title: Neural and myogenic effects of leukotrienes C4, D4, and E4 on canine bronchial smooth muscle.
abstract: The leukotrienes (LTs), referred to as the slow-reacting substance of anaphylaxis (SRS-A), are reported to have little or no activity in the canine airway. The objective of this study was to determine whether LTC4, LTD4, and LTE4 (10(-10)-10(-7) M) play a role in neuromuscular control of third- to fifth-order canine bronchi. In the presence of 1 microM indomethacin (Indo), canine bronchial smooth muscle contracted and was depolarized in a concentration-dependent manner by LTC4 or LTD4 but not by LTE4. LTC4 and LTD4 concentration-response curves were not significantly affected when conducted in the presence of any of the following: 10(-7) M propranolol (beta-adrenoceptor antagonist), 10(-6) M chlorpheniramine (H1-receptor antagonist), 10(-6) M ketanserin (nonselective 5-hydroxytryptamine receptor antagonist), 10(-7) M atropine (muscarinic receptor antagonist), and 10(-6) M tetrodotoxin (sodium channel blocker). LTC4 and LTD4 also potentiated electrical field-stimulated (EFS) excitatory junction potentials (EJPs), suggesting a possible prejunctional enhancement of acetylcholine release. In the absence of Indo, no postjunctional responses to LTC4 and LTD4 occurred. Endogenous prostaglandin E2 (PGE2) and 6-keto-PGF1 alpha (a stable metabolite of PGI2) levels from canine bronchi were significantly reduced by Indo. In the presence of Indo, addition of > or = 10(-8) M of PGE2 suppressed contractions to LTC4 and LTD4. These data suggest that the decrease in PGE2 and PGI2 production by Indo is sufficient to unmask the excitatory postjunctional actions of LTC4 and LTD4 on bronchial smooth muscle. Serine borate (45 mM; an inhibitor of gamma-glutamyl transpeptidase, which prevents the conversion of LTC4 to LTD4) increased selectively the contractile activity of LTC4. L-Cysteine (3 mM; an inhibitor of an aminopeptidase, which prevents the conversion of LTD4 to LTE4) enhanced the contractile responses to LTD4. Serine borate increased the amplitude and duration of EFS contractions and potentiated the amplitude of EFS EJPs; the last effects were prevented by nordihydroguaiaretic acid. These and other studies suggest that LTs are synthesized by canine bronchi and have receptors on canine bronchial smooth muscle but that contractions to LTC4 and LTD4 in the canine airway are usually not observed because of the presence of inhibitory prostanoids (PGE2 and PGI2). We suggest that decreases in PGE2 and PGI2 in models of airway disease in combination with increases in LTC4, LTD4, and thromboxane A2 may contribute to airway hyperresponsiveness in vitro.
authors.affiliation: Department of Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Abela
authors.forename: E E
authors.initials: EE
authors.lastname: Daniel
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000294:innervation*; D016084:Bronchoconstriction / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists; D017997:Leukotriene C4 / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology*; D017999:Leukotriene E4 / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D009420:Nervous System / Q000187:drug effects; D011863:Radioimmunoassay
chemical_list: D020024:Leukotriene Antagonists; D017997:Leukotriene C4; D015121:6-Ketoprostaglandin F1 alpha; D017998:Leukotriene D4; D017999:Leukotriene E4; D015232:Dinoprostone