TY - JOUR T1 - PHARMACOLOGY OF INDOLEALKYLAMINES JF - Pharmacological Reviews JO - Pharmacol Rev SP - 425 LP - 487 VL - 6 IS - 4 AU - V. ERSPAMER Y1 - 1954/12/01 UR - http://pharmrev.aspetjournals.org/content/6/4/425.abstract N2 - 1. The gastrointestinal mucosa of all vertebrates, with the exception of Tekostei and Cyckstomata, and of ascidians contains a peculiar system of cells, known as the "enterochromaffin cell system," which is furnished with specific granules characterized by several well-defined and distinctive histochemical and physicochemical features. The gastrointestinal enterochromaffin system, or enterochromaffin system in the strict sense, is a part of a broader system, which includes also the chromaffin cells of the posterior salivary glands of Octopoda and of the hypobranchial body of Muricidae, as well as the granular chromaffin cells of the cutaneous glands of amphibians. The specific secretion or storage product of the enterochromaffin system is 5-hydroxytryptamine (enteramine, serotonin), possibly together with its immediate precursor 5-hydroxytryptophan and, in the case of amphibian skin, with closely related indolealkylamines. The enterochromaffin cells of the gastrointestinal mucosa are believed to release their secretion product only into the blood or lymph; for other cells of the enterochromaffin system an external secretion must be admitted, alone or together with an internal secretion. 5-HT released into the blood seems to be selectively absorbed by the thrombocytes, which represent authentic circulating reservoirs of the substance. The conditions which regulate the physiological liberation of 5-HT from the intact thrombocytes are obscure. Of course, when these cells disintegrate, 5-HT diffuses into their suspending medium or temporarily accumulates in the organs in which thrombocyte destruction is particularly intense (spleen). The occurrence of 5-HT and related indolealkylamines in a histochemically undetectable form or concentration has been demonstrated, besides in platelets and in spleen, in other animal tissues, as well as in vegetable tissues. All these findings emphasize the widespread distribution of the substance in the living organism. Data are now available on the 5-HT content in blood, spleen, gastrointestinal mucosa, and hence in the entire organism of numerous vertebrate species. 2. The pharmacology of the indolealkylamines must be considered separately for each member of this group of substances. Slight modifications in the indole ring (displacement or suppression of the phenolic hydroxy group) or in the side chain may produce, in certain instances, insignificant changes in the pharmacological effects, or, on the contrary, profound alterations. Moreover, it seems quite arbitrary to generalize to all animal species the results obtained in a single species. The most characteristic and important pharmacological property of the indolealkylamines is certainly that of being smooth muscle stimulants. With few exceptions all extravascular smooth muscles are brought into contraction by these substances, both in vitro and in vivo. Some muscular preparations are particularly sensitive and may be used in the biological assay of 5-HT and other indolealkylamines (estrous uterus of the rat, rat's colon). The isolated vascular smooth muscle is predominantly constricted by the indolealkylamines, but this does not necessarily imply that the same occurs for the vessels in situ in the intact animal. Indeed, the changes in the tone of the most important vascular areas of the organism, and consequently in the systemic blood pressure, induced by these substances are the result of manifold, direct and reflex cardiovascular actions. The importance of the various factors which participate in determining the pressure response to the indolealkylamines varies not only according to the substance administered but, for the same substance, according to the dose, the route of administration, the anesthetic used, the neurogenic vasoconstrictor tone and, above all, the animal species. The effect on the systemic blood pressure is particularly erratic and unpredictable in the case of 5-HT. Tryptamine and closely related substances, without hydroxy groups on the indole ring, are predominantly hypertensive. The same is true for bufotenidine. Other indolealkylamines behave in a manner similar to 5-HT; still others are entirely inactive (Table V). Some vascular areas seem to possess an exceedingly high sensitivity to 5-HT. Among them the renal one is worthy of particular attention since the constriction of the afferent vascular bed is believed to be the most important cause of anti-diuresis observed in rats after small, "physiological" doses of 5-HT. 5-HT has no influence whatever on the blood clotting system. The ability of the substance to shorten the bleeding time, on which much emphasis has been laid by several investigators, is a pure consequence of its vasoconstrictor action. The action of 5-HT and tryptamine on the mammalian heart is stimulant, but generally rather moderate. Very sensitive to 5-HT are the hearts of some molluscs. Respiration is influenced by the indolealkylamines through different mechanisms. The final result varies according to the dose, the experimental conditions and the animal species. Stimulation seems on the whole predominant, but it is often preceded, followed or interrupted by periods of apnea or reduced respiratory rate. Several other effects have been described, mainly for 5-HT: on the central nervous system and intraganglionar nerve impulse transmission, on the permeability of capillaries, on the production of cutaneous pain, on the adrenal medulla, on the release of histamine, on the eosinophils, and on the blood sugar. The importance of these effects is, with some possible exceptions, purely pharmacological. 3. The primary precursor of all indolealkylamines containing two carbon atoms on the lateral chain is L-tryptophan. L-Tryptophan oxidase catalyses the oxidation of this product to 5-hydroxytryptophan which, in its turn, is transformed into the corresponding amine, 5-HT, by 5-hydroxytryptophan decarboxylase. It is probable that all other natural 5-hydroxyindolealkylamines originate from 5-HT through methylation, dehydrogenation and condensation processes. Amine oxidase is of fundamental importance in the inactivation of 5-HT and related indolealkylamines in the living organism. Substrates of amine oxidase are not only amines with a primary amino group in the lateral chain, but also those with a secondary and even with a tertiary amino group. The quaternary ammonium bases, e.g., bufotenidine, seem, on the contrary, not to be attacked by the enzyme. The main breakdown product resulting from the attack of amine oxidase on 5-HT is 5-hydroxyindoleacetic acid, which is a normal constituent of the urine of carnivorous and omnivorous mammals, and probably of other groups of vertebrates. Administration of 5-HT provokes a very remarkable increase in the urinary output of 5-hydroxyindoleacetic acid, but this only in those animal species whose urine contains the acid as a normal constituent. Five to 60 per cent of the 5-HT administered may be recovered from urine as 5-hydroxyindoleacetic acid. Administration of 5-methoxytryptamine is followed by the appearance in urine of great amounts of 5-methoxyindoleacetic acid, that of tryptamine and N-methyl tryptamines by the appearance of varying amounts of indoleacetic acid, both free and conjugated with glycine (indoleaceturic acid). From the study of the excretion of 5-hydroxyindoleacetic acid in normal urine and in urine of animals given 5-HT it is apparent that the metabolism of endogenous 5-HT is very intense. It is, therefore, to be expected that the biosynthesis of 5-HT also occurs very rapidly starting from the widely distributed L-tryptophan, and that the storage of 5-HT in the enterochromaffin cells can be easily and promptly renewed, when exhausted. 4. The biological significance of the indolealkylamines other than 5-HT is entirely unknown. It may be that most of them simply represent metabolic end-products destined to be eliminated from the organism. For 5-HT four principal hypotheses, each one virtually independent of the other, have been advanced: one sees in 5-HT a factor influencing hemostasis; another considers that it controls vascular tone and therefore the systemic blood pressure; a third regards the substance as a hormone participating in the regulation of the function of the kidney; the last attributes to 5-HT an important role in maintaining normal mental processes, and considers the lack of 5-HT in the central nervous system as a possible cause of some mental disorders. None of these hypotheses is fully satisfactory, and against more than one of them the fundamental objection may be raised that it does not take into necessary account the distribution of 5-HT in the animal kingdom, nor the essential data on the 5-HT content and on the rate of metabolism of the substance in the organism of the experimental animal. Indeed, when trying to explain the function of 5-HT, the wide distribution of this product in vertebrates and invertebrates should be always kept in mind. Moreover, it is quite obvious that amongst the many biological actions possessed by 5-HT, the only ones which are to be taken as possibly "physiological" are those provoked by doses smaller than the total 5-HT content of the entire organism of the experimental animal. ER -