M.J. Halsey

Anticonvulsant profile of the dihydropyridine calcium channel antagonists, nitredipine 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.

Gamma-aminobutyric acid and the high pressure neurological syndrome

Sodium valproate, nipecotic acid, diaminobutyric acid (DABA) and beta-alanine are drugs which enhance transmission mediated by gamma-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.

Effects of the calcium channel activator Bay K 8644 on general anaesthetic potency in mice

1 The effects of the calcium channel activator, Bay K 8644, on the anaesthetic potencies of ethanol, argon and pentobarbitone were examined in mice. 2 Bay K 8644, at 1 mg kg−1 i.p., significantly antagonized the general anaesthetic potencies of ethanol and argon, but at 5 and 10 mg kg−1 this compound increased the general anaesthetic potency of these drugs. 3 At doses of 1, 5 and 10 mg kg−1 Bay K 8644 antagonized the anaesthetic effects of pentobarbitone. 4 Bay K 8644, at the highest dose used, did not alter the brain concentrations of pentobarbitone or the blood concentrations of ethanol. 5 The effects of the different doses of Bay K 8644 on the actions of ethanol and of argon are compatible with the known partial agonist properties of this compound on calcium channels in vitro. 6 The actions of Bay K 8644 on the anaesthetic effects of pentobarbitone suggests that specific interactions may be involved in the anaesthetic actions of this compound.

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.

SummaryThe 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.

PRESSURE REVERSAL OF THE EFFECT OF URETHANE ON THE EVOKED SOMATOSENSORY CORTICAL RESPONSE IN THE RAT

1 The cerebral response evoked by stimulation of the forepaw in the rat shows an increase in latency and decrease in the amplitude of its initial components as anaesthetic dose (urethane) is increased. 2 These changes are reversed if the ambient pressure is increased with helium and the electrocorticogram shows an increase in basic frequency. 3 The dose of urethane needed to prevent reflex response to tail stimulation is increased as pressure increases. 4 The implications of these behavioural and somatosensory responsiveness changes as pressure is increased 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 γ‐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.

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.

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 beta-D-aspartyl aminomethylphosphonate (Asp-Amp) 1 mumol, or Y-D-glutamylaminomethylsulphonate (GAMS) 1 mumol, 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.

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.

Pressure reversal of alphaxalone/alphadolone and methohexitone in tadpoles: evidence for different molecular sites for general anaesthesia

1 Tadpoles were used to study quantitative interactions between high pressure and two intravenous anaesthetics, alphaxalone/alphadolone and methohexitone. 2 The potencies of the two agents were decreased by high pressure but to different extents. The maximum effect was seen in the pressure range 70–130 atmospheres absolute (ATA). The increases in the normobaric anaesthetizing concentration (ED50) required at 100 ATA were alphaxalone/alphadolone:405 ± 5 (s.d.)%; methohexitone:658 ± 80 (s.d.)%. 3 For both alphaxalone/alphadalone and methohexitone, the curves obtained when the increase in ED50 was plotted against increasing pressure showed plateaux at pressures above 70 ATA. 4 These data support the concept of the two intravenous drugs causing general anaesthesia by the occupation of separate molecular ‘sites’ with different but finite capacities.