Lahaie I, Hardy P, Hou X, Hasséssian H, Asselin P, Lachapelle P, Almazan G, Varma D R, Morrow J D, Roberts L J, Chemtob S
Department of Pediatrics, Research Center of Hôpital Sainte Justine, University of Montréal, Quebec.
Am J Physiol. 1998 May;274(5):R1406-16. doi: 10.1152/ajpregu.1998.274.5.R1406.
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.
我们使用视频成像技术，研究了8-异前列腺素F2α（8-iso-PGF2α）对仔猪视网膜血管系统的影响。8-iso-PGF2α能有效收缩（EC50 = 5.9±0.5 nM）视网膜血管。环氧合酶抑制剂吲哚美辛、血栓素合酶阻滞剂CGS-12970、血栓素受体拮抗剂L-670596以及非电压依赖性受体操纵的Ca2+通道假定抑制剂SKF-96365可完全拮抗这些作用；ETA受体阻滞剂BQ-123和内皮素转化酶抑制剂磷酰胺也可部分减弱8-iso-PGF2α的收缩作用，但L型电压门控Ca2+通道阻滞剂硝苯地平对其影响可忽略不计。相应地，8-iso-PGF2α可促使视网膜制剂释放内皮素，而SKF-96365可显著减少内皮素的释放。8-iso-PGF2α还可增加视网膜及培养的内皮细胞中血栓素的生成，但对视网膜血管平滑肌细胞无此作用；吲哚美辛、CGS-12970、SKF-96365和乙二醇双四乙酸可阻断8-iso-PGF2α的这些作用，但硝苯地平无此作用。8-iso-PGF2α还可增加视网膜内皮细胞中的Ca2+瞬变，SKF-96365和乙二醇双四乙酸可抑制这种瞬变，但硝苯地平无此作用，而在平滑肌细胞中，U-46619可刺激Ca2+瞬变升高，8-iso-PGF2α则无此作用。最后，H2O2 + FeCl2（体外）和缺氧后再给氧（体内）可刺激视网膜中8-iso-PGF2α的形成。总之，8-iso-PGF2α诱导的视网膜血管收缩是由环氧合酶生成血栓素介导的，在较小程度上是由Ca2+进入细胞后内皮素介导的，可能是通过受体操纵的通道。视网膜对8-异前列腺素的血管收缩可能在缺血性视网膜病变的发生中起作用。
