ovalbumin and pobilukast

Ovalbumin at low doses (0.1 microg/ml) caused pronounced relaxations in the precontracted pulmonary arteries of sensitized guinea pigs but, at high doses, (1-100 microg/ml) the relaxations were blunted by the contractions. The relaxations in response to ovalbumin challenge were related to histamine, which is released during the immediate hypersensitivity reaction, because they were almost blocked by mepyramine (10(-5) M) plus cimetidine (10(-4) M) pretreatment and never observed in unsensitized animal arteries. Additionally, the inhibition of relaxations by endothelium removal or N(G)-nitro-L-arginine (L-NOARG, 10(-4) M) treatment implies that the phenomenon requires endothelial nitric oxide synthesis. However, the contractions appear to depend on leukotriene production since they were markedly blocked in the presence of 2(S)-hydroxy-3(R)-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl)pheny l]- propanoic acid (SKF 104353, 10(-5) M), a leukotriene receptor antagonist. These results indicate that ovalbumin-induced nitric oxide and histamine H(2) receptor dependent relaxations in pulmonary artery may have an important role in the recovery of the increased pulmonary vascular resistance during the hypersensitivity reaction.

Topics: Animals; Dicarboxylic Acids; Dose-Response Relationship, Drug; Endothelins; Endothelium, Vascular; Enzyme Inhibitors; Female; Guinea Pigs; Histamine H1 Antagonists; Hypersensitivity, Immediate; In Vitro Techniques; Leukotriene Antagonists; Male; Nitric Oxide Synthase; Nitroarginine; Ovalbumin; Pulmonary Artery; Pyrilamine; Vasoconstriction; Vasodilation

We characterized the kinetics of and determined the mediators involved in antigen-induced contraction of pulmonary arteries (PA) and lung parenchyma isolated from actively sensitized guinea pigs. Ovalbumin (10(-2) mg/ml) induced contractions of PA rings, which reached maximum amplitude by 2 min and decayed to 50% of maximum by 4-6 min. Pyrilamine (10(-6) M) delayed the onset of contraction and decreased the peak of the response by > 50%. Metiamide (10(-4) M) partially reversed this effect. The addition of indomethacin (10(-6) M) to the combination of pyrilamine and metiamide had no significant effect. The further addition of the leukotriene (LT) D4/LTE4 receptor antagonist SKF 104353 (10(-5) M) reduced the contraction by > 80%. The maximum amplitude of antigen-induced contraction of parenchymal strips was reached by 15 min and was sustained for > 60 min. In these tissues, SKF 104353 inhibited the contraction by approximately 35%, but the histamine receptor antagonists and indomethacin had no significant effect. These results suggest that both histamine and sulfidopeptide LTs mediate antigen-induced contraction of PA, whereas sulfidopeptide LTs, but not histamine, are involved in the parenchymal response.

Topics: Animals; Antigens; Dicarboxylic Acids; Guinea Pigs; In Vitro Techniques; Indomethacin; Lung; Male; Metiamide; Muscle Contraction; Ovalbumin; Pulmonary Artery; Pyrilamine; SRS-A; Vasoconstriction

We determined the pulmonary obstructive response to aerosolized antigen challenge, and its sensitivity to antagonists of specific lipid mediators, in IgG, passively sensitized (IgG1-PS) guinea pigs. Antiovalbumin (OA)-IgG1 was isolated by affinity chromatography from serum derived from actively immunized Hartley guinea pigs. Propranolol and pyrilamine pretreated, IgG1-PS guinea pigs were challenged with aerosolized antigen and pulmonary obstruction was quantified by measurements of excised lung gas volume (ELGV). ELGV increased between 150 and 1,035% in a dose-proportional fashion with increasing antigen exposure (0.001 to 0.1% nebulizer concentration). The leukotriene antagonists ICI-204,219 and SKF-104,353 exhibited dose-proportional inhibitions in antigen-induced elevations in ELGV, inhibiting up to 65 and 87% at the maximal concentrations examined. Similarly, the platelet-activating factor (PAF) antagonists WEB-2086 and L-659,989 inhibited antigen-induced elevations in ELGV, inhibiting up to 94 and 59% at the maximal concentrations examined. In contrast, the cyclooxygenase (CO) inhibitor piroxicam significantly enhanced (p less than 0.05) the OA-induced elevations in ELGV. Aerosolized PAF challenge produced dose-proportional elevations in ELGV that were significantly inhibited by the LTD, antagonist ICI-204,219 (38 and 43% inhibition) and the CO inhibitor piroxicam (62 and 48% inhibition) in sensitized and nonsensitized animals, respectively. We hypothesize that IgG1-dependent airway obstruction is mediated in part by LTD, produced in response to PAF generation.

Topics: Acute Disease; Animals; Azepines; Bronchoconstriction; Dicarboxylic Acids; Dose-Response Relationship, Drug; Furans; Guinea Pigs; Immunization; Immunoglobulin G; Indoles; Lipids; Lung; Male; Ovalbumin; Phenylcarbamates; Piroxicam; Platelet Activating Factor; Propranolol; Pyrilamine; Respiratory Hypersensitivity; SRS-A; Sulfonamides; Tosyl Compounds; Triazoles

The involvement of peptidoleukotrienes (LTs) in mediating the increase in microvascular permeability associated with experimental cutaneous immediate hypersensitivity was studied by examining the effect of SK&F 104353, a potent and selective LT-antagonist, on the response evoked by graded, intradermal injections of antigen. SK&F 104353, employed at doses that profoundly blocked LTC4, LTD4 and LTE4 responses, significantly reduced the response produced by experimental cutaneous immediate hypersensitivity. The response to the lowest antigen dose (0.1 microgram) was, however, entirely insusceptible to SK&F 104353. The effect of SK&F 104353 was also examined in combination with a pyrilamine-cimetidine dosing regimen sufficient to remove the histaminergic component of cutaneous immediate hypersensitivity. The non-histaminergic component associated with higher antigen doses (10 and 100 micrograms) was significantly reduced but not abolished by SK&F 104353; the non-histaminergic component associated with low antigen doses (0.1 and 1 microgram) was not susceptible to SK&F 104353. Thus, the increase in cutaneous microvascular permeability evoked by immediate hypersensitivity appears to comprise three components: (1) A histaminergic response apparent for all antigen doses; (2) a LT-mediated component which is manifest in response to high antigen doses; (3) a third, unidentified component that is present for the entire antigen dose-range but contributes less to the overall response when high antigen doses are used. A distinct non-histaminergic, non-leukotriene mediated component was not a feature of conjunctival immediate hypersensitivity. SK&F 104353 administered in combinatio with pyrilamine-cimetidine virtually abolished the response with a small residual remaining only for the highest antigen dose. In further contrast to cutaneous immediate hypersensitivity, SK&F 104353 alone was comparatively ineffective in type 1 allergic conjunctivitis. This difference in susceptibility to SK&F 104353 appears to reflect the type of histamine-LTD4 interactive effect on microvascular permeability. Histamine and LTD4 were additive in terms of cutaneous microvascular permeability. In the conjunctiva, histamine and LTD4 appeared mutually exclusive in that the level of response produced by the combination tended not to exceed that of the single component which caused the greater effect.

Topics: Animals; Capillary Permeability; Chromium Radioisotopes; Cimetidine; Conjunctiva; Dicarboxylic Acids; Guinea Pigs; Histamine; Hypersensitivity, Immediate; Iodine Radioisotopes; Leukotrienes; Male; Ovalbumin; Pyrilamine; Skin

In this report, we describe the in vitro and in vivo pharmacologic profile of 2(S)-hydroxy-3(R)-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl)pheny l]- propanoic acid (SK&F 104353) in guinea pig and human airways. In the isolated guinea pig trachea, SK&F 104353 was a potent, competitive antagonist of leukotriene (LT) D4-induced contractions (pA2 = 8.6). In contrast, SK&F 104353 produced little effect on LTC4 concentration-response curves under conditions where the bioconversion of LTC4 to LTD4 was inhibited. LTE4-induced contractions in guinea pig trachea were sensitive to inhibition by SK&F 104353 (pKB greater than 8.9). SK&F 104353 (10 microM) had no intrinsic contractile activity and was without effect on contractions produced by KCl, histamine, prostaglandin D2, platelet-activating factor or U-44069 in guinea pig trachea. Furthermore, unlike other purported LT antagonists, LT 171883 and FPL 55712, SK&F 104353 (30 microM) did not inhibit cyclic nucleotide phosphodiesterase activity measured in homogenates from canine tracheal smooth muscle. In the isolated human bronchus, SK&F 104353 produced concentration-dependent rightward shifts in LTD4 concentration-response curves and, unlike in guinea pig trachea, was an effective antagonist of LTC4-induced contractions with a pKB of 8.0 to 8.4. This provides further evidence that, in contrast to guinea pig airways, responses produced by LTC4 and LTD4 in human bronchus appear to be mediated via the same LT receptor population. SK&F 104353 was also an effective antagonist of LTE4-induced responses in human bronchus (pKB greater than 8.2).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Adult; Animals; Borates; Bronchi; Child; Dicarboxylic Acids; Female; Guinea Pigs; Humans; Immunoglobulin E; In Vitro Techniques; Male; Muscle Contraction; Ovalbumin; Pyrilamine; Receptors, Leukotriene; Receptors, Prostaglandin; Serine; SRS-A; Trachea