[Show abstract][Hide abstract] ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population, and the prevalence of the disease increases exponentially with every decade after the age of 50 years. While VEGF inhibitors are promising drugs for treating patients with ocular neovascularization, there are limitations to their potential for improving vision in AMD patients. Thus, future therapies are required to have the potential to improve visual outcomes. This paper will summarize the future strategies and therapeutic targets that are aimed at enhancing the efficacy and duration of effect of antiangiogenic strategies.
Preview · Article · Feb 2015 · Journal of Ophthalmology
[Show abstract][Hide abstract] ABSTRACT: Abstract Purpose: To clarify the mechanism of prostaglandin (PG) analogue-dependent relaxation in ciliary arteries from wild-type (WT) and PG receptor-deficient mice. Methods: The intracellular-free calcium concentration ([Ca(2+)](i)) in isolated WT mouse ciliary arteries was measured by fluorescence photometry. Reduction of [Ca(2+)](i) leading to vascular relaxation by PG analogues latanoprost, isopropyl unoprostone, or tafluprost was compared to the maximum increase of [Ca(2+)](i) by 50 mM KCl. The cyclooxygenase inhibitor indomethacin and the NO synthase inhibitor N(G)-nitro-(L)-arginine methylester ((L)-NAME) were added to investigate the involvement of vascular endothelial factors. Moreover, PG analogue-dependent reduction of [Ca(2+)](i) was measured in ciliary artery strips from FP, EP1, EP2, and EP3 receptor-deficient mice. Results: The 3 PG analogues reduced K(+)-dependent increase in [Ca(2+)](i) in a concentration-dependent manner. Indomethacin (10 μM) had little effect. The reductions of [Ca(2+)](i) induced by 10 μM PG analogues were not significantly affected by the treatment with the NO synthase inhibitor (L)-NAME (10(-4) M). The effect of all 3 PG analogues in FP and EP3 receptor-deficient arteries was similar to the effect in WT arteries. Latanoprost significantly enhanced the reduction of [Ca(2+)](i) in ciliary arteries from prostanoid EP1 and EP2 receptor-deficient mice compared to WT mice. Tafluprost had a similar effect in arteries from EP2 receptor-deficient mice. Conclusions: PG analogues latanoprost, isopropyl unoprostone, and tafluprost reduced the K(+)-dependent increase in [Ca(2+)](i) in isolated mouse ciliary arteries. Endothelial-derived factors and FP and EP3 receptors were not involved in the responses. The increased effectiveness of latanoprost and tafluprost in reducing [Ca(2+)](i) in EP1 and EP2 receptor-deficient arteries suggests that the PG analogues may act, at least partially, through nonprostanoid receptor pathways. For glaucoma patients, PG analogues can be selected to reduce the intraocular pressure and increase the ocular blood flow.
No preview · Article · Oct 2012 · Journal of ocular pharmacology and therapeutics: the official journal of the Association for Ocular Pharmacology and Therapeutics
[Show abstract][Hide abstract] ABSTRACT: In normotensive eyes, reduced ocular blood flow can lead to glaucoma pathogenesis. Drugs that reduce intraocular pressure (IOP) often cause vasodilation of the ciliary arteries and improve blood flow to the eye. A novel class of drugs called Rho-associated coiled coil-forming protein kinase (ROCK) inhibitors can lower IOP. Therefore, we tested the ability of two ROCK inhibitors, Y-27632 and Y39983, to relax rabbit ciliary arteries.
We measured in vitro ciliary artery smooth muscle contractions by isometric tension recordings and changes of intracellular free calcium concentration ([Ca(2+)](i)) by fluorescence photometry.
Both Y-27632 and Y-39983 induced a concentration-dependent relaxation in rabbit ciliary arteries precontracted with a high-potassium (high-K) solution. The amplitude of relaxation induced by Y-27632 and Y-39983 was not affected by either 100 μM N (G)-nitro-L: -arginine methyl ester (L: -NAME) or 10 μM indomethacin. In Ca(2+)-free solution, Y-27632 and Y-39983 significantly inhibited the transient contraction of ciliary arteries induced by 10 μM histamine. However, neither Y-27632 nor Y-39983 affected the elevation of [Ca(2+)](i) induced by high-K solution and histamine.
We concluded that Y-27632 and Y-39983 relaxed isolated rabbit ciliary artery segments in vitro. The mechanism of relaxation was not dependent on endothelial-derived factors such as nitric oxide (NO) or prostacyclin, nor was it dependent on changes in intracellular Ca(2+) concentration.
Full-text · Article · Jun 2011 · Japanese Journal of Ophthalmology
[Show abstract][Hide abstract] ABSTRACT: We investigated the effects of prostaglandin F(2α) (PGF(2α)) analogues on the endothelin-1 (ET-1)-induced impairment of optic nerve head (ONH) blood flow and on ET-1-induced contraction in isolated ciliary artery segments. In male rabbits, one of four PGF(2α) analogues [0.0015% tafluprost, 0.0015% 15-hydroxyl tafluprost (15-OH tafluprost), 0.005% latanoprost, or 0.004% travoprost] was topically administered at various pretreatment times before intravitreal ET-1 injection. ONH blood flow was estimated by the laser speckle method, which expresses blood velocity as a quantitative index, the squared blur rate (SBR). SBR was measured just before (baseline value) and at 30, 60, and 120 min after ET-1 injection. SBR was significantly decreased from 4.47 ± 0.20 to 3.50 ± 0.10 (78.6 ± 2.4% of baseline) at 120 min after intravitreal ET-1 injection (5 pmol/eye). The ET-1-induced decrease was almost completely prevented by tafluprost and significantly inhibited by the other three analogues. The inhibitory effect lasted longest with tafluprost, as indicated by the effective pretreatment times (tafluprost: 90, 120, or 240 min; 15-OH tafluprost: 90, but not 120 or 240 min; latanoprost and travoprost: 120, but not 240 min). In vitro, the effects of PGF(2α) analogues on ET-1-induced contractions in male rabbit ciliary arteries were evaluated using an isometric tension recording system. Tafluprost, latanoprost, travoprost, and 15-OH tafluprost concentration-dependently relaxed the 10 nM ET-1-induced ciliary artery contraction. Improvement of the ocular circulation may be superior with tafluprost than with the other PGF(2α) analogues. The underlying mechanism may involve relaxation of ocular resistance vessels.
Full-text · Article · Dec 2010 · Experimental Eye Research
[Show abstract][Hide abstract] ABSTRACT: Vascular peripheral resistance is increased during hypertension, and endothelium-derived hyperpolarizing factor (EDHF) is an important for regulating vasodilation in small arteries. Therefore we characterized the role of EDHF in regulating vascular resistance of ocular ciliary arteries from spontaneous hypertensive rats (SHR) and age-matched Wistar Kyoto rats (WKY). Isometric tension recordings were used in isolated ocular ciliary artery segments from SHR and WKY. Ocular ciliary arteries pre-contracted with 100 microM norepinephrine exhibited a concentration-dependent relaxation to acetylcholine, and the effect on SHR arteries was smaller than that on WKY arteries (P < 0.05). The EDHF-mediated component of this relaxation, determined in the presence of 100 microM l-NAME plus 10 microM indomethacin, was also smaller in SHR than in WKY arteries (P < 0.05). Apamin (1 microM), a blocker of small-conductance calcium-activated K(+) (K(Ca)) channels, had no effect on EDHF-mediated relaxation in either preparation. However, charybdotoxin (0.1 microM), which blocks intermediate- and large-conductance K(Ca) channels, and iberiotoxin (0.1 microM), which blocks large-conductance K(Ca) channels, almost completely suppressed EDHF-mediated relaxation in both preparations. The tension of ciliary arteries from both SHR and WKY was increased above baseline by 100 microM l-NAME plus 10 microM indomethacin. In these preparations, apamin had no effect on the tension in arteries from either SHR or WKY. However, both charybdotoxin and iberiotoxin further increased tension above that induced by l-NAME and indomethacin. The increase was smaller for SHR than WKY (P < 0.05). In summary, the ability of EDHF to relax ocular ciliary artery vascular tone in SHR is smaller than in WKY. The large-conductance calcium-activated K(+) channel is utilized in EDHF-signaling pathway.
No preview · Article · Nov 2009 · Experimental Eye Research