A novel mechanism for vasoconstrictor action of 8-isoprostaglandin F2 alpha on retinal vessels.
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.
Lahaie
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I
Department of Pediatrics, Research Center of Hôpital Sainte Justine, University of Montréal, Quebec.
Hardy
P
P
Hou
X
X
Hasséssian
H
H
Asselin
P
P
Lachapelle
P
P
Almazan
G
G
Varma
D R
DR
Morrow
J D
JD
Roberts
L J
LJ
Chemtob
S
S
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*
D028441:F2-Isoprostanes; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D002118:Calcium