Effect of some benzodiazepines on peripheral neuromuscular function in the rat in-vitro hemidiaphragm preparation

Abstract

The effect of equimolar cumulative concentrations of 11 different benzodiazepines on the indirectly evoked twitch contraction was investigated in the rat in-vitro phrenic nerve-hemidiaphragm preparation. Depending on the pattern of the concentration-response curves two groups of benzodiazepines can be distinguished: (i) a first group with a biphasic action, e.g. potentiation of twitch tension in low concentrations and depression of twitch tension in high concentrations, and (ii) a second group with primary depression of twitch tension with increasing concentrations. All of the tested compounds ultimately caused a 100% depression of twitch tension at concentrations ranging from 0.175 to 0.35 mmol litre-1. Although this peripheral effect of benzodiazepines on neuromuscular function is not the main site of action of these compounds, there are enough arguments to state that it is not a simple toxic effect. There is some evidence from this study that the peripheral component of the benzodiazepine effect on muscle relaxation may involve a multi- rather than one single receptor system.

Peripheral benzodiazepine binding sites on striated muscles of the rat: Properties and effect of denervation

“…The IC50 of diazepam, flunitrazepam, and temazepam are between 100 and 500 nmol/1 (Table 1). However, the EDs0 of the same compounds for decreasing the twitch tension of the rat diaphragm are between 100,000 and 300,000 nmol/1 as previously reported by Driessen et al (1984). Moreover, in this preparation, desmethyldiazepam is about as similarly acitve as the three compounds just mentioned but exhibits a much lower affinity for the peripheral sites.…”

“…On the other hand, other evidence suggests that at least some benzodiazepine derivatives may also have direct effects on striated muscles or motoric nerves. For example, benzodiazepines reduce the indirect electrical stimulation response of the rat phrenic nerve diaphragm preparation (Hamilton and Stone, 1982;Driessen et al, 1984), reduce the conduction velocity ofmotoric nerves (Hopfand Billmann, 1973) and have various effects on frog muscle preparations (Degroofet aL, 1980;Hamilton and Stone, 1982;RaufKhan and Edman, 1983). The CNS specific benzodiazepine receptor is not present on peripheral organs (Miiller, 1981;Squires, 1984) so the mechanism of action of these peripheral effects is not yet known.…”

In Vitro Interaction of Diazepam and Oxazepam With Pancuronium and Suxamethonium

“…One may speculate that the effect is postsynaptic and involves the acetylcholine receptor, because there was no significant difference between the slopes of control concentration-response curves and curves obtained after addition of diazepam or oxazepam. A direct effect on the muscle, however, may also contribute to the effect (deGroof, Bianchi and Narayan, 1980). The incomplete recovery after washing out the preparation in part A of our study affords more evidence for a direct muscle effect.…”

Interaction of Midazolam With Two Non-Depolarizing Neuromuscular Blocking Drugs in the Rat in Vivo Sciatic Nerve-Tibialis Anterior Muscle Preparation

“…The solvent of commercial diazepam (Valium) and some other injectable benzodiazepines may well obscure possible potentiating effects of the active substances. Studies in the rat in vitro phrenic nerve-hemidiaphragm preparation showed differences in the response of the twitch contraction to several benzodiazepines (Driessen et al, 1984).…”