Cellular Mechanisms of Atracurium‐Induced Tetanic Fade in the Isolated Rat Muscle

Abstract

Although atracurium is a widely used neuromuscular blocker, we still lack knowledge regarding some of its cellular mechanisms of action. Thus, similar to other clinically used blockers atracurium induces, both in vivo and in vitro, fade of the tetanic contraction. However, the cellular mechanisms underlying this tetanic fade have never been systematically studied. In the present work these mechanisms were investigated in vitro. A sciatic nerve extensor digitorum longus muscle preparation of the rat was used. A combination of myographical and electrophysiological techniques was employed. Indirect twitches were evoked at 0.1 Hz and tetanic contractions at 50 Hz. Trains of end-plate potentials were evoked at a frequency of 50 Hz. The electrophysiological variables used in the analysis of the trains of end-plate potentials were: peak amplitude of the first end-plate potential in the train, peak amplitude of plateau end-plate potentials in the train, tetanic run-down of the end-plate potentials' train, quantal content of first and plateau end-plate potentials in the train, quantal size. In the myographical study atracurium, at a concentration of 2.4 mM, induced a complete fade of the tetanic contraction while only slightly affected the twitch. In the electrophysiological study atracurium, at the same 2.4 mM concentration, significantly decreased the amplitude of both first end-plate potentials in the train (control: 14.4 mV; atracurium: 3.2 mV) and plateau end-plate potentials (control: 10.8 mV; atracurium: 2.4 mV) and reinforced the tetanic run-down of the train of end-plate potentials, evaluated as the percent loss in amplitude of plateau end-plate potentials compared to first end-plate potentials in the trains (control: 25.2%; atracurium: 33.2%). Atracurium also significantly decreased the quantal content of first end-plate potentials in the train (control: 231; atracurium: 68), the quantal content of plateau end-plate potentials (control: 159; atracurium: 42) and the quantal size (control: 0.119 mV; atracurium: 0.075 mV). In relative terms the decrease in quantal content was about twice as large as the decrease in quantal size. This indicates that the fade of the tetanic contraction induced by atracurium (2.4 mM) is due to both pre-and postsynaptic blocking effects, the presynaptic one being stronger.

Cisatracurium: myographical and electrophysiological studies in the isolated rat muscle

“…The muscles were soaked in this solution for 1 h and subsequently returned to the isotonic solution, where they were kept for at least another hour before starting the experiment. Although this procedure was originally established using frog muscles [18,19], we find that the glycerol shock works equally well in the rat's extensor digitorum longus muscle [10–15]. This is in accordance with the experience of a number of other laboratories, using the same rat's extensor digitorum longus muscle [20,21] as we did, or rat's diaphragm [22] or sternomastoid [23] muscles.…”

“…Compared with atracurium, previously studied in this laboratory [10,11], cisatracurium is relatively more potent pre‐synaptically, as the comparison of their differential effects on the epps quantal contents (an index of the pre‐synaptic effect) and on the quantal size (an index of the post‐synaptic effect) shows.…”

“…Furthermore, previous microelectrode electrophysiological studies have shown atracurium to display differential pre‐ and post‐synaptic effects at the neuromuscular junction [9–11] a feature that also has not been studied in the case of cisatracurium. Such a study is important, seeing it has been shown previously in this laboratory that different blockers of the neuromuscular junction: atracurium [10–11], hexamethonium [12], pancuronium [13] and vecuronium [14] vary in the relative potency of pre‐ and post‐synaptic effects at the neuromuscular junction, and this probably explains why they vary in their ratios of differential effects on twitches and tetani, studied myographically in the whole muscle [7].…”

Differential effects of neuromuscular blockers on twitches and tetani in the isolated rat muscle: a multiple comparison study using simultaneous confidence intervals

“…Regarding other compounds previously studied electrophysiologically, atracurium [16], that displays an electrophysiological profile of cellular effects similar to that of cisatracurium [15], also discriminates well between twitches and tetani, as its ratio of IC 50 (9.0) is the second largest within all of the compounds. Furthermore, pancuronium, which has an electrophysiological profile [17] similar to that of vecuronium [14] in that it blocks the neuromuscular transmission via a conjunction of pre-and post-synaptic mechanisms [17], displays a ratio of IC 50 value (3.9) which ranks relatively close to that of vecuronium (2.6).…”