AUTONOMIC NEUROEFFECTOR TRANSMISSION 



227 



eluded that the epinephrine-Hke substance was re- 

 leased from intracardiac adrenergic neurons con- 

 trolled bv preganglionic fibers in the vagus. Whether 

 the substance was released from neurons proper or 

 from chromaffin cells is not clear, however. 



STIMULATION OF ISOLATED NERVES. Attempts havc been 

 made to study the release of the adrenergic trans- 

 mitter by stimulating isolated nerves, thus avoiding 

 the possibility of interaction of the inner\'ated tissues. 

 In unpublished experiments Gaddum & Khayyal 

 (50) stimulated an isolated sympathetic nerve sus- 

 pended in salt solution and found that a sympathomi- 

 metic substance was released into the solution. This 

 efTect was later attributed to damage to the nerve by 

 the stimulating electrodes (53). However, the original 

 finding was later confirined (79). This is in agreement 

 with the fact that the whole nerve trunk contains 

 norepinephrine. 



EXHAUSTIBILITY. Studies on the exhaustibility of the 

 transmitter sources have shown that even prolonged 

 stimulation, reflex or direct, does not seem to lessen 

 the release. Orias (104) stimulated the preganglionic 

 fibers of the cervical sympathetic 10 times a sec. for 

 I hour and found no .signs of fatigue in the responses 

 of the nictitating membrane. These experiments were 

 repeated by Dye (39) who applied not less than 

 108,000 Stimuli during 3 hours to the preganglionic 

 nerves without evidence of exhaustion. Luco & Goni 

 (88) found that stimulation of sympathetic nerves 

 for I hour did not diminish the content of transmitter 

 in the nerve. It may therefore be assumed that release 

 of the transmitter can continue for an unlimited time. 

 This is an indication in the first place that the trans- 

 mitter is readily resynthesized but also that the 

 release mechanism is built to render continuous 

 service. 



Removal of Transmitter 



Although it is apparent from the observations of 

 remote effects of adrenergic nerve stimulation and 

 from the excretion of norepinephrine in urine that a 

 certain proportion of the released neurotransmitter 

 is transferred into the circulating blood, it is generally 

 assumed that most of the transmitter is being inacti- 

 vated at or near the site of release (16, 47}. 



The experiments of Brown & Gillespie (14) indicate 

 that the removal of the transmitter is more efficient 

 when it is released at a slow rate. As to the mechanism 

 of removal, their experiments suggest that the trans- 



mitter is being attached to a certain extent to the 

 effector cells and presumably inactivated at this site. 



Our knowledge about the mechanism of inactiva- 

 tion is still very incoinplete. The inability of iso- 

 propyl isonicotinyl hydrazine (Marsilid) to affect to 

 any noticeable extent the amount of transmitter re- 

 covered in the effluent blood after stimulation of the 

 splenic nerves does not support the common opinion 

 that amine oxiclase pla ys an importan t part in this 

 respect. 



In experiments in which the transmitter was re- 

 leased from a perfused spleen by various chemical 

 means, the amount of norepinephrine found in the 

 effluent was not greatly influenced by adding amine 

 oxidase inhibitors to the perfusion fluid (129). More- 

 over, administration of Marsilid to an animal does 

 not augment the degree or duration of adrenergic 

 reflex actions in the cat, such as the pressor eflfect of 

 carotid occlusion, indicating that amine oxidase, at 

 any rate, does not attack the transmitter between the 

 moment of release and the action on the efTector cell. 



The problem of the removal of the transmitter 

 after its release may be regarded from two aspects. 

 One part of the transmitter apparently is d]rectly 

 at_tached to the effector cells [or 'utilized' (14)] while 

 another portion is leaking into the blood vessels, or 

 by-passing the target cells as it were. It is conceivable 

 that after saturation of the target cells the remainder 

 of the released transmitter diffuses through the capil- 

 lary wall and enters the blood stream. The situation 

 might be regarded as analogous to that prevailing 

 during reabsorption of a threshold substance by the 

 renal tubules where an excess causes an ' overflow' 

 into the urine. If the amount of the transmitter which 

 is caught by the effector cells is considered first, it 

 appears probable that it is being inactivated by some 

 process so far unknown. It may well be that on many 

 occasions this part represents the greatest part of the 

 released transmitter. The second part which is not 

 taken up by the cells may theoretically be attacked 

 by enzymes on its diffusion way to the blood or 

 lymph capillaries. Apparently this is not the case since 

 amine oxidase inhibitors did not appreciably alter 

 the yield in the effluent Ijlood (14). Not even after 

 having reached the blood stream is the inactivation 

 complete as seen by the excretion in urine of neuro- 

 transmitter which undoubtedly originates in adre- 

 nergic nerves, as indicated by the excretion in 

 adrenalectomized patients. Knowing the proportion 

 of norepinephrine e.xcreted in urine after intravenous 

 infusion at a constant rate, it seems po.ssible to obtain 

 an idea of the ' overflow' of adrenergic transmitter 



