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

Abstract

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 ED30 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.

Possible NMDA antagonist properties of drugs that affect high pressure neurological syndrome

“…The initial observation that the effect of strychnine was strictly additive with pressure led to the theory that increased hydrostatic pressure might have some effect on inhibitory glycinergic transmission (Bowser-Riley et al, 1988). However, the present experiments suggest that some of these drugs might instead act at the excitatory SI-glycine site associated with the NMDA receptor.…”

“…Both these hypotheses predict that NMDA antagonists would be effective against HPNS, and indeed they are (Meldrum et al, 1983;Milan et al, 1990). However, the facts that bicuculline (Bowser-Riley et al, 1989a) and picrotoxin (Bowser-Riley et al, 1988) do not act additively with pressure, and that pressure selectively inhibits currents evoked by glycine (as opposed to GABA or kainate (Daniels et al, 1993)), both favour the second hypothesis; that pressure reduces glycinergic inhibition and hence indirectly regulates the NMDA gated channel.…”

“…Previous studies have shown that strychnine acts strictly additively with pressure in producing convulsions in mice (Bowser-Riley et al, 1988) and that a series of drugs with molecular structures related to strychnine affect the threshold pressure for producing convulsions (Bowser-Riley et al, 1989b). These observations led to the theory that increased hydrostatic pressure depresses inhibitory glycinergic synaptic transmission and that the drugs tested exert their effects via an action at the strychninesensitive glycine receptor.…”

An evaluation of the structure‐activity relationships of a series of analogues of mephenesin and strychnine on the response to pressure in mice

“…These effects not only represent a serious threat to the safety of divers presently operating at pressures up to 45 bar but also provide a barrier to deeper human diving. propan-1,2-diol), a centrally acting muscle relaxant, has been shown to be a most potent anti-HPNS drug in mice: it raised the onset pressure for tremors by a factor of 2.5 and that for convulsions by a factor of 1.5 (Bowser-Riley, 1984;Bowser-Riley et al, 1988). Experiments with simple structural isomers of mephenesin also suggested a possible mechanism for the convulsive action of pressure.…”

“…properties against strychnine, picrotoxin and metrazol (Bowser-Riley, 1984), with the aromatic propandiols being effective only against strychnine and ineffective against metrazol or picrotoxin and the reverse being the case for the aliphatic compounds. In addition, it was shown that the ortho, meta and para isomers of mephensin and the ortho and para isomers of chlorphenesin (3[2-chlorphenoxy]propan-1,2-diol) exhibited an identical order of potency against both the convulsive action of pressure and that of strychnine (Bowser-Riley et al, 1988). The apparent link between the action of pressure and strychnine and their mutual antagonism by mephenesin was strengthened by the finding that strychnine and pressure act in a strictly additive manner in the production of convulsions and that this relationship was maintained in the presence of mephenesin (Bowser-Riley et al, 1988).…”