The purpose of a critical appraisal of the various hypotheses concerned with the mechanism of supersensitivity to sympathomimetic amines is not so much to belabor the negative aspect (that none of them can, at the present time, provide a full explanation) but rather to emphasize the pressing need for the recognition that this field is much more complicated than is generally realized. The main complications may be enumerated as follows:
1) The mechanism responsible for the termination of the biologically active life of injected or released norepinephrine is not known. Present evidence indicates that neither catechol-O-methyl transferase nor monoamine oxidase is involved; a binding process, a carrier mechanism, a storage process, or diffusion seems to be responsible.
2) The exact mechanism of action of indirectly acting (tyramine-like) substances remains a field of some justified disagreement. The evidence for actual displacement of the transmitter by the nontransmitter sympathomimetic amines with indirect actions has become increasingly, but not yet fully, convincing.
3) The concept that the norepinephrine stores of the tissue consist of only one uniform compartment must be abandoned in favor of the view that the stores consist of at least two (and possibly more) compartments of different size and different physiological and pharmacological importance. There is an urgent need for a proper definition of these compartments and for methods which will permit measurement of their norepinephrine contents individually. The usefulness of measurements of total norepinephrine content of tissues is questionable in the absence of detailed knowledge about the distribution of norepinephrine within the different compartments.
4) Supersensitivity should not be regarded as a simple phenomenon. As far as organs with adrenergic innervation are concerned, it should be recognized that decentralization supersensitivity is quite different from the type of supersensitivity observed after the administration of cocaine. Furthermore, it should be recognized that denervation supersensitivity is apparently a combination of both these types of supersensitivity. If, in fact, there are different types of supersensitivity, then entirely different mechanisms may be involved.
5) Any study concerned with supersensitivity should take into account the striking differences between sympathomimetic amines of closely related chemical structure. Any comprehensive theory of supersensitivity should also furnish an explanation for these differences. Comparative, quantitative studies of the pharmacology of such closely related compounds may be very helpful in elucidating the mechanisms involved in the development of supersensitivity.
6) It should be borne in mind that any well-established correlation does not necessarily indicate a causal relationship. For example, it has been found that the administration of cocaine delays the disappearance of injected norepinephrine from the circulation and that the resultant increase in the plasma level of norepinephrine has been correlated significantly with the increased response of the blood pressure to the injection of norepinephrine (143a). It is tempting to speculate that this supersensitivity is the consequence of the increase in the plasma concentration of norepinephrine. However, there are three serious objections to this view: (a) this observation fails to explain why the administration of cocaine increases the sensitivity of the cardiovascular system to norepinephrine by a factor of about 5 but increases that of the nictitating membrane by a factor of about 50 (60); (b) prolonged pretreatment with reserpine also causes supersensitivity to norepinephrine, but fails to produce such an increase in norepinephrine plasma levels (152); (c) if the norepinephrine plasma level were determining importance, then the administration of cocaine should cause further increase in sensitivity of the already supersensitive denervated nictitating membrane; this is contrary to the experimental evidence which indicates that cocaine is unable to cause further sensitization beyond that already achieved by denervation (87). It is quite possible that the increased norepinephrine plasma level is the consequence of the impairment of the mechanism responsible for the uptake of norepinephrine into the tissue stores (or into one specific compartment of these stores), while a second and completely different action of cocaine responsible for the phenomenon of supersensitivity. If it is assumed that cocaine prevents the uptake of sympathomimetic amines into the tissue (or a compartment of the store) by an action on the membrane of the postganglionic nerve terminal (i.e., a presynaptic site of action), then it is not unreasonable to assume that cocaine in a similar concentration is also able to affect the postsynaptic membrane in such a manner that supersensitivity results.
7) There is growing evidence for the view that many of the compounds considered in this review have multiple sites of action. This is by no means astonishing, since the "master key," norepinephrine, must fit all of the following receptor-like sites: the postulated carrier mechanism responsible for uptake into the stores (or compartments of stores), the binding site inside the stores, the postulated less specific binding sites outside the actual stores, catechol-O-methyl transferase, monoamine oxidase, and the alpha- and beta-receptors. Any substance capable of fitting into one of these sites should be suspected of fitting into one, or some, or all of the others. This would account for the large variety substances recently described to interfere with the storage, the release, or the action of norepinephrine.
8) Several years ago, presynaptic adrenergic nerve endings were generally believed to have only one function: to release norepinephrine in response to the arrival of a nerve impulse. When Burn (24) first advanced the idea that nerve terminals might also function as a site for uptake of sympathomimetic amines, the suggestion failed to find the proper receptor. During recent years this situation has changed markedly; in fact, it has changed to such a degree that it now seems necessary to point out that postsynaptic events are in danger of being neglected. Recent discussions about the mechanism of supersensitivity have dealt almost exclusively with hypotheses concerned with presynaptic events. this connection, it may be worthwhile to point out that supersensitivity skeletal muscle has clearly been demonstrated to be a postsynaptic event: after degeneration of the motor fiber the acetylcholine-sensitive area (which normally is restricted to the endplate region) extends until it covers the whole the postsynaptic (muscle) membrane (9, 10, 48, 100, 101). Smooth muscle has no obvious equivalent of the endplate region, and norepinephrine receptors may be more or less uniformly distributed over the cell membrane. Nevertheless, supersensitivity of smooth muscle might be visualized as the consequence of an increase in the number of receptors (in analogy to skeletal muscle). As a result of such an increase in the density of the receptor population, one would expect to obtain a uniform type of supersensitivity such as is actually observed after decentralization. Moreover, the time element involved in the development of decentralization supersensitivity in the nictitating membrane (69) resembles closely the time course of the development of denervation supersensitivity in skeletal muscle (48). Finally, just as a pharmacological interruption of the pathway to the endplate (by the administration of botulinum toxin) is enough to produce this type of supersensitivity in skeletal muscle (134), so also are various pharmacological procedures (all resulting in prolonged interruption of the pathway between the center and the end organ) capable of producing the decentralization-type of supersensitivity in the nictitating membrane. Hence, if supersensitivity in smooth muscle is due to a general increase in receptors, as appears to be the case in skeletal muscle, one could account for at least the decentralization-type of supersensitivity On a postsynaptic base. This is, of course, pure speculation; it has been claimed, to the contrary, that denervation of the iris results in a reduction of the number of receptors (155). But such considerations serve to point out that our intense interest in presynaptic events should not lead to the tacit assumption that postsynaptic events can safely be excluded. It is hoped that electrophysiological studies will help to classify the relative importance of these two possibilities.