360 H. MCLENNAN 



ship, if any, between these and the materials discussed above cannot at 

 present be determined. 



Thus far mention has been made only of possible mediators at inhibitory 

 synapses in the vertebrate central nervous system. Some aspects of peripheral 

 inhibition, largely in invertebrate animals, will be given in the pages which 

 follow. 



HEART 



The vertebrate heart provided the object for the classical experiments in 

 the field of synaptic transmission, i.e. the studies of Loewi. As is universally 

 known, he demonstrated the liberation of a substance into the perfusion 

 fluid in response to stimulation of the vagus, which upon application to a 

 second heart mimicked the effect of vagal stimulation. The substance was 

 later identified as acetylchoHne. It is worthwhile to remember that the 

 earliest demonstration of chemical transmission was an inhibitory process, 

 and further that the mediator there involved has excitatory functions at other 

 synapses. The obvious conclusion is that the inhibitory materials which were 

 discussed above may also be excitatory under certain circumstances, and 

 indeed such was indicated for Factor I by Florey (1956) and by Florey and 

 McLennan (1955b). The excitatory actions of Factor I could not be separated 

 chemically from the inhibitory ones. 



The membrane potential changes in the fibres of the sinus venosus of the 

 frog heart are characteristic of those found in spontaneously excitable struc- 

 tures. Thus during diastole a slow depolarization (the pacemaker potential) 

 develops, at the peak of whose ampUtude (13-15 mV) an action potential is 

 initiated. If the vagi are stimulated during the phase which follows the action 

 potential the repolarization process is speeded, and continued until the 

 membrane potential is more negative than the point reached in previous 

 cycles. The next beat is delayed because the slope of the pacemaker potential 

 is reduced (Hutter and Trautwein, 1956). Stronger vagal stimulation gives 

 rise to an hyperpolarization averaging 10 mV and the heart is stopped. On 

 cessation of stimulation the pacemaker potential slowly builds up again. 



The events in the fibres of the sinus then are analagous to those described 

 above as occurring at motor neurons. The inJiibitory action of the vagus is 

 abolished by atropine, as is the eff"ect of apphed acetylcholine, and there can 

 be Uttle doubt that in this instance acetylchoHne is acting as the mediator of 

 the inhibitory synaptic action. 



The hearts of Crustacea are hkewise inhibited by peripheral nerve stimula- 

 tion although in this case the effects are upon the neurons of a heart ganglion. 

 Stimulation of the inliibitory fibres results in a diastolic arrest of the heart 

 during which an occasional normal beat may occur. The effect is duplicated 

 in every way by the application to the heart (either in a perfusion fluid or 

 added to a bath) of Factor I solutions (Florey, 1954), extracts of crustacean 



