title: A novel mechanism for vasoconstrictor action of 8-isoprostaglandin F2 alpha on retinal vessels.
abstract: Using a video-imaging technique, we characterized the effects of 8-isoprostaglandin F2 alpha (8-iso-PGF2 alpha) on retinal vasculature from piglets. 8-Iso-PGF2 alpha potently contracted (EC50 = 5.9 +/- 0.5 nM) retinal vessels. These effects were completely antagonized by the cyclooxygenase inhibitor indomethacin, the thromboxane synthase blocker CGS-12970, the thromboxane receptor antagonist L-670596, and the putative inhibitor of the non-voltage-dependent receptor-operated Ca2+ pathway SKF-96365; constrictor effects of 8-iso-PGF2 alpha were also partly attenuated by the ETA-receptor blocker BQ-123 and an inhibitor of endothelin-converting enzyme, phosphoramidon, but was negligibly affected by the L-type voltage-gated Ca2+ channel blocker nifedipine. Correspondingly, 8-iso-PGF2 alpha elicited endothelin release from retinal preparations, which was markedly reduced by SKF-96365. 8-Iso-PGF2 alpha also increased thromboxane production in the retina and cultured endothelial cells, but not on retinovascular smooth muscle cells; these effects of 8-iso-PGF2 alpha were blocked by indomethacin, CGS-12970, SKF-96365, and EGTA, but not by nifedipine. 8-Iso-PGF2 alpha also increased Ca2+ transients in retinal endothelial cells, which were inhibited by SKF-96365 and EGTA, but not by nifedipine, whereas in smooth muscle cells U-46619, but not 8-iso-PGF2 alpha, stimulated a rise in Ca2+ transients. Finally, H2O2 + FeCl2 (in vitro) and anoxia followed by reoxygenation (in vivo) stimulated formation of 8-iso-PGF2 alpha in the retina. In conclusion, 8-iso-PGF2 alpha-induced retinal vasoconstriction is mediated by cyclooxygenase-generated formation of thromboxane and, to a lesser extent, by endothelin after Ca2+ entry into cells, possibly through receptor-operated channels. Retinal vasoconstriction to 8-isoprostanes might play a role in the genesis of ischemic retinopathies.
authors.affiliation: Department of Pediatrics, Research Center of Hôpital Sainte Justine, University of Montréal, Quebec.
authors.forename: I
authors.initials: I
authors.lastname: Lahaie
authors.forename: P
authors.initials: P
authors.lastname: Hardy
authors.forename: X
authors.initials: X
authors.lastname: Hou
authors.forename: H
authors.initials: H
authors.lastname: Hasséssian
authors.forename: P
authors.initials: P
authors.lastname: Asselin
authors.forename: P
authors.initials: P
authors.lastname: Lachapelle
authors.forename: G
authors.initials: G
authors.lastname: Almazan
authors.forename: D R
authors.initials: DR
authors.lastname: Varma
authors.forename: J D
authors.initials: JD
authors.lastname: Morrow
authors.forename: L J
authors.initials: LJ
authors.lastname: Roberts
authors.forename: S
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D028441:F2-Isoprostanes; D012171:Retinal Vessels / Q000187:drug effects* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D028441:F2-Isoprostanes; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D002118:Calcium