Albert S. Kuperman

THE PRESYNAPTIC ELEMENT IN NEUROMUSCULAR TRANSMISSION

During the past two decades the neuromuscular blocking drugs have proved to be an exceedingly popular subject for pharmacological and physiological study. Oddly, the opposite aspect, that is, the facilitation of neuromuscular transmission by drugs, has been given relatively little attention. This topic was first exposed to serious scrutiny when Brown et al. (1936) demonstrated the effect of physostigmine in enhancing the contractile response of mammalian striated muscle. Immediately thereafter Brown (1037) ascertained that the mechanism of this effect results from the conversion of each single muscle response to a repetitive one. Just two years earlier the clinical expression of neuromuscular facilitation was recorded when Walker (1934) described the dramatic alleviation of the myasthenic syndrome through the administration of either physostigmine or its newly synthesized congener neostigmine. Later research i n man (Harvey and Lilienthal, 1041) related these laboratory and clinical observations, and it. was revealed that the transmission deficit in myasthenia gravis could be temporarily repaired by neostigmine. At this time Eccles and his co-workers (1941) employed physostigmine to examine the newly discovered end-plate potential and found that the alkaloid greatly prolonged junctional negativity. This seemed a reasonable consequence of the drug’s anticholinesterase (anti-ChE) activity, and Eccles and MacFarlane thereafter (1940) showed a similar effect for other carbamates and di-isopropylfluorophosphate (DFP). On the basis of this work, the prolongation of junctional negativity is often considered synonymous with ChE inhibition. Whether or not this evidence assures a causal relationship may be questioned. In any case, the findings of Eccles et al. (1941) are important., for they disclose a mechanism by which physostigmine and similar drugs cause the junctional region to initiate repetitive discharges in response to individual nerve volleys. In 1946 W. C. Wescoe and I were engaged in an evaluation of DFP in the management of myasthenia gravis. Our efforts only impressed us the more with the remarkable therapeutic efficacy of neostigmine in this disease. Consideration of structure-activity relationship led to a search of the existing lit.erature that revealed, for neostigmine and its congeners, only a concern with the dependence of ChE inhibition on the presence of an alkyl carbamino group; strangely, the possible functional importance of the quaternary ammonium grouping was unmentioned. Simple experiment showed (Riker and Wescoe, 1946) the functional nature of the quaternary ammonium grouping. It was found that chronically denervated cat striated muscle is susceptible to direct excitation by neostigmine, just *.s it is by acetylcholine and other quaternary ammonium ions in which the N .r.tGm is substituted with 3 methyl groups. To * The work reported in this paper was supported in part by a research grant from the Nat ional Institute of Neurological Diseases and Blindness, Public Health Service, Bcthesda, Mtl. t Fellow, Lederle Faculty Fund, Pearl River, N. Y. 1 Fellow, United States Public Health Service, Bethesda, Md. Department of Phannucology, Cornell University Medical College, New Y o r k , N . Y .

Actions at the Neuromuscular Junction

The transmitter process at the neuromuscular junction is defined as the causal chain of events which relates two all-or-none excitatory processes, namely a conducted excitation of motor nerve axons and a propagated response of corresponding muscle fibres. The individual events constituting the transmitter process may be affected discretely by appropriate chemical agents, resulting in phenomena observable at different levels of experimental procedure. Consequently, a set of data is obtained which stands in a signal-event relationship to the transmitter process.

Procaine Action: Antagonism by Adenosine Triphosphate and Other Nucleotides

Appropriate concentrations of adenosine tri-, di-, and monophosphate antagonize the depressant action of procaine on isolated nerve. Some calcium ion is required in the external solution in order for these nucleotides to produce their maximum effects. When applied either to normal or sodium deficient nerves, the nucleotides do not increase action-potential amplitude.

Reversal of the Actions of Tetraethyl Pyrophosphate in Surviving Mammalian Tissue.

Summary and Conclusions 1. Experiments were made to determine the effect of a new compound, nicotinhydroxamic acid methio-dide (NHMI), on isolated mammalian tissue treated with TEPP. 2. NHMI possesses the property of reversing to a significant degree the TEPP-induced actions in isolated auricles and intestinal strips of the rabbit. 3. That this effect of NHMI was not the result of an anticholinergic action was shown by the inability of the compound to reverse the effects of ACh or MCh. 4. That this reversal phenomenon was not the result of a direct action upon the tissue was shown by the negligible response of the organs to the compound alone. 5. These studies indicate that reversal of TEPP-in-duced effects by NHMI may be due to a true chemical reactivation of cholinesterase.