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T. Yoshitomi, K. Yamaji, H. Ishikawa, Y. Ohnishi; Mechanisms of Vasodilatory Effect of Unoprostone Isopropyl on Isolated Rabbit Ciliary Artery . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2083.
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Purpose: Unoprostone isopropyl (unoprostone) is a PG F2α-related compound used for treatment of glaucoma. To clarify the vasodilatory mechanisms of unoprostone, we investigated the effect of this drug and its oxidized metabolites on isolated rabbit ciliary artery in vitro. Methods: Under the dissecting microscope, ciliary arteries were prepared from rabbit eyes and superfused with Krebs incubation medium after being mounted in a myograph system. Unoprostone and pharmacologically related agents were added to the superfusion medium of pre-contracted arteries, and the vasodilatory effects were determined by isometric tension recording methods. Results: Unoprostone induced dose-dependent (1µM to 30µM) relaxation in ciliary arteries that were pre-contracted with high-K solution, 10 µM histamine or 10 µM PG F2α. The unoprostone oxidation metabolites M1 and M2 had no relaxant effect on vessels pre-contracted with high-K solutions. Inhibition of adenylyl cyclase with 9-(Tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22536), gyanylyl cyclase with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), or maxi-K channels with iberiotoxin had no effect on the unoprostone-induced relaxation. Transient contractions were evoked by removal and re-introduction of Ca2+to the incubation medium. Unoprostone had no effect on these transients. However, 1-[b-(3-(4-methoxy-phenyl)propoxy)-4-methoxyphenethyl]-1H-imidazole hydrochloride (SKF96365), a general Ca2+ channel blocker, evoked relaxation with a magnitude and rate of onset that were similar to that achieved with unoprostone. Conclusions: Unoprostone relaxed pre-contracted rabbit ciliary artery. M1 and M2, oxidation metabolites of unoprostone that lower IOP, had no effect. Thus, the mechanism by which unoprostone lowers IOP differs from that by which it relaxes vascular smooth muscle. The ciliary artery relaxation induced by unoprostone was not dependent on adenylyl cyclase, guanylyl cyclase, maxi-K channels, or voltage-dependent Ca2+ channels. However relaxation was dependent on Ca2+ entry and may be mediated through unoprostone-sensitive capacitative Ca2+ channels.
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