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HANDBOOK OF PHYSIOLOGY 



NEUROPHYSIOLOGY I 



per unit of time. From infusion experiments in m^n 

 it has been found that the proportion of norepi- 

 nephrine excreted in urine is 1.5 to 4 per cent of that 

 infused durinc; the same time (129). If the total ex- 

 cretion of norepinephrine (free and conjugated) in 

 man during 24 hours, when the subject is performing 

 daily routine work but no severe muscular work, can 

 be estimated at 60 fxg (109, 129), the amount of 

 neurotransmitter overflow may be estimated at ap- 

 proximately 2 to 3 mg per 24 hours. 



The careful study of the distribution of monoamine 

 oxidase (MAO) in various nerve cells by Koelle & 

 Valk (76) does not support the opinion that MAO is 

 specifically occurring in adrenergic nerves, since no 

 significant differences were found in the MAO ac- 

 tivity in nerve cell bodies and fibers of the stellate, 

 superior cervical, nodose, dorsal root and ciliary 

 ganglia of the cat. The enzyme is localized in smooth 

 muscle cells of blood vessels. It is absent in cardiac 

 muscle, but high activity is found in renal tubule 

 cells and hepatic cells. Since the removal of the trans- 

 mitter by inactivating enzymes is more likely to occur 

 in the target cells than in the neurons producing the 

 transmitter this result is not unexpected. 



Small amounts of the transmitter are successfully 

 removed during the passage of blood through the 

 tissue, up to 90 per cent during a single passage 

 through muscle and skin. This is in harmony with 

 the findings that after infusion of norepinephrine and 

 epinephrine in man only a small percentage appears 

 in the urine, the rest being inactivated. 



Mechanisms of inactivation other than by MAO 

 are conceivable, such as by catechol oxidases and 

 peroxidases and by conjugation. The relative unim- 

 portance of the inactivation of circulating catechol 

 amines by MAO is further borne out by the observa- 

 tion that cobefrine (a-methyl-rfZ-norepinephrine) is 

 excreted in a similar small proportion as epinephrine 

 and norepinephrine after injection in man (129), 

 although it is not attacked by this enzyme. It must 

 therefore have been inactivated (to more than 90 per 

 cent) by some other mechanism which presumably 

 would have been similarly active on the catechol 

 hormones. 



POSSIBLE ADRENERGIC NERVE TRANSMITTERS 

 OTHER THAN NOREPINEPHRINE 



It may well be asked whether there is any way of 

 distinguishing between the release of the chemotrans- 



mitter from the nerve terminals and the secretory 

 products from chromaffin cells in the tissues. Since 

 very little is known about the mass and distribution 

 of such scattered chromaffin cells or whether they 

 secrete epinephrine or norepinephrine or both (and 

 in the latter case the relative proportions), it is hard 

 to evaluate the amount of neurotransmitter sensu 

 strictwn which is released upon stimulation of svinpa- 

 thetic nerves. Assuming that chromaffin cells are 

 present in an organ, they would be made to release 

 their secretory products by stimulation of the pre- 

 ganglionic fil:)ers in the sympathetic nerve. 



A partial answer to this problem has been afTorded 

 by studies on the content of the active catechol 

 amines in tissues and organs. There is good evidence 

 that the catechol amines found in extracts of organs 

 and tissues are derived from their adrenergic nerves 

 and chromaffin cells. This is shown by a) the large 

 reduction or disappearance of the catechol amines 

 after postganglionic denervation (18, 55, 129), h) the 

 absence of these suijstances in the nerve-free placenta 

 (i 16, 124) and c) the reappearance of such substances 

 upon regeneration of the postganglionic nerves 

 (55, 129). It is known that section and degeneration 

 of the preganglionic fibers that innervate the chro- 

 maffin cells do not cause depletion of the secretory 

 products of these cells, while section of the postgangli- 

 onic fibers causes disappearance of their transmitter 

 substance. It is thus possible by analysis of the cate- 

 chol amine content of an organ after preganglionic 

 and postganglionic denervation to obtain information 

 on the occurrence of chromaffin cells. The results of 

 such experiments liave been that ' postganglionic' 

 nerve section usually leaves a small remnant of 

 activity. It is typical of this that the proportion of 

 epinephrine is higher than it is in the organ with its 

 nerves intact (55, 129). Sometimes the epinephrine 

 content is unchanged. The conclusion has been 

 drawn from these experiments that_gractic_ally all of 

 the norepinephrine_is present in the postganglionic 

 nerves while the epinephrine must have been located 

 outside the adrenergic neurons, in all likelihood in 

 chrouKiffin^cells. Such cells have been described in the 

 heart b\ Trinci (123). 



Further evidence along the same line has been ob- 

 tained from experiments on the isolated perfused 

 rabbit heart either beating spontaneously or dri\'en 

 electrically at a faster rate (32). By recirculation of 

 the perfusing fluid it is possible to concentrate the 

 active substances released from the heart. After sepa- 



