In recent years, research on neurohormones has yielded valuable data on enzymatic pathways of synthesis and metabolism, processes of storage and release, and interactions with receptor sites. A far more difficult problem, which transcends the molecular level, concerns the mechanism whereby nerve endings translate nerve impulses into the discharge of precise amounts of neurohormone to the receptor. An inherent difficulty in bridging physiological and molecular events lies in the nature of the approach. The properties of an organ are not the sum of the properties of the component parts, nor is functional change the sum of the molecular alterations. It is not surprising then that the mechanism of action of drugs that exert functional changes might not be disclosed by studies of their effects on isolated cell components.
A new perspective in studies of nerve endings was introduced by the discovery that NE is in a state of continual flux with amine stores maintained in constant amount by a rate of input by synthesis in balance with a rate of exit by breakdown or transport. The significance of this dynamic steady-state is best appreciated when the separate processes are measured by the use of highly labeled H3-NE.
Results of studies at the steady-state lend themselves to the formation of theoretical models in which NE is located in interconnecting compartments. A model must be simple enough to aid the research worker, yet complete enough to avoid gross inaccuracies. To achieve this, the rules of simple kinetics should be applied. Because of the failure to measure rates when NE concentration has been changed, many conclusions from earlier work with drugs must be discarded or reappraised. For example, the demonstration that truly tracer amounts of H3-NE disappear from the heart by a single exponential phase, and that tyramine and reserpine cause a rapid and exponential release of NE stores, shows that the amine is transferred so rapidly between compartments that they behave towards drugs essentially as a single pool. In addition, the application of kinetics indicates that at the steady-state NE flows from the neuron at a rate proportional to concentration, and that after maximally effective doses of reserpine the increased flow is best explained by a primary action of the drug on a transport system in the neuronal membrane. Again kinetic studies make it unlikely that cocaine or desmethylimipramine act directly on a membrane pump since these drugs not only block the uptake of NE, but also reduce the spontaneous efflux and nervestimulated release. Thus the membrane effects of these substances cannot as yet be simply formulated.
The kinetic approach has yielded a working hypothesis of the nerve ending that is readily amenable to change. The model leaves much to be answered and presumably includes much that is in error. We can only repeat the words attributed to Kepler, "Give me a fruitful error any time, full of seeds, bursting with its own corrections. You can keep your sterile truths for yourself."