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Full Text PDF (221K) Effects of Isopropyl Unoprostone on Rabbit Ciliary Artery Eri Hayashi,* Takeshi Yoshitomi,† Hitoshi Ishikawa,* Ryoko Hayashi* and Kimiya Shimizu* *Department of Ophthalmology, Kitasato University School of Medicine, Kanagawa, Japan; †Department of Ophthalmology, Wakayama Medical College, Wakayama, Japan Purpose: Isopropyl unoprostone (unoprostone), a prostaglandin F2␣ (PG F2␣)-related com- pound, is widely used for treatment of glaucoma in Japan and is reported to have effects on ocular circulation. To investigate the action of this drug, we have studied the effect of uno- prostone on the isolated rabbit ciliary artery. Methods: Under microscopic observation, ciliary arteries were prepared from rabbit eyes and mounted in a myograph system. The effects of unoprostone on the isolated rabbit ciliary artery were investigated in vitro using isometric tension recordings. Results: Exogenously applied PG F2␣ but not unoprostone evoked contraction in the rabbit ciliary artery. After precontraction with excess-[K]o solution, unoprostone evoked dose-depen- dent relaxation. The relaxation was not blocked by 10 ␮M/L NG-nitro-L-arginine methylester (L-NAME), 1 ␮M/L 8-37 calcitonin gene-related peptide (8-37 CGRP) or 10 ␮M/L in- domethacin. Moreover, unoprostone could induce relaxation even in preparations without endothelium. The relaxation induced by diltiazem was greater in muscle precontracted in ex- ␮ cess-[K]o solution than that precontracted by 10 M/L histamine. On the other hand, uno- prostone induced a similar amplitude of relaxation in muscles precontracted by either drug. Conclusions: These results indicate that unoprostone acts directly to relax rabbit ciliary ar- tery. The relaxation was not dependent on the endothelium and was not caused by intrinsic prostoglandins CGRP, or nitric oxide. Moreover, the relaxation was different from that caused by a Ca2ϩ antagonist. The mechanism for this relaxation is not yet determined. Jpn J Ophthalmol 2000;44:214–220 © 2000 Japanese Ophthalmological Society Key Words: Ciliary artery, isopropyl unoprostone, ocular blood flow, relaxation, vascular smooth muscle. Introduction flow, which has been studied in vivo by many investi- gators.8–11 8 Although it is generally accepted that increased Nishi et al reported that topical applica- intraocular pressure is a major risk factor in glau- tion of unoprostone increased end-diastric velocity coma, vascular factors are also considered to be im- of both the central retinal artery and the short poste- portant in the pathogenesis of optic nerve damage rior ciliary artery in normal volunteers using color and visual field loss,1 especially in patients with nor- Doppler ultrasound imaging. Topical application of mal tension glaucoma.2,3 Unoprostone, a prostoglan- unoprostone is also reported to increase choroidal blood flow in rabbits, as determined by the hydrogen din (PG) F ␣-related compound, has been widely 2 clearance method.9,10 Topical application of unopro- used for the treatment of glaucoma in Japan.4 The drug is thought to reduce intraocular pressure by in- stone increased normalized blur (NB; indicator of retinal blood flow rate) in humans using the laser creasing conventional or uveoscleral outflow.5–7 This speckle microcirculation analyzer.11 drug is reported to have some effect on ocular blood These reports support the idea that unoprostone can increase ocu- lar blood flow. However, the underlying mechanisms Received: March 15, 1999 of this effect are not yet clear. In an attempt to clar- Correspondence and reprint requests to: Takeshi YOSHITOMI, MD, Department of Ophthalmology, Wakayama Medical College, ify the mechanisms involved in the effectiveness of 81 1-1 Kimiidera, Wakayama, Wakayama, 641-0012, Japan unoprostone on the ocular circulation, we have in- Jpn J Ophthalmol 44, 214–220 (2000) © 2000 Japanese Ophthalmological Society 0021-5155/00/$–see front matter Published by Elsevier Science Inc. PII S0021-5155(99)00215-4 E. HAYASHI ET AL. 215 UNOPROSTONE ON RABBIT CILIARY ARTERY vestigated the effects of this drug on ciliary arterial USA), isopropyl 20–ethyl-9 ␣, 11 ␣-dihydroxy-15-keto- smooth muscle in vitro using isometric tension re- cis-⌬5-prostanoate (unoprostone; Ueno Seiyaku, Os- cording methods. aka), NG-nitro-L-arginine methylester (L-NAME), diltiazem (Wako Pure Chemical, Osaka), 8-37 calci- Materials and Methods tonin gene-related peptide (8-37 CGRP; Peptide In- stitute, Osaka) All experiments were performed according to the ARVO Resolution on the Use of Animals in Re- search. Male albino rabbits weighing 2–3 kg were Results sacrificed with an overdose of intravenous pentobar- Mechanical Responses to PG F2␣ bital sodium (Abbott, North Chicago, IL, USA). As unoprostone is a PG F ␣-related compound, we The eyes were immediately enucleated with a maxi- 2 investigated the effect of PG F ␣ mum length of optic nerve and placed in oxygenated 2 itself on rabbit cili- ␣ evoked contraction beginning at a Krebs solution of the following composition (mM): ary artery. PG F2 concentration of 1 ␮M/L. As shown in Figure 1a, 10 NaCl 94.8, KCl 4.7, MgSO4 1.2, CaCl2 2.5, KH2PO4 ␮ M/L PG F2␣ evoked an initial twitch contraction 1.2, NaHCO3 25.0, and glucose 11.7. The ciliary artery with connective tissue was care- followed by a slow contraction in rabbit ciliary ar- fully dissected free from the optic nerve. Vascular tery. The contraction was also observed when the solutions. ring segments (150–300 ␮m in diameter, 1–2 mm muscle was precontracted by excess-[K]o Relaxation was not observed in any preparation length) were cut from the distal section of the ciliary tested (4 cases). artery and mounted in a double myograph system (JP Trading, Denmark)12 under microscopic obser- vation. The myograph system allowed direct deter- mination of vessel isometric tension while the inter- Mechanical Responses to Unoprostone nal circumference was controlled. The blood vessels Unoprostone had no effect on the mechanical prop- were equilibrated for 30 minutes in oxygenated erties of rabbit ciliary artery up to a concentration of ␮ Krebs solution with 5% CO2 and 95% O2 and main- 10 M/L (Figure 1b). However, after precontraction tained at 38ºC. For active tension development, the by excess-[K]o solution, application of unoprostone blood vessels were stretched to their optimal lumen elicited relaxation in a dose-dependent manner, and ϫ diameter, IO, corresponding to 0.9 I100, where I100 the minimum concentration of this drug required to is the diameter the vessels would have in situ if sub- generate relaxation was 1 ␮M/L (Figure 1b). Figure 2a jected to a passive transmural pressure of 13.3 kPa shows dose–response relationships of unoprostone (100 mm Hg).13 on rabbit ciliary artery precontracted with excess- After the mounting and equilibration period, the [K]o solution, where the amplitude of contraction amplitudes of three successive contractions evoked evoked by excess-[K]o solution was defined as 100%. by excess-[K]o solutions were measured at 10-minute To further investigate the mechanisms on the re- intervals to establish preparation viability and stabil- laxation induced by unoprostone, effects of a nitric ity. Excess-[K]o solutions were prepared by replac- oxide synthase (NOS) inhibitor (L-NAME), in- ing equimolar NaCl with KCl. During a contraction domethacin, and the CGRP antagonist, 8-37 CGRP, ␮ evoked by excess-[K]o solutions, 10 M/L carbachol were studied. Figure 2a shows the dose–response re- was shown to induce relaxation in all preparations lationships of unoprostone, in the presence of 10 indicating that the preparations had an intact endot- ␮M/L indomethacin, 10 ␮M/L L-NAME, or 1 ␮M/L helium. 8-37 CGRP. None of these drugs had an inhibitory The endothelium was removed by gently rubbing effect on the dose–response curves, which indicates the inside of the vessel with a human scalp hair in- that intrinsic NO, PG, or CGRP are not responsible serted through the lumen. Successful denudation of for the unoprostone-induced relaxation. the vessel was confirmed by the lack of the relaxant effect of carbachol in vessels precontracted by ex- cess-[K]o solutions. Role of Endothelium in Unoprostone-Induced Relaxation Chemicals To investigate the role of the endothelium in uno- The following drugs were used: carbachol hydro- prostone-induced relaxation, the effect of unopros- chloride, histamine (Sigma Chemical, St. Louis, MO, tone was compared in preparations with intact en- 216 Jpn J Ophthalmol Vol 44: 214–220, 2000 ␮ ␮ Figure 1. (a) Effects of 10 M/L prostaglandin (PG) F2␣ on rabbit ciliary artery (left). Effects of 10 M/L PG F2␣ on rabbit ciliary artery that was precontracted by excess-[K]o solution (right). Vertical scale shows active force in millinewtons (mN). (b) Effects of 10 ␮M/L unoprostone on rabbit ciliary artery (left). Effects of multiple applications of unoprostone on rabbit ciliary artery that was precontracted by excess-[K]o solution (right). dothelium and in preparations from which endothelium without the endothelium (Figures 2b, c). Unopros- was mechanically removed. Carbachol induced re- tone, on the other hand, provoked relaxation in laxation of the ciliary artery muscle with intact en- preparations both with and without endothelium. dothelium, and it had no effect in the preparation These results indicate that the relaxation induced by E. HAYASHI ET AL. 217 UNOPROSTONE ON RABBIT CILIARY ARTERY ᭹ Figure 2. (a) Dose–response relationships of unoprostone ( ) on rabbit ciliary artery precontracted with excess-[K]o solu- tion, where the relative amplitude of contraction evoked by excess-[K]o solution was defined as 100%. Unoprostone relax- ation was not affected by pretreatment with 10 ␮M/L indomethacin (ᮀ), 10 ␮M/L NG-nitro-L-arginine methylester (᭿), and 1 ␮M/L 8-37 calcitonin gene-related peptide (⌬). Each point is mean and vertical bars indicate 2 ϫ SD (n ϭ 6 to 8). ␮ (b) Effects of carbachol (10 M/L) on rabbit ciliary artery that was precontracted by excess-[K]o solution (intact endothe- lium preparation).
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