HUMORAL FACTORS AFFECTING PULMONARY INFLATION DURING ACUTE ANAPHYLAXIS IN THE GUINEA‐PIG IN VIVO

1 Ovalbumin induced dose-dependent contractions of lung parenchyma strips from sensitized guinea-pigs, whereas Paf-acether (I -alkyl-2-acetyl-sn-glycero-3-phosphoryl choline), a potential mediator of immediate hypersensitivity, induced a single contraction, followed by specific desensitization to a second exposure. 2 Lung strips desensitized to Paf-acether contracted to ovalbumin as did non-desensitized controls, even in the presence of inhibitors of other mediators of anaphylaxis. 3 Contractions by Paf-acether and by ovalbumin were reduced by nordihydroguaiaretic acid (NDGA) and by the phospholipase A2 inhibitorp-bromophenacyl bromide (0.1 -0.3 mM). Three other anti-lipoxygenase agents (diethylcarbamazine, 5 mM; eicosatetraynoic acid and BW755c, 0.1 mM), reduced the contractions by ovalbumin but also those due to acetylcholine, indicating non-specific effects. Neither the anti-allergic compound sodium cromoglycate (3 mM) nor the anti-leukotriene agent, FPL 55712 (0.01 mM), inhibited the contractions by ovalbumin or by Paf-acether. 4 A sensitized strip stimulated with ovalbumin released substances which contracted a non-sensitized strip mounted in the same organ bath. The contractions of the non-sensitized strip were abolished by FPL 55712 (0.01 mM), by NDGA and BW755c, (0.1 mM), whereas those of the sensitized one were unaffected. Leukotrienes are formed by the lung strips during shock but alone, they do not explain the contractile activity.5 The intravenous administration of ovalbumin (1 mg kg-') led to bronchoconstriction and thrombocytopenia, which were not modified by the anti-leukotriene substance FPL 55712 nor by aspirin. Bronchoconstriction was suppressed if FPL 55712 was used in combination with aspirin (20 mg kg-'), mepyramine and methysergide (200 jg kg-of either). Pretreatment of the guinea-pigs with propranolol reduced this inhibition to approximately 60%. In no instance was thrombocytopenia prevented. 6 In vitro contractions of the actively sensitized lung strip are not fully accounted for by histamine, FPL 55712-inhibitable leukotrienes or Paf-acether, whereas in systemic anaphylaxis histamine and leukotrienes (inhibited respectively by mepyramine and by FPL 55712) have a significant role.

Section: Discussionmentioning

confidence: 99%

Histamine and leukotriene‐independent guinea‐pig anaphylactic shock unaccounted for by Paf‐acether

Detsouli

Lefort

Vargaftig

1985

“…Since the major mediator of anaphylactic bronchoconstriction in the guinea-pig is believed to be histamine (Collier & James, 1967;Ritchie, Sierchio, Capetola & Rosenthale, 1981) it was important to establish that the selected dose of pynlamine to be used in these studies (2 mg/kg) completely inhibited the changes in ventilatory pressure due to the released histamine. Thus a dose-response curve to pyrilamine (0.01-5.Omg/kg) was determined (Figure 3).…”

Section: Srs-a Mediated Bronchoconstrictionmentioning

confidence: 99%

An in vivo model for measuring antigen‐induced SRS‐A‐mediated bronchoconstriction and plasma S RS‐ A levels in the guinea‐pig

Anderson

O’Donnell

Simko

et al. 1983

1 Pharmacological modulation of antigen-induced anaphylaxis in actively sensitized guinea-pigs with intravenously administered indomethacin (10 mg/kg), pyrilamine (2.0 mg/kg) and propranolol (0.1 mg/kg) resulted in a delayed onset, slowly developing bronchoconstriction indicative of a slow-reacting substance of anaphylaxis (SRS-A) response. 2 Measurements of pulmonary mechanics on the drug-pretreated animals challenged with ovalbumin demonstrated a more prominent effect on dynamic compliance than resistance. This is consistent with the more potent effects of SRS-A on peripheral rather than central airways. 3 The slowly developing bronchoconstriction obtained after treatment with indomethacin, pyrilamine and propranolol was inhibited by the standard SRS-A antagonist, FPL 55712 and the SRS-A synthesis inhibitors, phenidone, BW 755C and nordihydroguaiaretic acid. 4 Plasma SRS-A levels were determined in guinea-pigs following antigen challenge. The appearance of SRS-A in the plasma preceded the onset of bronchoconstriction and SRS-A levels remained elevated throughout its development. Coincident with the inhibition of bronchoconstriction by the SRS-A synthesis inhibitor, phenidone, was a dose-dependent reduction in plasma SRS-A. The intravenous ED50 in each case was 4 mg/kg. 5This model of antigen-induced SRS-A-mediated bronchoconstriction should prove useful for the in vivo evaluation and development of therapeutics which regulate the synthesis of SRS-A.

“…This is mainly because of the relative ease with which immediate allergic bronchoconstriction can be provoked in this species, and the demonstrable role of other humoral factors (Collier & James, 1967), notably prostanoids and leukotrienes, in this process. These mediators, in particular leukotrienes, have been 'Present address: Institute of Pharmacological Science, University of Milan, 20129 Milan, Italy. 2Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological modulation of bronchial anaphylaxis induced by aerosol challenge in anaesthetized guinea‐pigs

Daffonchio

Lees

Payne

et al. 1987

Anaphylactic bronchoconstriction provoked by aerosol challenge, and its pharmacological modulation, has been investigated in anaesthetized pump‐ventilated guinea‐pigs actively sensitized to ovalbumin (OA). Aerosol challenge (OA 0.03–10 mg ml−1) provoked immediate bronchoconstriction, the degree of which, and its rate of development, was directly related to antigen concentration. Concomitant changes in heart rate and systemic arterial blood pressure following aerosol challenge were reduced compared with systemic (OA, 1 mg kg−1 i.v.) challenge. Unlike systemic challenge, aerosol challenge did not cause a concomitant fall in either circulating leukocyte or platelet count. When a submaximal (microshock) aerosol challenge stimulus (OA, 0.3 mg ml−1, 5 s) was employed, bronchoconstriction was markedly reduced by mepyramine (2 mg kg−1 i.v.). The residual component of bronchoconstriction was enhanced by indomethacin (10 mg kg−1 i.v.), an effect which was reversed by either BW755C (30 mg kg−1 i.v.) or FPL55712 (10 mg kg−1 i.v.). When a supramaximal (macroshock) aerosol challenge stimulus (OA, 10 mg ml−1, 5 s) was employed, bronchoconstriction was also markedly reduced by mepyramine. Residual bronchoconstriction was not altered by indomethacin, slowed but not reduced by indomethacin plus BW755C, and substantially reduced by indomethacin plus FPL55712. The successive incremental antagonism of anaphylactic bronchoconstriction by mepyramine and mepyramine plus indomethacin and FPL55712 indicates that the predominant mediators involved are histamine and leukotrienes, respectively. The failure of indomethacin plus BW755C to inhibit the mepyramine‐resistant bronchoconstriction provoked by OA macroshock may reflect the increased generation of leukotrienes via a 5‐lipoxygenase isoenzyme resistant to inhibition by BW755C. Aerosol challenge of actively sensitized anaesthetized guinea‐pigs by this method may be a useful model of human allergic bronchoconstriction, particularly when the effects of a drug given itself as an aerosol are being evaluated.