AUTONOMIC NEUROEFFECTOR TRANSMISSION 



•^33 



RELEASE FROM ISOLATED NERVES. Although no experi- 

 ments seem to have been made with stimulation of 

 postgansrlionic cholinergic nerves, several authors 

 have reported that stimulation of cholinergic pre- 

 ganglionic nerves causes a release of acetylcholine 

 (2, 10, 23, 79). It may be assumed that similar events 

 take place during stimulation of postganglionic 

 cholinergic nerves. 



The inhibitory action of atropine on the effect of 

 cholinergic nerve stimulation has been shown to 

 depend on blocking of the target cell to the released 

 transmitter. It was demonstrated by Feldberg & 

 Krayer (44) that atropine d oes ri otjnte rfere w ith the 

 release as such. 



The failure of atropine to block the effect of stimu- 

 lating the vagus nerve on the intestine may be due to 

 an action of a transmitter different from acetylcholine, 

 released from the enteric nerve system. The nature of 

 this postulated transmitter is not known, but it should 

 be recalled that substance P (51} occurs in the in- 

 testine and is insensitive to atropine. 



Rosenblueth (113) has advanced the idea that the 

 cholinergic nerve transmission proceeds in two stages 

 of which the first is a release of acetylcholine followed 

 ijy a .second in which the nerve transmitter subse- 

 ciucntly forms ' paras)mpathin' which then acts 

 directly on the target cell. 



Stimulation experiments on postganglionic cho- 

 linergic nerves (short ciliary nerves) have shown that 

 the optimum frequency is about 25 per sec. (89). As 

 in the case of adrenergic nerves, prolonged stimula- 

 tion caused Qnlj' slight signs of exhaustibility. Thus 

 stimulation for i to 2 hours caused a sustained con- 

 traction of the iris; thereafter the effect gradually 

 declined. 



Removal of Trorumitter 



As early as 191 4 Dale (25) had assumed that 

 acetylcholine was destroyed rapidly in the organism 

 by some hydrolyzing enzyme. Such an enzyme was 

 actually discovered by Loewi & Navratil (87) in ex- 

 tracts of frog's heart. They also found that this .en^ 

 zyme could i)c inhibited by physostiginine. This was 

 in agreement with the results of earlier experiinents 

 of Dixon & Brodie (35) and others who found that 

 this drug increased some of the effects of parasympa- 

 thetic nerve stimulation. Moreover, Loewi & Navratil 

 were able to show that it increased the effect of the 

 substance liberated from the frog's heart upon stimu- 

 lation. The ' Vagusstoff ' thus behaved like a choline 

 ester since it was a) inhibited by atropine which is a 



specific inhibitor, at least in small doses, and A) pro- 

 tected by physostigmine which is known to inhibit 

 choline esterase. It is generally assumed that the 

 cholinergic transmitter is being inactivated locally to 

 a great extent. Information about the distribution of 

 cholinesterase in the peripheral tissue is accumulating 

 rapidly as a result of the development of suitable 

 methods. This includes important findings about the 

 distribution of cholinesterase at the motor endplates 

 and in the central nervous system (43, 77). It may be 

 assumed that part of the transmitter released in 

 peripheral organs, such as the smooth inuscle organs 

 and glands, is diffusing out in the blood stream where 

 it is rapidly inactivated by the cholinesterase present. 

 It is also possible that cholinesterase is present in the 

 target cells in amounts large enough to destroy any 

 ainount of the transmitter diffusing into the cell. 



MECHANISM OF ACTION OF NEUROTRANSMITTERS 



The neurotransmitters exert direct action on target 

 cells independently of whether or not the cells are 

 autonomically innervated. This is shown by the pro- 

 nounced action of the transmitter substances on nerve- 

 free organs, like the placenta, or on denervated struc- 

 tures. 



The mode of action of the neurotransmitters on the 

 target cells has been much discussed. Clark (24) 

 related the minimal effective doses of acetylcholine 

 and epinephrine on the frog's heart and the frog's 

 stomach to the total surface of the cells affected and 

 arrived at the conclusion that while the effective dose 

 of 0.02 /tig per gm covered a surface of al)out i cm- the 

 total area of the cells was 6000 to 20000 cm-. For this 

 reason it was obvious that the aQjive suijstance only 

 needed to attack a minute part of the cell in order to 

 elicit itijction. 



It is generally a.ssumed that the active substance, 

 be it a neurotransmitter or a pharmacologically 

 active drug of a different kind, has to unite in some 

 way with the target cell before e.xerting its action. 

 Often the sites of binding between the cell and the 

 active molecule are referred to as receptors. According 

 to Clark these postulated receptors, in or on the cell, 

 occupy only a very small portion of the cell volume 

 or surface. Morphological evidence for specific re- 

 ceptor patches on the cell surface is still lacking, 

 however. 



A discussion of the number of inolecules of a trans- 

 mitter required to activate a single cell depends obvi- 

 ously on the type of administration and on the sensi- 



