N. N. Durant

Potentiation of neuromuscular blockade by verapamil.

The effects of intravenous (iv) verapamil (0.01 to 1.0 mg/kg) on the constant neuromuscular block produced by an iv infusion of either pancuronium or succinylcholine were studied on the indirectly stimulated gastrocnemius and tibialis-anterior muscles of the rabbit anesthetized with halothane in oxygen. Verapamil alone (n = 6) had no significant effect. However, the drug did significantly potentiate the 50% twitch depression of the gastrocnemius muscle produced by a constant iv infusion of either pancuronium (n = 5) or succinylcholine (n = 5) to 36 ± 6% and 45 ± 1% of control, respectively. This effect of verapamil occurred with doses of 0.1 mg/kg for pancuronium and 0.01 mg/kg for succinylcholine; these doses of verapamil were the lowest which produced a significant effect. In contrast, verapamil had no significant effect on the progression of the neuromuscular blockade of either the gastrocnemius or tibialis-anterior muscles produced by alpha-bungarotoxin (n = 5). Verapamil also significantly prolonged the P-R interval of the ECG from a control value of 71 ± 2 ms to 78 ± 3 ms at a dose of 0.1 mg/kg and to 93 ± 6 ms at a dose of 0.3 mg/kg. The possible mechanisms of the neuromuscular actions of verapamil are discussed and it is concluded that verapamil can produce potentiation of either pancuronium- or succinylcholine-induced neuromuscular block at doses within the therapeutic range.

THE ACTION OF POLYMYXIN B AT THE FROG NEUROMUSCULAR JUNCTION

1 The effects of polymyxin B at the neuromuscular junction of the frog were studied by conventional electrophysiological and voltage clamp techniques. 2 At a concentration of 2.5 μg/ml polymyxin B produced neuromuscular blockade in 10 to 15 min and endplate potentials (e.p.ps) could be recorded. Resting membrane potential was unaffected. The neuromuscular block was characterized by a depressed e.p.p. quantal content (28 ± 7), which was similar to that determined from endplates exposed to 13 mm magnesium (23 ± 3), and a low e.p.p. quantal size, which was similar to that determined from endplates exposed to 3 μm (+)‐tubocurarine. 3 Polymyxin B (0.25 to 0.75 μg/ml) decreased mean miniature e.p.p. amplitude with little effect on frequency. 4 At a concentration of 5 μg/ml polymyxin B markedly shortened the duration of endplate currents (e.p.cs) and abolished the relationship between holding potential and the time to half‐decay at negative potentials greater than −;60 mV. This action is consistent with block of open acetylcholine activated ionic channels. 5 4‐Aminopyridine (20 μm) antagonized the depressed e.p.p. quantal content produced by polymyxin B but did not alter the shortened e.p.c. duration. 6 It is concluded that polymyxin B decreases quantal release and produces some degree of postjunctional receptor blockade and a marked and persistent blockade of acetylcholine activated channels. The latter action may explain the difficulty of reversal of polymyxin B‐induced neuromuscular blockade and its non‐competitive nature.

The effects of acute and chronic hydrocortisone treatment on neuromuscular blockade in the anesthetized cat.

It is fairly widespread clinical practice to administer large doses of corticosteroids to patients in cases of shock; doses of hydrocortisone as high as 50 mg · kg−1 given intravenously have been proposed and used. Hydrocortisone, when administered in this way during surgery, has been implicated in interactions with neuromuscular blocking agents. In order to determine the type and mechanism of this interaction, the authors undertook further investigation. The effects of hydrocortisone were studied in two ways. Firstly, a constant 50% depression of the indirectly elicited twitch tension of the tibialis–anterior muscle was established in cats, using a constant intravenous infusion of either pancuronium (1.0 · 0.2 μg · kg−1 · min−1) or succinylcholine (3.6 · 0.8 μg · kg−1 · min−1). The effects of intravenous hydrocortisone then were studied on this block. Secondly, cats chronically were treated with 2 mg · kg−1 of intramuscular hydrocortisone three times a week for 1 month, and then dose-response curves were constructed for pancuronium or succinylcholine. Acute administration of intravenous hydrocortisone (1–15 mg · kg−1) alone had no affect on the twitch tension of either the tibialis–anterior or soleus muscles, however, the corticosteroid (7 and 15 mg · kg−1) did significantly (P < 0.05) enhance the 50% depression of the indirectly elicited twitch tension of the tibialis–anterior muscle produced by the constant intravenous infusion of pancuronium. The soleus muscle was affected similarly (n = 6). Under the same conditions, with a constant infusion of succinylcholine, hydrocortisone had no effect on the blockade of the tibialis–anterior muscle or the soleus muscle (n = 6). The chronic treatment of male cats with hydrocortisone had no effect on the sensitivity to pancuronium (n = 6) of both the tibialis–anterior and soleus muscles. However, this treatment did produce a significant (P < 0.05) change in sensitivity to succinylcholine (n = 6) on the tibialis–anterior muscle but not on the soleus muscle. Two of the 12 cats chronically treated with hydrocortisone exhibited histologic evidence of myopathy. It is concluded that hydrocortisone can enhance the neuromuscular blocking effect of pancuronium and that chronic hydrocortisone treatment can modify the response to succinylcholine. In either case, monitoring of neuromuscular transmission during anesthesia is suggested when a patient is receiving either high-dose acute or chronic hydrocortisone therapy.

4-Aminopyridine Reversal of Sympathetic Ganglionic Blockade in the Anesthetized Cat

The effects of 4-aminopyridine on the blockades of transmission of the superior cervical ganglion produced by hexamethonium, d-tubocurarine, and polymyxin B were investigated in 15 anesthetized cats. Isometric contractions of the nictitating membrane resulting from pre- and postganglionic stimulation were quantified. A 75–85 per cent ganglionic blockade produced by hexamethonium, 3 mg/kg, or by d-tubocurarine, 1.0 to 1.2 mg/kg, was completely reversed by 4-aminopyridine, 1 mg/kg. After injection of 4-aminopyridine, the times required for the contractions of the nictitating membrane to increase from 25 to 75 per cent of control with preganglionic stimulation were 6 ± 3 (mean ± SEM) and 7 ± 2 min for hexamethonium and d-tubocurarine, respectively. Both values are significantly (P lt; 0.05) shorter than their respective control spontaneous recovery times of 26 ± 8 and 25 ± 7 min. Polymyxin B, 20–35 mg/kg, depressed the contractions of the nictitating membrane resulting from pre- and postganglionic stimulation by 84 ± 2 and 66 ± 10 per cent, respectively. 4-Aminopyridine, 1 mg/kg, lessened the polymyxin B-induced depression of the contractions of the nictitating membrane resulting from preganglionic stimulation to 50 ± 13 per cent, but had less effect, 61 ± 13 per cent, on the contractions resulting from postganglionic stimulation. It is concluded that 4-aminopyridine rapidly and completely reverses the sympathetic ganglion blockade produced by hexamethonium or d-tubocurarine, and is partially effective in the reversal of the autonomic effects of polymyxin B.

The action of dantrolene on transmitter mobilization at the rat neuromuscular junction.

Dantrolene sodium (20 microM) was found to decrease transmitter mobilization and the apparent available store of acetylcholine at frequencies of nerve stimulation of 50 and 100 Hz at the neuromuscular junction of the rat hemidiaphragm preparation treated with 2 microM (+)-tubocurarine. This effect of dantrolene sodium was not as marked at frequencies of nerve stimulation of 25 Hz or less, also no significant effect of the drug was observed on the amplitude of endplate potentials (EPPS) at any frequency of nerve stimulation. No effect of dantrolene sodium (20 microM) on mean miniature EPP amplitude or frequency was observed. It is suggested that the action of dantrolene sodium on mean EPP quantal content may be due to an action on stores of bound calcium within the motor nerve terminal. This effect of the drug is unlikely to be of physiological consequence in vivo, since it was only observed at high frequencies of nerve stimulation and did not cause a significant reduction of EPP amplitude during trains of stimuli.

A comparison of 3,4-diaminopyridine and 4-aminopyridine in the anaesthetized cat.

3,4-Diaminopyridine and 4-aminopyridine were compared in the anaesthetized cat and found to be equiactive in their anti-curare activity. This in vivo similarity is at variance with previous in vitro studies which demonstrate 3,4-diaminopyridine to be more active than 4-aminopyridine at the neuromuscular junction. Possible reasons for the similarity between the two aminopyridines at the in vivo neuromuscular junction are discussed and it is concluded that 3,4-diaminopyridine has only marginal advantages over 4-aminopyridine as a potential anti-curare agent.

Reversal of Dantrolene Sodium-induced Depression of Skeletal Muscle in the Cat

Dantrolene sodium, a muscle relaxant, does not have a clinically useful antagonist. The present study was undertaken to test the efficacies of germine monoacetate, 4-aminopyridine, neostigmine, and calcium chloride as possible agents for the reversal of the direct skeletal muscle depression produced by dantrolene sodium in the cat anesthetized with α-chloralose. Depression of the indirectly elicited twitch responses (0.1 Hz) of the tibialis anterior muscle by 25, 50, 75 and 84 per cent was produced by dantrolene, 0.16, 0.36, 0.88 and 1.13 mg/kg respectively; spontaneous recovery of twitch tension during the subsequent 30 min was negligible. After the 30-min observation period had elapsed, one of the reversal agents under study was given (iv) in divided doses at intervals of 10 min (five cats for each agent). Germine monoacetate (2 × 0.5 mg/kg) immediately reversed the dantrolene-induced twitch depression, with an overshoot that persisted for an hour. 4-Aminopyridine (4 × 0.5 mg/kg) caused a steady but incomplete reversal to 17 per cent depression, 30 min after the last dose. Neostigmine (4 × 0.04 mg/kg) caused an immediate, but transient, reversal of the twitch depression, with overshoot. Calcium chloride (4 × 10 mg/kg) was without effect. It is concluded that germine monoacetate is the drug of choice for reversal of the muscle depression produced by dantrolene sodium in the cat.