Chest
Clinical InvestigationsLeukotriene-associated Toxic Oxygen Metabolites Induce Airway Hyperreactivity
Section snippets
Materials and Methods
Isometric tension of guinea pig trachealis to agonists was obtained after equilibration at a resting tension of 2.0 g for 60 min at 37°C in Krebs-Henseleit (KH) buffer gassed with 95 percent O2-5 percent CO2. KH contained either physiologic extracellular calcium (2.5 mM)E or was calcium-free/low calcium (OmM). Isometric tension methods and KH composition have been recently detailed.4 Cumulative histamine concentration-response curves by successive microliter increments were acquired in a paired
Results
Cumulative histamine concentration-tension responses in 2.5 mM (Ca++)E following LTD4 (10−9 to 10−7M) incubation were hyperresponsive, exhibiting an increase in both maximal tension and a leftward shift of the EC50 (Fig 1; Table 1). The maximal mg isometric tension values for histamine alone and for histamine with LTD4 (10−7M) were 1,710 ± 195 and 2,308 ± 305, respectively (p<0.01). Although acetylcholine alone (10−5M) increased the isometric tension baseline by 53 percent (Fig 1), the maximal
Discussion
This study confirms an enhancement of histamine contractures upon guinea pig airways smooth muscle induced by leukotriene-D4. The sulfidopeptide leukotrienes are spasmogenic upon airways smooth muscle with effects upon both small and central airways. In human airways they are 200 to 3,000 times more potent than histamine, with several studies indicating their extremely potent bronchoconstrictor activity.2, 10, 11, 12, 13
It is currently not clear whether leukotrienes per se cause hyperreactivity
References (37)
Toxic oxygen products alter calcium homeostasis in an asthma model
J Allergy Clin Immunol
(1985)- et al.
Leukotriene effect in airways smooth muscle: calcium dependency and verapamil inhibition
Prostaglandins Leukotrienes Med
(1983) - et al.
Enhancement of chemotactic factor-stimulated neutrophil oxidative metabolism by leukotriene B4
Blood
(1984) - et al.
Hyperreactivity of airways smooth muscle produced in vitro by leukotrienes
Prostaglandins Leukotrienes Med
(1983) Mediators of immediate hypersensitivity
J Allergy Clin Immunol
(1983)- et al.
Studies on the mechanism of superoxide release from human neutrophils stimulated with arachidonate
J Biol Chem
(1984) - et al.
Comparative biological activities by synthetic leukotriene B4 and its ω-oxidation products
Prostaglandins
(1983) - et al.
Airway responses to aerosolized leukotriene D4 (LTD4) in normal and Ascaris reactors primates
Prostaglandins
(1985) - et al.
Pharmacologic receptors for the leukotrienes
Biochem Pharmacol
(1984) - et al.
Superoxide ion as active intermediate in the auto-oxidation of ascorbate by molecular oxygen
J Biol Chem
(1983)
Effects of ascorbic acid and indomethacin on the airways of healthy male subjects with and without induced bronchoconstriction
J Allergy Clin Immunol
Prevention of free radical-mediated vascular permeability increases in lung using superoxide dismutase
Chest
The actions of 5-, 12-, and 15-HETE on tracheobronchial smooth muscle
Prostaglandins Leukotrienes Med
Mast cell-dependent inflammatory mediators and their putative role in bronchial asthma
Clin Sci
Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro.
Proc Natl Acad Sci
Cumulative dose-response curves. II. Techniques for the making of dose-response curves in isolated organs and the evaluation of drug parameters
Arch Int Pharmacodyn Ther
Activity and activation of the granulocyte superoxide-generating system
Blood
Some quantitative uses of drug antagonists
Br J Pharmacol
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Supported in part by a grant from the Foundation for Research in Bronchial Asthma and Related Disorders.
Manuscript received June 27; revision accepted November 4.