222 



HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY I 



around 20 times the amount per mg dry weight found 

 in the whole nerve before homogenization. 



The theory may then be advanced that the adrener- 

 gic nerve transmitter is bound to elements which in 

 principle are of a kind similar to those found in the 

 chromaffin cells. Since these can be regarded as 

 homologues of the postganglionic neurons it might 

 be expected that their constituents with specific activ- 

 ity are stored in a similar way. The structural ele- 

 ments serving as stores may also well be the units for 

 bio.synthesis. Apparently this takes place very rapidly 

 so as to maintain a practically constant store. Con- 

 tinuous and prolonged stimulation of nerves in vitro 

 (88) or in vivo (129) does not deplete the stores. There 

 is no evidence that the granules of the chromaffin 

 cells leave the cell body in connection with the re- 

 lease of the hormones; this may be assumed also for 

 the storing elements of the postganglionic adrenergic 

 neurons. It may be postulated that the microstruc- 

 tures elaborating and containing the neurotrans- 

 mitter are formed in the cell soma and transported 

 along the axon towards the periphery by the axo- 

 plasm flow (135). These assumptions would provide 

 a satisfactory explanation for the findings that a) the 

 chemotransmitter is accumulated in the terminal parts 

 of the neuron, and that h~) continuous stimulation does 

 not deplete the nerves of its chemotransmitter. The 

 theory involving the assumption of intra-axonal 

 microstructural elements thus seems to explain 

 several phenomena encountered in the field of neuro- 

 transmission. 



Release 



Stimulation of the adrenergic nerves, either directly 

 or reflexly, immediately releases norepinephrine 

 which is then allowed to diffuse to the adjacent tar- 

 get cells. From the above section it may be inferred 

 that the transmitter is released from microstructures 

 and accumulated at the terminal parts of the nerves, 

 presumably in a way similar to that operating in the 

 chromaffin cells. The large number of discrete 

 terminal ramifications ofl"er only short diffusion dis- 

 tances, enabling each cell to be reached by the chemi- 

 cal transmitter in a very short time. While under 

 normal conditions the adrenergic chemotransmitter 

 is released chiefly, if not entirely, as a result of reflex 

 stimulation, various experimental approaches have 

 been made in order to study the release in more 

 detail, such as a) observation of the effects of direct 

 nerve stimulation on the innervated organ. A) record- 

 ing of the effects of stimulation of adrenergic nerves 



on remote organs, c) quantitatixe estimation of the 

 content of the neurotransmitter in the venous effluent 

 from the stimulated organ, and (T) measuring the 

 release of transmitter from isolated nerves stimulated 

 in vitro, or from organs perfused in vitro. 



INFLUENCE OF STIMUL.XTION FREQUENCY. The effect of 



Stimulation of the adrenergic nerves — or usually 

 mixed nerves containing adrenergic fibers — provides 

 the basis for most of our knowledge of the action of 

 the adrenergic system on various target organs. A 

 study of these effects not only permits qualitative in- 

 formation on the type of effect on the organ but also 

 offers opportunities for gaining quantitative infor- 

 mation, for instance about the influence of stimulus 

 strength and frequency on the effect. In this way the 

 relea.se mechanism can be studied at least on a semi- 

 quantitative basis which can hardly be accom- 

 plished by reflex stimulation. 



While the technique of studying the response of an 

 organ to variation in the intensity of the stimulus 

 gives an idea of the excitability of the nerve fibers, 

 information about the release mechanism is better 

 obtained by varying the stimulus frequency. Such 

 experiments are preferably performed u.sing stimu- 

 lation intensities which will allow participation of 

 all fibers. As shown in figure 8, the curves obtained 

 by Rosenblueth (112) showing the relationship of 

 stimulus frequency and effect on various autonomic 

 effectors have the general shape of rectangular 

 hyperbolas. The results show the noteworthy feature 

 that considerable effects are achieved even at very 

 low frequencies. As can be seen from figure 8, e\en 

 frequencies of less than i per sec. are capable of 

 causing marked effects. Nearly maximal actions have 

 been recorded with frequencies of the order of 5 per 

 sec, for instance on the piloerectors and the nictitat- 

 ing membrane. The results imply that even very low 

 frequencies are sufficient to release considerable 

 amounts of the transmitter. In table 3 the optimum 

 frequencies for a numjjer of effectors are given. Maxi- 

 mal effects are obtained with frequencies varying 

 from 20 to 30 per sec. in most effector systems. Even 

 a frequency of 10 per sec. generally elicits more than 

 80 per cent of the maximal response. 



.\n interesting difference is noted between the 

 ratio of the effects of single stimuli and those of 

 maximal tetanic stimuli on smooth and skeletal mus- 

 cles, no doubt depending on the trigger mechanism in 

 the latter. Thus the ratio between the effects is much 

 higher for the smooth muscle than for the skeletal 

 muscle. 



