Excitatory and inhibitory actions of isoprostanes in human and canine airway smooth muscle.
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) E(2), 8-iso-PGF(1 alpha), and 8-iso-PGF(2 alpha) being the most efficacious (and with logEC(50) values of 7.0, 5.9, and 6.2 microM, respectively). These contractions were sensitive to the prostanoid TP receptor antagonist ICI 192,605 (0.1-1 microM), but not the EP prostanoid receptor antagonist AH-6809 (50 microM), or the leukotriene receptor antagonists monteleukast or ICI 198,615 (both 1 microM). 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-PGE(1), 8-iso-PGE(2), and 8-iso-PGF(3 alpha) were the most potent, with logIC(50) values of 6.9, 6.9, and 5.7, respectively. Only 8-iso-PGF(3 alpha) relaxed human airways (logIC(50) = 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.
Janssen
L J
LJ
Asthma Research Group, Father Sean O'Sullivan Research Centre, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. janssenl@fhs.csu.mcmaster.ca
Premji
M
M
Netherton
S
S
Catalli
A
A
Cox
G
G
Keshavjee
S
S
Crankshaw
D J
DJ
D000818:Animals; D001980:Bronchi / Q000187:drug effects*; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D028441:F2-Isoprostanes; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D028421:Isoprostanes; D007700:Kinetics; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011458:Prostaglandins E / Q000494:pharmacology*; D011460:Prostaglandins F / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects*
D028441:F2-Isoprostanes; D028421:Isoprostanes; D011458:Prostaglandins E; D011460:Prostaglandins F; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D015232:Dinoprostone; C011987:8-isoprostaglandin E2