234 



HANDBOOK OF PHYSIOLOGY 



NEUROPHYSIOLOGY I 



tivitv of the cell. If 0.02 fig acetylcholine is necessary 

 to inhibit one gram of frog's heart, as in Clark's ex- 

 ample, the minimal effective amount per gm of tissue 

 is about 10" molecules per cell. In isolated organs 

 entirely different results may be obtained. Thus 

 0.05 mjug epinephrine per ml suspension fluid is some- 

 times enough to elicit an inhibitory effect on the 

 fowl's isolated rectal cecum. In this case obviously a 

 much smaller numijcr of molecules are capable of 

 producing the action, since most of them are in the 

 suspension fluid without contact with the organ. If it 

 is assumed that i o per cent of the molecules are acting 

 on I gm of organ containing 10'" cells, then the num- 

 ber of molecules per cell will be only 10, provided 

 that the active substance is distributed on all cells. 

 This is probably not the case. All calculations of this 

 kind therefore appear very dubious. 



It is conceivable that the neurotransmitter takes 

 part in a chemical reaction sequence which is influ- 

 enced thereby in a quantitative or even qualitative 

 manner. Whether this action is initiated at specific 

 receptor patches at the surface or at specific metabolic 

 structure elements in the interior of the cell is not 

 known. It may be recalled that there is good evidence 

 for the permeation of neurotransmitters through cell 

 membranes, since this is the basis for most of our 

 information regarding their release. 



Elaborate schemes of receptor mechanisms have 

 been presented by several authors and terms sug- 

 gested for the postulated receptors. Since these efforts 

 primarilv represent an attempt to put the known facts 

 in a formal system but hardly contribute to our actual 

 knowledge, these systems will not be dealt with here. 

 Recent contributions to the discussion have been 

 given by Zupancic (137) and Stephenson (iig). 



How the neurotransmitter elicits a relaxation or a 

 contraction of the target cell is still ob.scure. It can be 

 assumed that the active substance initiates or rein- 

 forces soine process which eventually causes physico- 

 chemical changes in the contractile material con- 

 ducive to such effects. 



Attempts have been made to correlate the inhibi- 

 tory actions of epinephrine with the formation of 

 lactic acid (99), which is believed to be the metabolic 

 product directly responsible for the inhiljitory action. 

 The hypothesis obviously requires that the widely 

 varying activity ratios of epinephrine and norepi- 

 nephrine for an organ like the fowl's rectal cecum 

 (from 4 to 200) are associated with corresponding 

 variations in the formation of lactic acid in the react- 

 ing target cells, a demonstration which has not been 

 made 



On account of the large differences in action be- 

 tween the levo- and dextroisomers of epinephrine, 

 for instance, it has been inferred that the active sub- 

 stance combines with an optically active constituent 

 of the cell (122). Recent careful studies on the bio- 

 logical activity of optical isomers of sympathomimetic 

 amines have shown that the difference in action be- 

 tween the isomers is even greater than has been 

 hitherto recognized (90). 



These results suggest that the neurotransmitter is 

 involved in enzymatic reactions, a conclusion which 

 also appears most likely for other reasons. 



Another approach to the study of the mode of 

 action of neurotransmitters on the target cell is based 

 on the quantitative relationships between do.se and 

 action. Such quantitation of the effects has ijeen used 

 for the elaboration of formulae of \arious kinds. It is 

 outside the scope of this article to discuss these studies. 

 It may be said generally, however, that by applying 

 this principle to single cells more information may be 

 gained. In most cases the relationship between dose 

 and action is approximately expressed by a rectangu- 

 lar hyperbola. Its precise biological significance is 

 not as yet clear. 



Summarizing, it may be concluded that not much 

 more knowledge aijout the mode of action of the 

 neurotransmitters on target cells has been gained 

 since Langley's time when he ascribed the differenti- 

 ating effect of the transmitter, relaxation or contrac- 

 tion, to a receptor substance in the cell. 



A relevant question is whether two neurotrans- 

 mitters released in the same organ act on the same or 

 different cells and to what extent they interfere with 

 one another's actions. Morison & Acheson (20) found 

 similar hyperijolic concentration-action curves for 

 epinephrine and acetylcholine on the nictitating mem- 

 brane of the cat. When the two substances were in- 

 jected together, their actions added up along the same 

 curve. These results would seem to allow the impor- 

 tant conclusion that the two neurotransmitters act 

 independently by exerting separate actions. Whether 

 or not these are on the same or different cells cannot 

 be decided from these experiments. 



NEUROTRANSMITTERS IN BLOOD AND URINE 



It has been discussed above that some of the neuro- 

 transmitter released at the autonomic postganglionic 

 nerve endings passes bevond the target cells and 

 reaches the l)lood stream. If this occurs to any con- 

 siderable extent it should be possible to demonstrate 



