Dissection of physiological mechanisms with drugs is perhaps the oldest technique of experimental physiology. Its permanence attests to its value. Certainly, we, as pharmacologists, are enthusiastic for its continued use, but we are quick to admit that it has limitations. The principal drawback is usually the lack of singular specificity. If specificities are not precisely known, a major premise can be incorrect and subsequent reasoning wrong. Consequently, the difficult task of continually defining and redefining the specificities of drug reagents is ever present as newer knowledge becomes available.I t is mainly our purpose to re-examine the specificity of facilitatory3 drug actions a t the neuromuscular junction, e.g., physostigmine, neostigmine and edrophonium; also to inquire similarly about the specificities of acetylcholine (ACh) and curare, since these are traditionally interrelated with the facilitatory drugs.A definition of facilitatory drug is in order. The most characteristic pharmacologic effect is the potentiation of the isometric contractile response of skeletal muscle, stimulated through its nerve, singly and maximally. Secondly, the facilitatory drugs are anticurare and antimyasthenic. These are sine qua non. Nearly all cause spontaneous fasciculation of innervated muscle; for example, 3-hydroxyphenyltriethylammonium ion (3-OH PTEA) does not.Likewise, most, but not all, are potent inhibitors of AcChE; guanidine and the veratrum alkaloids are not.The post-drug potentiation (PDP) has been confirmed many times, and i t is shown in FIGURE 1 as it occurs in the cat soleus nerve-muscle preparation following the injection of 3-OH PTEA, a close congener of edrophonium (Tensilon). The noteworthy features of this response are the speed with which the peak potentiation is attained, and that the effect is uncomplicated by neuromuscular block.Electromyograms (FIGURE 2) recorded during potentiation disclose in answer to each single nerve volley the underlying repetitive response of muscle. The impressive aspect of this drug effect is the highly synchronous repetition of a muscle fiber population. This led us (Riker et al., 1957) to think *The researches reported on here were supported by the United States Public Health Service research grant No. NB-01447. t Research Career Development Awardee (5-K3-GM-15,517).$We choose to refer to these drugs as facilitatory rather than as anticholinesterases. Our purpose is to retain a descriptive reference in order to avoid mechanistic implications that may be presumptuous in respect to this neuromuscular effect.
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