Drug actions at mammalian motor nerve endings: the suppression of neostigmine-induced fasciculations by vecuronium and isoflurane.

The occurrence of fasciculations following administration of agents is a well-known pharmacologic phenomenon. Using the cat soleus nerve-muscle preparation, intravenous neostigmine doses between 20-200 micrograms/kg evoked fasciculations in a dose-related manner. The data demonstrate that the fasciculations were the result of the direct effect of neostigmine acting at the motor nerve endings. Vecuronium in a dose-related manner (3 and 5 micrograms/kg iv) suppressed this prejunctional activity of neostigmine. The prejunctional effect of vecuronium explains its effectiveness in preventing succinylcholine-induced fasciculations. In the presence of isoflurane (end-tidal concentration 0.20-0.25%), the suppressant effect of vecuronium on motor nerve endings was enhanced. The prejunctional action of isoflurane may be a major contribution to the additive effects of non-depolarizing muscle relaxants and potent inhalation agents.

Prejunctional effects of vecuronium in the cat.

This study explored the prejunctional actions of vecuronium using the in vivo cat soleus nerve-muscle preparation. Vecuronium doses of 1 to 5 micrograms/kg iv suppressed the repetitive firing of the motor nerve endings, and the obligatory potentiation of the twitch response following high-frequency conditioning at 400 Hz for 10 s without attenuating neuromuscular transmission at 0.4 Hz. It was also found that extremely low doses of vecuronium had excitatory effects at the cat soleus motor nerve endings: doses of 0.5 and 1 microgram/kg iv evoked a modest postdrug repetitive firing of the nerve endings and a concomitant potentiation of the muscle responses. These dose-related agonist and antagonist activities suggest that at the motor nerve endings, vecuronium is a weak partial agonist. The major action of vecuronium at the motor nerve endings, however, was suppressive, and this antagonist action contributed to the neuromuscular blocking action of this muscle relaxant.

Methylprednisolone treatment of an organophosphorus-induced delayed neuropathy.

Diisopropylfluorophosphate (DFP) injected into the femoral artery of cats causes a localized organophosphorus-induced delayed neuropathy (OPIDN). Gait disturbances develop in the treated leg 14 days after DFP exposure and reaches a maximum at 21 to 28 days after DFP. In vivo high-frequency conditioning of soleus motor nerve endings evokes stimulus-bound repetitive neural discharges (SBR) and an obligatory potentiation of the muscle contractile response (PTP). In this OPIDN model, SBR and PTP are maximally suppressed at 21 to 28 days after DFP. A high-dose regimen of methylprednisolone started 30 to 40 min after DFP exposure and lasting for 20 days prevented the development of OPIDN. In the methylprednisolone-DFP treated cats, SBR and PTP functions were not suppressed and not different from those in untreated normal cats.

Cyclic AMP in normal and malignant hyperpyrexia susceptible individuals following exercise.

Plasma cAMP concentrations were compared in normal and malignant hyperpyrexia susceptible individuals. Samples were taken before, at the peak, and at 60 and 120 min after a standardized physical stress test. It was found that, at the peak of the test, cAMP concentrations were significantly higher in malignant hyperpyrexia susceptible individuals. In addition, the return to control values was significantly prolonged in this group. The results support the hypothesis of abnormal cAMP metabolism in malignant hyperpyrexia susceptible individuals.

Prejunctional and postjunctional effects of tubocurarine and pancuronium in man.

The effects of small doses of tubocurarine and pancuronium on peak tetanic tension and tetanic maintenance were compared. Forty patients undergoing elective orthopaedic procedures under general anaesthesia were studied. Changes in neuromuscular transmission were measured by recording the isometric contraction of the adductor pollicis muscle evoked by supramaximal stimulation of the ulnar nerve at the wrist. Small doses of pancuronium affected predominantly the peak tetanic tension, while small doses of tubocurarine affected mainly tetanic maintenance. Thus, different degrees of depression of peak tetanic tension and tetanic maintenance were observed with tubocurarine and pancuronium. This clinical study supports Bowman's hypothesis, based upon laboratory findings in the cat, that prejunctional and postjunctional effects of neuromuscular blocking agents depend on their affinity for cholinoceptors at different sites.

Correlation between anticurare activity of tetanic stimulation and neostigmine in anesthetized man.

Frequency and dose-dependent changes in neuromuscular transmission were examined in 70 patients undergoing elective surgical procedures requiring the use of muscle relaxants. Anesthesia was induced with sodium thiopental and maintained with N2O-O2 and fractional dose of meperidine or fentanyl. Neuromuscular block was produced and maintained at 80% level with incremental intravenous doses of d-tubocurarine. Neuromuscular function was measured by recording the force of thumb adduction evoked by supramaximal stimulation of the ulnar nerve at the wrist. Single stimuli were applied every 2.5 seconds as square pulses of 0.1-msec duration. In 30 patients tetanic trains of 10-second duration ranging from 10 to 400 Hz were used. In 40 patients neostigmine doses ranging from 0.5 to 5.0 mg were used. Criteria for responses to 10-second tetanic trains during 80% neuromuscular block were determined and compared with responses after neostigmine. At a frequency of 50 Hz a complete tetanic fade was followed by partial posttetanic relief of block. At a frequency of 200 Hz tetanic fade was followed by complete but transient posttetanic decurarization. The original control twitch tension was not exceeded in posttetanic or postdrug responses. It is concluded that the transient after effects of tetanic stimulation are closely related to the anticurare effects of neostigmine.

Tetanic fade and post-tetanic tension in the absence of neuromuscular blocking agents in anesthetized man.

Frequency and time dependent changes in neuromuscular transmission were examined in 30 patients undergoing elective minor surgical procedures not requiring the use of muscle relaxants. Anesthesia was induced with sodium thiopenthal and maintained with N2O-O2 and fractional does of meperidine or fentanyl. Neuromuscular function was measured by recording the force of thumb adduction evoked by supramaximal stimulation of the ulnar nerve at the wrist. Single stimuli were applied every 2.5 seconds as square pulses of 0.1-millisecond duration. Tetanic trains of 10-second duration ranging from 10 Hz to 400 Hz were used. From analysis of present data, criteria for normal responses to 10-second tetanic trains of varying frequencies were established. At a frequency of 30 Hz, the tetanic response is fully maintained and followed by post-tetanic potentiation; at a frequency of 50 Hz, both tetanic and post-tetanic responses are maintained; at a frequency of 100 Hz, there is tetanic fade, followed by a post-tetanic depression of the single indirect twitch responses. It is concluded that frequency and duration of indirect stimulation are the most important factors in using tetanic maintenance and post-tetanic events in assessment of recovery from neuromuscular block.