Histamine release by compounds of simple chemical structure / W.D.M. Paton.

  • William Paton
Date:
[1957?]
Catalogue details

Licence: In copyright

Credit: Histamine release by compounds of simple chemical structure / W.D.M. Paton. Source: Wellcome Collection.

    30/60 page 298
    VIII. HISTAMINE-RELEASING AGENTS OF NATURAL ORIGIN The existence of any potent drug inevitably suggests that a similar substance may play some part in normal physiology. Hence the interest which attaches to the existence of histamine liberators of natural origin, of which a number are known to exist, in addition to the well-known peptone preparations. 1. Amino acids. The ability of peptone to imitate anaphylaxis has long been familiar; and it is known that it will release histamine into the blood of the whole animal, from perfused liver, and from rabbit blood cells. But it is relatively in¬ active, and doses of the order of 100 mg/kg are necessary to obtain useful effects. A failure to obtain any highly active fraction from one of the more active prepara¬ tions, Difco Proteose Peptone, led Eldridge and Paton (60) to suspect that hista¬ mine-releasing activity of a low order might be diffused throughout its constitu¬ ents, and that the aminoacids themselves might be active. This proved to be the case; aminoacids with an isoelectric point greater than 8 (arginine and lysine) together with their derivatives ornithine and carnosine were active. Potency was very low (about 1/10,000 that of 48/80), but comparable with that of peptone. A polylysine, with fifteen residues, has been shown (86) to be active, about the potency of diaminodecane. Reduction of clotting power of the blood in the dog, and the appearance in the blood of “slow-reacting substance” were also found. Poly lysine will form a complex with heparin. Protamine was also active, about the potency of diaminodecane. 2. Antibiotics. Licheniformin, an antibiotic polypeptide containing arginine and lysine (38) has been shown to produce the delayed depressor response, to raise the plasma histamine in the cat and to produce a number of histamine- mediated reactions, including a weal by intradermal injection. It has about 3dm the activity of 48/80 (139). Polymyxins B and E, polypeptides containing a, 7-diaminobutyric acid (105) are also effective histamine liberators (37, 161). In cats, 2 mg/kg will elicit the typical blood pressure response. In dogs, 2 to 10 mg/kg are needed to reduce the blood pressure. Repeated doses become ineffective. Antihistamines delay the fall in blood pressure, without altering the ultimate level attained. Polymyxin B, injected under the dorsal skin of a rat, will cause depletion of histamine content of ventral skin; Polymyxin E is less effective. Given intra- peritoneally in rats, mast cell disruption was produced, with histamine release into the peritoneal fluid. Polymyxin is known to produce a triple response in human skin, and it causes bluing in guinea-pig skin. Compared to 48/80, the polymyxins are about 34200 as active on cat or dog blood pressure, and Yi as active by the guinea-pig “bluing” test.6 Norton and de Beer (161) have studied quantitatively the degranulation of mast cells in vitro by a number of antibiotics. Polymyxin, at 0.4 ng/ml, and Aureo- mycin, at 77 /ig/ml, produced 50% fragmentation. Bacitracin, penicillin, achro- 6 It has been shown that polymyxin releases histamine almost selectively from rat skin, little 5-HT being mobilised. Compound 48/80 releases both amines, reserpine only 5-HT. (J. R. Parratt and G. B. West: Action of polymyxin B on tissue mast cells of the rat. J. Physiol. 135: 24P, 1957.)
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