Synthetic Polypeptides Related to Corticotrophin Acting as Histamine Liberators

On the Paw Oedema Resulting from Subcutaneous Injection of Histamine Liberators in the Rat

“…II is therefore safe to conclude that the 'releaser polypeptides' owe their ability to act as histamine-liber ating and oedema-inducing agents to the special physico-chemical characteristics of the entire molecule which resemble qualitatively though not quantitatively those of a typical tenside polypeptide of natural origin such as melittin [23J. It is furthermore evident from the results presented above that prolyl alkyl derivatives of short-chain corticotrophin polypeptides (CI HA 44,368-Ba, CIBA 44,680-Ba), which have previously been shown to be highly potent histamine liberators in the peritoneal cavity of the rat [18), also belong to the most active oedema-inducing agents described so far. In fact, the well-known histamine liberator, compound 48/80, is, at most, twice as active with regard to induction of paw oedema in the rat as the two 'releaser polypeptides' just mentioned.…”

“…In this connection the fact must, however, be borne in mind that such bases have been found to liberate histamine in vitro as well as in vivo only at a dosage superior [34] to the highest dosage employed in the experiments reported above. The view that a hypothetical mechanism involving diffusion rate such as the one outlined above may have con tributed to the differences in the order of activity of the com pounds with regard to histamine liberation on the one hand and oedema induction on the other is supported by the following find ings: The alkyl polypeptides injected in a large volume into the peritoneal cavity attain their maximal amine-releasing capacity within as little as 10 min [18] whereas, when injected in a minute volume into the hind-paw of the same species, they induce maximal swelling only after a time-lag of 30 to 60 min. Considering the anatomical and/or histological disparity of the 2 target organs under discussion, viz.…”

“…peri toneum, skin). In rat peritoneal fluid, rich in amine-containing mast cells, the amount of serotonin represents only a fraction of that of histamine [1,7,18). From these data one can assume that, for instance, for an amount of 20 fig of histamine released, some 0.4 fig of serotonin would be released concomitantly.…”

“…It is conceivable that the dif ferent orders of activity as established in the 2 test systems could be a consequence, to some extent at least, of the widely differing volumes in which the substances arc injected. Thus, in testing for histamine-liberating capacity, the compounds are injected in a total volume of 10 ml into the peritoneal cavity [18] in order to ensure optimal contact with the peritoneum and the peritoneal fluid. On the other hand, the size of the inoculum used in the paw oedema lest is kept very small so as to avoid any influence on the volume.…”

“…Such polypeptides have recently been found to liberate histamine in vivo when injected intraperitoneally in the rat: in fact, some alkyl derivatives of these polypeptides proved highly potent liberators inasmuch as a minimal quantity, e.g. 1 y of a particular derivative, was capable of liberating almost maximal amounts of the avail able histamine [18], Under the experimental conditions employed in the above-mentioned study, no evidence was obtained of a sub stance other than histamine being released although serotonin was detectable in small amounts in the peritoneal fluid of untreated rats after it had been brought to a brief boil. Furthermore, no kinin-like material could be traced even in samples containing high amounts of histamine: also, no histamine was released when bradykinin nonapeptide was injected instead of the corticotrophin polypeptides.…”