. Mephenesin ameliorated the combined effects of pressure and strychnine equally. 4. The marked dependence on structure of the anticonvulsant activity of the mephenesin isomers can be interpreted as evidence that pressure acts not by some general perturbation of the membranes of excitable cells but rather via some specific interaction. The finding that strychnine and pressure are strictly additive supports the idea of specificity and also indicates that they may share a common mechanism in the production of convulsions. By analogy with the established mechanism of action of strychnine, it is suggested that the hyperexcitability associated with pressure might arise from an action on glycine-mediated inhibitory processes.

The effect of two novel dipeptide antagonists of excitatory amino acid neurotransmission on the high pressure neurological syndrome in the rat

Intracerebroventricular injection in the rat of β- D-aspartyl aminomethylphosphonate (Asp-Amp) 1 μmol, or Y-D-glutamylaminomethylsulphonate (GAMS) 1 μmol, increases the onset pressure for the initial tremor phase of the high pressure neurological syndrome (HPNS) by 50%. Asp-Amp also significantly increases the onset pressures for myoclonus and for tonic-clonic seizures. GAMS did not significantly change the onset pressures for myoclonus or tonic clonic seizures, but it caused the appearance of brief clonic seizures prior to the onset of the HPNS.

Effect of habituation to subanesthetic N2 or N2O levels on pressure and anesthesia tolerance.

Exposure of CD-1 mice to subanesthetic partial pressures of N2O (0.5 atm) or N2 (10-20 atm) for periods up to 14 days results in up to 40% decreases in the mean threshold pressure eliciting type I high-pressure neurological syndrome (HPNS) seizures, and in increases up to 38% in the N2 partial pressure producing anesthesia. For all combinations of preexposure time, N2 partial pressure, as well as identity of the conditioning gas the relations between the convulsion threshold pressure (Pc) and the anesthesia N2 pressure (Pa) appear to be uniquely correlated by the equation Pa = 54.5 - 0.2(Pc - 60)1.2. The potency of N2O with respect to these habituation phenomena is between 28 and 33 times higher than that of N2, depending on the aspects compared. Evidence is presented indicating that after 14 days of habituation the animals have attained between 75 and 85% compensation for the anesthetic as well as the anticonvulsant effects of the conditioning gas. The bearing of the results on the problem of the nature of the antagonism between inert gas narcotic agents and high pressure and on the hypothesis that habituation tends toward restoration of isofluidity (or some analogous normalization process) are discussed.

Prolonged exposure of mice to He-O2 at high pressure: effects on seizure and anesthesia liability.

Multiday exposures of CD-1 mice to He-O2 atmospheres at pressures from 30 to 100 atm result in marked increases of threshold pressures for type I high-pressure neurological syndrome seizures. The effect develops with a half time (t1/2) of 12 h and is reversible (t1/2 = 7 h). The maximum enhancement of Pc is attained at a conditioning pressure of 80 ATA. Pressure conditioning also results in suppression of the compression rate effect on Pc. Furthermore, reserpine blocks the increase in Pc during prolonged pressure exposure. The entire effect thus appears to be an extension in time of the monoaminergic compression rate effect on Pc. Pressure conditioning does not modify anesthesia tolerance, unlike N2 habituation which affects anesthesia threshold pressure as well as Pc. The results are compared with the effects of habituation to inert-gas narcotics and the implications of the data for an understanding of inert-gas high-pressure antagonism in intact animals are discussed.

Regional Amino Acid Concentration in the Brains of Rats Exposed to High Pressures

Regional amino acid concentrations were measured in rat brain fixed by microwave irradiation at three levels of elevated atmospheric pressure corresponding to different phases of the high-pressure neurological syndrome [20 atmospheres absolute (ATA), no clinical signs; 60 ATA, tremor; 85 ATA, severe tremor and myoclonic jerks]. No changes in amino acid content occurred at 20 or 60 ATA. At 85 ATA glutamine content increased in hippocampus, striatum, cerebellum, and substantia nigra, and gamma-aminobutyric acid content increased in hippocampus. It is suggested that enhanced glutamate release in various subcortical structures contributes to the myoclonic activity observed at 85 ATA.

Gamma-aminobutyric acid and the high pressure neurological syndrome

Sodium valproate, nipecotic acid, diaminobutyric acid (DABA) and beta-adanine are drugs which enhance transmission mediated by γ-aminobutyric acid (GABA) by a variety of mechanisms. They were used to study the role of GABA in the high pressure neurological syndrome (HPNS) in the rat. Sodium valproate, nipecotic acid and DABA reduced the increase in slow waves seen in the electroencephalogram (EEG) of control rats at pressures above 10–20 ATA; however, only sodium valproate had a beneficial effect on the behavioural signs of the high pressure neurological syndrome (tremor, myoclonus and convulsions). Sodium valproate is also thought to decrease neurotransmission produced by excitatory amino acids; thus, these results suggest that GABA is not one of the major neurotransmitters involved in all aspects of the high pressure neurological syndrome and that changes in excitatory neurotransmission may affect the behavioural signs.

Effect of excitatory amino acid antagonists on the high pressure neurological syndrome in rats

The onset pressures for the tremor, myoclonus and convulsions seen in the high pressure neurological syndrome (HPNS) are increased following cis-2,3-piperidine dicarboxylic acid 1 mmol/kg in the rat. Glutamic acid diethyl ester 1–3 mmol/kg has no effect on tremor or myoclonus, but increases the convulsion pressure when 3 mmol/kg is given immediately before compression. These and earlier data with 2-amino-7-phosphonoheptanoic acid suggest that excitation at the N-methyl-D-aspartate receptor is important in HPNS tremor, and that excitation at the quisqualate receptor contributes to HPNS convulsions.

The high pressure neurological syndrome and 2-amino-7-phosphonoheptanoic acid: Differences between fed and fasted rats

The elevated atmospheric pressure at which the main features of the high pressure neurological syndrome (HPNS), i.e. tremor, myoclonus and convulsions, successively appear, have been studied in fed and fasted rats with and without pretreatment with 2-amino-7-phosphonoheptanoic acid (180 mg/kg). The onset pressure for tremor is lower in fasted rats. 2-Amino-7-phosphonoheptanoic acid raises the onset pressure for all three phases of HPNS in fed rats, but only for tremor and convulsions in fasted rats. The results are interpreted in terms of changes in aspartergic and related excitatory neurotransmission.

Mechanistic studies on the high pressure neurological syndrome.

The high pressure neurological syndrome (h.p.n.s.) constitutes a major barrier to deep sea exploration by man. Although the signs and symptoms of h.p.n.s. are well documented in both man and experimental animals, the underlying mechanisms remain to be elucidated. Physiological and pharmacological evidence will be presented that confirms that the principal sites of action of pressure are within the central nervous system (c.n.s.). Results from physiological studies not only indicate that there are separate sites of action of pressure within the c.n.s., which mediate the different components of h.p.n.s., but also the response to pressure may be controlled by descending inhibitory pathways. Pharmacological studies support this view and suggest that h.p.n.s. involves a failure of central inhibition.

The biological effects of high pressures: underlying principles.

Physico-chemical principles set constraints on the response of biological systems to high-pressure gases and to pressure per se. They also indicate the mechanisms that may be involved. Classical thermodynamics, intermolecular forces and the theory of solutions and many other areas of physical chemistry have contributed to our understanding of the problems faced by divers breathing gases at high pressure, in particular the high pressure neurological syndrome, inert gas narcosis and decompression sickness. The value and the limitations of physico-chemical arguments when applied to the problems of underwater physiology are analysed.

Specific effects of drugs at pressure: animal investigations.

The interactions of anaesthetics and other drugs with high pressure suggest that protection against the high pressure neurological syndrome (h.p.n.s.) can no longer be considered in terms of generalized non-specific mechanisms. The evidence from our work shows that anaesthetics may either protect, have no effect, or potentiate h.p.n.s. Structural analogues of the steroid anaesthetic Althesin have a protective effect against high pressure tremors in spite of the fact that they have no anaesthetic effects. Low doses of flurazepam are effective against tremor but can be antagonized by Ro 15-1788, which implies in this case a role for the benzodiazepine receptor complex. Pressure interactions with other drugs have included the classic anticonvulsants--which, in general, were relatively ineffective--and various agents perturbing the balance of specific neurotransmitter systems. Representative examples from different studies include 6-hydroxydopamine, muscimol, and sodium valproate. Finally, the potent protection against h.p.n.s. by 2-amino-phosphonoheptanoic acid, an antagonist with preferential action against excitation produced by aspartate and N-methyl-D-aspartate, provides the first evidence that enhanced excitatory amino acid neurotransmission may have an important role in the h.p.n.s.

Hydrostatic pressure effects on the central nervous system: perspectives and outlook.

The high pressure neurological syndrome (h.p.n.s.) represents a complex of behavioural changes observed in all vertebrates when exposed to progressively increasing pressures. The general characteristics of the syndrome will be described and discussed in the light of alternative hypotheses about its aetiology and biophysical characteristics. Recent investigations in this area have dealt with the problem of the discretion of the several stages of the h.p.n.s. in their dependence on compression parameters; with the problem of individual variability in sensitivity to h.p.n.s. development, the genetic basis thereof, and its implications from the point of view of personnel selection; and with exploration of the characteristics and nature of the antagonism between high pressure and general anaesthetics in the production of h.p.n.s. symptoms. A final part of the discussion will deal with the current status of investigations into the problem of hazard assessment, and with the several possible approaches to controlling the h.p.n.s. associated hazards encountered in deep diving operations.

The interactions between pressure and anaesthetics.

Compression of animals causes excitation, which has recently posed a barrier to deeper diving. The broad question addressed here is how far the inert gas breathed modifies the excitatory effects of hydrostatic pressure. By using aquatic animals we first show that helium postpones the onset of pressure-induced paralysis by some 35 atm. Next we show that in mammals compressed with helium, five anaesthetic gases (nitrogen, argon, nitrous oxide, carbon tetrafluoride, sulphur hexafluoride) all elevated dose-dependently the median pressure of four distinct phases of the high pressure neurological syndrome (h.p.n.s.) (complete spasms, clonic convulsions, tonic convulsions and non-tonic death). All the gases were equally efficacious relative to their anaesthetic potency. However, the sensitivity of each phase of the h.p.n.s. to anaesthetic gases differed. Most notably, the median pressure for tonic convulsions was elevated about three times more by a given partial pressure of anaesthetic gas than were the median pressures for complete spasms or non-tonic death. These observations can be fitted remarkably well by the hypothesis that a given phase of the h.p.n.s. is activated when some hydrophobic region is compressed beyond a certain critical amount by the application of pressure. Absorption of an inert gas in this region will cause it to expand, tending to elevate the median pressure for that phase of the h.p.n.s. Our data and analysis allow the following conclusions relevant to diving practice. All gases protect against the h.p.n.s. but some phases of this complex syndrome are more effectively controlled than others. Although addition of a second inert gas to helium allows substantial increases in the pressure at which h.p.n.s. occurs, the onset of anaesthesia (or inert gas narcosis) will limit the ultimate gain. The composition of therapeutic gas mixtures becomes more narrowly defined as the pressure increases. The optimum mixture may be different for each phase of the h.p.n.s., and the order of presentation of the h.p.n.s. symptoms may be changed by the second inert gas. We may also predict that physiological sites may exist where helium acts like an anaesthetic. If such sites resulted in physiological dysfunction, addition of a second gas would exacerbate the situation.

Interactions of gamma-aminobutyric acid and noradrenaline in the high pressure neurological syndrome.

The effects on the high pressure neurological syndrome (HPNS) of reducing brain noradrenaline (NA) levels were studied in adult rats. The onset of tremors and convulsions, which occur as pressure is increased, were used as endpoints for assessing the onset and severity of the HPNS. Neonatal treatment with 6-hydroxydopamine (6-OHDA; 100 mg kg-1 i.p. alternate days from birth for 2 weeks) which depleted brain NA, produced no change in the HPNS as assessed by the appearance of tremors and convulsions. A second series of NA-depleted rats and equivalent controls were treated with a GABA agonist, muscimol, 0.1 microgram intracerebroventricularly. Subsequently the rats were exposed to pressure and the onset and severity of the HPNS was assessed by observation of tremors and convulsions. A combination of NA depletion and intracerebroventricular injection of muscimol significantly raised the onset pressures for tremors and convulsions, i.e. delayed the appearance of the HPNS. These results are consistent with the HPNS being associated with a disturbance in the balance of two or more neurotransmitter systems, rather than simply an increase or reduction in levels of a single transmitter.

Force and duration of muscle twitch contractions in humans at pressures up to 70 bar

The contraction peak force (CPF) and contraction time (CT) of the soleus Hoffmann (H) reflex and motor (M) response muscle twitch were measured in three subjects during the 686-m seawater Atlantis III simulated dive at Duke University. The mean CPF of both H and M twitches was observed to be 40-60% larger during compression than in predive control studies (P less than 0.001 for M response). This effect was sustained during the first 300 m of decompression, while postdive values were normal. Rate of contraction, as measured by changes in CT, was slowed significantly but only during compression (by 23% in the H reflex at 66.4 bar, P less than 0.001). These marked effects in CPF and CT cannot be explained by the small increases observed in the muscle action potential latency and duration, or other neuronal mechanisms. It is concluded that the twitch contraction of skeletal muscle is significantly slowed and augmented at pressure due to changes in excitation-contraction coupling or in the contractile process itself. These findings may be of importance in interpreting the etiology of many neuromuscular signs of the high-pressure neurological syndrome.

2-Amino-phosphonoheptanoic acid protects against the high pressure neurological syndrome

2-Amino-phosphonoheptanoic acid protects against the high pressure neurological syndrome

Non-anaesthetic steroids ameliorate the high pressure neurological syndrome in rats

The hypothesis that non-anaesthetic compounds, structurally related to specific anaesthetics, can protect against the high pressure neurological syndrome was tested. Infusion of two structural analogues of alphaxalone (3α-hydroxy-5α pregnane-11,20 dione) during pressurisation of rats with helium and oxygen gas mixtures (total pressure 80–100 ATA; inspired oxygen partial pressure 0.5 ATA) ameliorated the severe tremors associated with the high pressure neurological syndrome without any shift in tremor frequency (11–14 Hz). The steroid analogues which were selected (Δ16 and 3β-hydroxy-alphaxalone) have no known general anaesthetic effects and present an unexpected structural approach to the pharmacology of the syndrome. It may now be possible to investigate, treat or prevent the syndrome by the use of selective drugs without more generalised anaesthetic effects.

Effects of high pressure on the central nervous system.

Effects of high pressure on the central nervous system.