Abstract
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-PGF1α, and 8-iso-PGF2α 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-PGF3α were the most potent, with logIC50 values of 6.9, 6.9, and 5.7, respectively. Only 8-iso-PGF3α 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.
Footnotes
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Send reprint requests to: Dr. L. J. Janssen, Department of Medicine, McMaster University, 50 Charlton Ave. East, Hamilton, Ontario, Canada, L8N 4A6. E-mail:janssenl{at}fhs.csu.mcmaster.ca
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↵1 This study was supported by an operating grant and a Scientist Award from the Medical Research Council of Canada (to L.J.J.).
- Abbreviations:
- PG
- prostaglandin
- HUA
- human umbilical artery
- PSS
- physiological salt solution
- Received April 4, 2000.
- Accepted July 11, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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