The equilibrium dissociation constants of various nondepolarizing muscle relaxants (MRs) with the postsynaptic nicotinic receptors at the end plates were previously postulated to influence the onset of neuromuscular block (NMB). The hypothesis was not rigorously tested. The goal of the present study was to analyze the course of NMB over time assuming different values for (i) the rate constants for interaction of MRs with the postsynaptic nicotinic receptors (the association, kassoc, and dissociation, kdossoc, rate constants) and (ii) the receptor concentration ([R]).

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Mild myasthenia gravis patients were compared with normals with respect to the capacity of their motor nerve endings (MNEs) to generate a neostigmine-induced postactivation repetition (PAR). Dose-response analyses of PAR recorded from muscle electrically and by contractile measurement disclose a loss of this pharmacologic responsiveness in myasthenia. Since mild myasthenics transmitted nerve impulse trains of 20 to 200 Hz, as did normals, it was evident that PAR is transmitted insofar as it can be generated by MNEs. The dose-response analyses support this. These data indicate an MNE disorder in the disease.

Department of Anesthesiology, Harvard Medical School at the Massachusetts General Hospital, Boston, Massachusetts, and the Department of Pharmacology, Georgetown University School of Medicine and Dentistry, Washington DC. Address correspondence to Dr. Goudsouzian, Department of Anesthesia, Massachusetts General Hospital, Boston, MA 02114. The authors are indebted to Mr. Michael Gionfriddo for reviewing and editing the manuscript, and to Ms. Kitt Booher for her help in assernhling the pertinent material. Accepted for publication May 1, 1986.

This study was designed to determine whether cholinergic drug interaction with cyclic (c) AMP phosphodiesterase (PDE) might account for part of the effects of this class of drugs at the neuromuscular junction. The activity levels of both high- and low-affinity forms of cAMP PDE from cat sciatic nerve were examined for drug inhibition or activation. Of the cholinergic drugs tested, only physostigmine and Tacrine produced significant cAMP PDE inhibition. Physostigmine was 10 times more potent than theophylline and half as potent as SQ 20,009 (known PDE inhibitors) in inhibiting motor nerve cAMP PDE. Tacrine inhibited this enzyme at concentrations comparable with theophylline. None of the other drugs tested (diisopropylfluorophosphate, edrophonium, neostigmine, ecothiophate, carbachol or d-tubocurarine) produced significant changes in cAMP PDE activity. The inhibitory effects of physostigmine were shown to be pH independent over a range of 7.0 to 8.5. Kinetic studies indicated a mixed form of inhibition for physostigmine and Tacrine comparable with that seen for theophylline. These data indicate that the anticholinesterase activity of physostigmine and Tacrine do not adequately describe the facilitatory actions of these drugs at the motor nerve ending.

The in vivo cat soleus and gastrocnemius muscles were used to compare isometric contraction strength and the train-of-four (T4) response (2 Hz for 2 s) of two muscle types (fast and slow) during onset of competitive neuromuscular blockade in order to determine the extent of the correlation between twitch depression and T4 fade. Prior to drug administration the muscles that were studied differed significantly in that the T4 ratio was 1.0 in the gastrocnemius and only 0.87 in the soleus. Three competitive neuromuscular-blocking agents were compared: d-tubocurarine, pancuronium, and vecuronium. d-Tubocurarine was found to produce a close correlation between the degrees of twitch strength depression and T4 for both muscles. However, these muscles demonstrated significantly different ED50 values (105 micrograms/kg for gastrocnemius, 150 micrograms/kg for soleus). Pancuronium also produced a similar relationship between twitch strength depression and T4 decrement for each muscle. In this case, however, there was little difference in their ED50 values for twitch depression (11.5 micrograms/kg for gastrocnemius, 13 micrograms/kg for soleus). The effects of vecuronium were quite different from the other two muscle relaxants. Although vecuronium produced a comparable correlation between twitch tension and T4 fade in fast muscle, no such relationship was found to exist in slow muscle. Even when the twitch strength was blocked to 18% of control, the soleus T4 response was depressed to only 75% of control. These results highlight major differences among competitive neuromuscular-blocking agents and suggest multiple sites of action.

Reports that theophylline increases the strength of myasthenic muscle provided some of the first clues that cyclic nucleotides might be involved in neuromuscular transmission. These and additional studies, reviewed recently by Standaert and Dretchen,' showed that intraneuronal cyclic AMP promotes the spontaneous and evoked release of transmitter from motor nerve endings, apparently by enhancing calcium flux into the nerve ending and possibly by mobilizing intraneuronal stores of the ion. Cyclic nucleotides also may affect other processes related to the synthesis, storage, mobilization, and release of transmitter, but they do not seem to be involved in the post-synaptic response of the motor end plate to acetylcholine. The neuromuscular effects of theophylline are strikingly similar to those of physostigmine in that both agents enhance contraction strength, reverse dtubocurarine and potentiate succinylcholine blockade, even though theophylline does not inhibit cholinesterase. Investigating this paradox we learned that physostigmine inhibits phosphodiesterases. The KI for inhibition by physostigmine of high and low affinity cAMP phosphodiesterase obtained from cat sciatic are 175 pm and 23 pm, respectively, while those for theophylline are 900 pm and 220 pm, and those for SQ 20,009 are 44 pm and 9 pm; i.e., physostigmine is about ten times more effective than theophylline and one fourth as effective as SQ 20,009. The inhibition of phosphodiesterase by physostigmine was observed over a pH range of 7 to 8.5 suggesting that the state of ionization was not responsible for the effect. Physostigmine is the only one of the facilitatory drugs with this action; neostigmine, edrophonium, isoflurophate and echothiophate do not have significant inhibitory actions on these phosphodiesterases (K, > pm). Edrophonium, neostigmine and physostigmine interact with cyclic nucleotides in other ways. The facilitatory effect on neuromuscular junctions of cat soleus muscle are increased by pretreatment with theophylline and each of these drugs increases the response of motor nerve endings to dibutyryl cAMP or any agents that increase the intraneuronal content of CAMP. Their neural actions are not affected by prior administration of tetrodotoxin, but are prevented by small doses of verapamil, lanthanic or cobaltic ions, materials that inhibit calcium flux. Their anti-curare effects are also abolished by pretreatment with calcium antagonists. These observations suggest that these facilitatory effects are exerted through a cyclic nucleotide system that enhances calcium flux into the nerve endings. In contrast, the prejunctional actions of acetylcholine do not seem to be immediately linked to a CAMP-related calcium flux. Intracellular recordings from in situ soleus muscles show that intra-arterial injections of acetylcholine evoke action potentials in motor nerves, and depolarize, end plates, but do not change the frequency or amplitude of spontaneous miniature end plate poten-

The effects of increased extracellular calcium levels on the responses of the motor nerve terminal to agents that increased intracellular levels of cyclic AMP was studied on the in vivo cat soleus muscle preparation. The neural and muscle responses to intra-arterially administered NaF, an activator of adenylate cyclase, and dbcAMP progressively increased as blood calcium levels rose. These results provide additional support for the hypothesis of an interaction between calcium and cyclic AMP in motor nerve endings.