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Vol. 295, Issue 2, 506-511, November 2000
Asthma Research Group, Father Sean O'Sullivan Research Centre,
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
(L.J.J., M.P., S.N., A.C., G.C.); Toronto Lung Transplant Program,
Division of Thoracic Surgery, University of Toronto, Ontario, Canada
(S.K.); and Department of Obstetrics and Gynecology, McMaster
University, Hamilton, Ontario, Canada (D.J.C.)
Isoprostanes are generated nonenzymatically during free
radical-mediated lipid peroxidation, and are used clinically and
experimentally as markers of oxidative stress. However, their
biological effects are poorly understood. We examined the effects of
seven different 8-isoprostanes in human and canine airway smooth
muscles. In large order airways (carina) of the human, several
isoprostanes evoked powerful contractions, with 8-iso-prostaglandin
(PG) E2, 8-iso-PGF1
, and
8-iso-PGF2 being the most efficacious (and
with logEC50 values of 7.0, 5.9, and 6.2 µM,
respectively). These contractions were sensitive to the prostanoid TP
receptor antagonist ICI 192,605 (0.1-1 µM), but not the EP
prostanoid receptor antagonist AH-6809 (50 µM), or the leukotriene
receptor antagonists monteleukast or ICI 198,615 (both 1 µM).
Qualitatively similar results were obtained in small order human
airways (<2 mm o.d.), except that the isoprostanes were generally
slightly less potent. None of the isoprostanes had any marked
excitatory effect in canine airways. In carbachol-preconstricted
tissues (pretreated with ICI 192,605 to block any potential
contraction), several isoprostanes completely relaxed canine airways:
8-iso-PGE1, 8-iso-PGE2, and
8-iso-PGF3 were the most potent,
with logIC50 values of 6.9, 6.9, and 5.7, respectively.
Only 8-iso-PGF3 relaxed human airways
(logIC50 = 4.9). Our results show that several
8-isoprostanes are highly biologically active in human and canine
airways, evoking both excitatory and/or inhibitory effects, and that
these effects are compound, species, and tissue dependent.
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