The release of histamine and formation of a slow‐reacting substance (SRS‐A) during anaphylactic shock

Abstract

The release of histamine during anaphylaxis has been demonstrated in several species and various tissues, but it is well known that histamine alone cannot satisfactorily account for all the effects on smooth muscle observed during the anaphylactic reaction. The experiments presented in the present paper show that in addition to the release of histamine, the antigen-antibody reaction results in the formation of another smoothmuscle-stimulating substance which causes a slow and long-lasting contraction of the guinea-pig ileum, and which is resistant to anti-histamine drugs. This substance will be referred to as SRS-A.The existence of a slow-reacting substance in the effluent collected during shock from the perfused lungs ofthe guinea-pig was recognized by Kellaway & Trethewie (1940). They were, however, unable to separate its effect upon the guinea-pig gut from that of histamine in the effluent, and their evidence for its presence was based on the observation that the active effluent caused a more prolonged contraction of the gut than did histamine alone. The use of anti-histamine drugs now makes it possible to study SRS-A separately. METHODSThe experiments were performed on perfused lungs or minced tissue from sensitized animals.Sensitization. Young albino guinea-pigs, usually male, of 200-250 g were given an intraperitoneal and a subcutaneous injection each of 100 mg dried egg albumin, as a 10% solution in saline, containing 0-5 % phenol. The animals were killed with N20, or by dislocation of the neck, 3-5 weeks later, when they were always found to be strongly sensitized to the antigen.Young male sandy-lop or albino rabbits were used. A primary antibody response was produced by two intramuscular injections of 25 mg of the antigen, in 1 ml. of adjuvant medium (Freund & McDermott, 1942) given 7 days apart. After 6 weeks, 5 or 6 graded doses of alum-precipitated antigen, rising from 2 to 10 mg, were given intravenously at intervals of 3 days. The animals were killed by dislocation of the neck, or bled out under pentobarbitone, 6-10 days after the last injection.Rats of both sexes, of a hooded strain maintained at the National Institute for Medical Research, London, and weighing about 120 g, were sensitized similarly to rabbits but with

Using guinea pigs in studies relevant to asthma and COPD

“…Many fundamental processes, mediators and regulators of airways disease pathogenesis were discovered or demonstrated first in guinea pigs, including the Schultz-Dale (immediate type hypersensitivity) reaction, the actions of histamine, the cysteinyl-leukotrienes and their two receptors, beta adrenoceptor subtypes, thromboxane, vascular endothelial growth factor (VEGF), eotaxin, alveolar macrophage derived neutrophil chemotactic factor(s) (leukotriene B 4 and/or IL-8) and the roles of cAMP and inositol triphosphate in signal transduction [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Receptor pharmacology in guinea pigs more closely matches that of human receptor pharmacology than most other commonly used species [1,20,21] (Table 1, Figs.…”

Leukotriene Signaling in Atherosclerosis and Ischemia

“…1) [5]. While the BLT receptors are denoted BLT 1 and BLT 2 , for the high and low affinity receptor subtypes, respectively, receptors activated by the cysteinyl-LTs are characterized by their sensitivity to available antagonists and are referred to as CysLT 1 and CysLT 2 [7,8] The latter nomenclature probably only in part describes the cysteinyl-LT signaling, since limitation of the currently available CysLT receptor antagonists [8], as well as cross-reactivities between CysLT and purinoreceptors [9] indicate more complex receptor ligation properties for cysteinyl-LTs.…”

Characterization of a leukotriene D4 receptor in guinea pig lung.

“…5A). To compare the relative affinities of each compound for the LTD4 receptor, ap-Biochemistry: Pong (1,15,16).…”

“…Slow-reacting substance of anaphylaxis is generated in lung by various stimuli, including immunological challenge, and is considered to be an important mediator of immediate hypersensitivity reactions, such as bronchoconstriction in allergic asthma (1,2). The major constituents of slow-reacting substance of anaphylaxis have been identified as 5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11, 14-cis-icosatetraenoic acid (leukotriene C4, LTC4) and the 6(R)-S-cysteinylglycyl (leukotriene D4, LTD4) and 6(R)-S-cysteinyl (leukotriene E4, LTE4) analogs (3)(4)(5)(6).…”