The effects of prostaglandin analogues on intracellular Ca2+ in ciliary arteries of wild-type and prostanoid receptor-deficient mice.

PURPOSE To clarify the mechanism of prostaglandin (PG) analogue-dependent relaxation in ciliary arteries from wild-type (WT) and prostanoid 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.

[1]  M. Araie,et al.  Intraocular Metabolites of Isopropyl Unoprostone , 2005, Current eye research.

[2]  K. Kashiwagi,et al.  Metabolites of isopropyl unoprostone as potential ophthalmic solutions to reduce intraocular pressure in pigmented rabbits. , 1999, Japanese journal of pharmacology.

[3]  A. Iwase,et al.  The prevalence of primary open-angle glaucoma in Japanese: the Tajimi Study. , 2004, Ophthalmology.

[4]  S. Narumiya,et al.  International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. , 1994, Pharmacological reviews.

[5]  Tetsuya Yamamoto,et al.  Target intraocular pressure for stability of visual field loss progression in normal-tension glaucoma , 2010, Japanese Journal of Ophthalmology.

[6]  Effects of Topical Travoprost and Unoprostone on Optic Nerve Head Circulation in Normal Rabbits , 2007, Current eye research.

[7]  T. Yoshitomi,et al.  Effects of prostaglandin F(2α) analogues on endothelin-1-induced impairment of rabbit ocular blood flow: comparison among tafluprost, travoprost, and latanoprost. , 2010, Experimental eye research.

[8]  C. Paterson,et al.  Prostaglandin E2 receptor subtypes, EP1, EP2, EP3 and EP4 in human and mouse ocular tissues--a comparative immunohistochemical study. , 2004, Prostaglandins, leukotrienes, and essential fatty acids.

[9]  E. Onrat,et al.  The comparative cardiovascular, pulmonary, ocular blood flow, and ocular hypotensive effects of topical travoprost, bimatoprost, brimonidine, and betaxolol. , 2004, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[10]  Y. Ohnishi,et al.  Vasodilatory mechanism of unoprostone isopropyl on isolated rabbit ciliary artery , 2004, Current eye research.

[11]  S. Moncada,et al.  L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. , 1988, Biochemical and biophysical research communications.

[12]  M. Araie,et al.  Topical nipradilol: effects on optic nerve head circulation in humans and periocular distribution in monkeys. , 2002, Investigative ophthalmology & visual science.

[13]  Noriko Odani-Kawabata,et al.  Effects of repeated administrations of tafluprost, latanoprost, and travoprost on optic nerve head blood flow in conscious normal rabbits. , 2010, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[14]  U. Schlötzer-Schrehardt,et al.  Expression and localization of FP and EP prostanoid receptor subtypes in human ocular tissues. , 2002, Investigative ophthalmology & visual science.

[15]  T. Yoshitomi,et al.  Effects of Rho-associated protein kinase inhibitors Y-27632 and Y-39983 on isolated rabbit ciliary arteries , 2011, Japanese Journal of Ophthalmology.

[16]  Hiroshi Ishikawa,et al.  Detecting the inner and outer borders of the retinal nerve fiber layer using optical coherence tomography , 2002, Graefe's Archive for Clinical and Experimental Ophthalmology.

[17]  M. Aihara.  Clinical appraisal of tafluprost in the reduction of elevated intraocular pressure (IOP) in open-angle glaucoma and ocular hypertension , 2010, Clinical ophthalmology.

[18]  S. Narumiya,et al.  The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice. , 2005, Investigative ophthalmology & visual science.

[19]  S. Narumiya,et al.  The effects of prostaglandin analogues on prostanoid EP1, EP2, and EP3 receptor-deficient mice. , 2006, Investigative ophthalmology & visual science.

[20]  M. Kageyama,et al.  New fluoroprostaglandin F(2alpha) derivatives with prostanoid FP-receptor agonistic activity as potent ocular-hypotensive agents. , 2003, Biological & pharmaceutical bulletin.

[21]  M. Araie,et al.  Topical latanoprost and optic nerve head and retinal circulation in humans. , 2001, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[22]  E. Stefánsson,et al.  The impact of ocular blood flow in glaucoma , 2002, Progress in Retinal and Eye Research.

[23]  S. Moncada,et al.  Comparative pharmacology of EDRF and nitric oxide on vascular strips. , 1987, European journal of pharmacology.

[24]  T. Yoshitomi,et al.  Relaxing effect and mechanism of tafluprost on isolated rabbit ciliary arteries. , 2008, Experimental eye research.