Ocular Hypotensive DP-Class Prostaglandin Receptor Affinities Determined by Quantitative Autoradiography on Human Eye Sections

Abstract

The aim of this study was to define the localization and pharmacology of DP-prostaglandin receptors in human eye sections using a novel DP-antagonist radioligand ([3H]-BWA868C), using various intraocular pressure (IOP)-lowering DP-prostaglandins and the technique of quantitative autoradiography on 20-microm sections of frozen human eyes. [3H]BWA868C yielded well-defined autoradiograms of DP-receptors in human eyes with up to 82% specific binding. High densities of DP-receptors were associated with the ciliary epithelium/process, iris, choroid, longitudinal and circular ciliary muscles, and retina. Low specific binding was observed in the lens and cornea. The DP-receptor agonists, BW245C (Ki = 4-8 nM), SQ27986 (Ki = 6-9 nM), ZK118182 (Ki = 12-33 nM), 3,4-dihydro-ZK118182 (AL-6556; Ki = 1.6-4.3 (microM) and 3,4-dihydro-ZK118182 isopropyl ester (AL-6598; Ki = 2.9-9.7 microM), exhibited varying affinities for human DP-receptors in the ciliary process, longitudinal and circular ciliary muscles, and iris, respectively. These human ocular tissue affinity values correlated well with nonocular tissue affinities and functional potencies of these prostaglandins in cultured cells (r = 0.93-0.99). In conclusion, these quantitative autoradiographic studies revealed a high density of DP-prostaglandin receptors in human ciliary muscles, ciliary process, and iris, indicating that this class of prostaglandin may lower IOP by uveoscleral pathway and also by inhibiting aqueous humor production. The pharmacological attributes of [3H]BWA868C-labeled receptor sites studied using in situ quantitative autoradiography matched those previously documented for several other DP-receptor-containing cells and tissues.

ATP-Induced Relaxation of Porcine Retinal Arterioles In Vitro Depends on Prostaglandin E Synthesized in the Perivascular Retinal Tissue

“…Furthermore, studies of the vasoactive effect of prostaglandins are hampered by the possible existence of still unidentified prostaglandins, by the fact that specific antagonists to receptors of some already-known prostaglandins are missing, and by the fact that known agonists and antagonists may show cross-reactivity to several receptors. 7 These facts may provide the background for the finding that, after preconstriction, all the studied prostaglandins showed a vasorelaxing effect at the highest concentrations used, that PGF 2␣ showed the opposite effect by decreasing the vascular tone after the vessels had been precontracted with U46619, and that CTA2 and U46619 had different effects, although both have been characterized as specific agonists to the TP receptor. 14 It has also been shown that the involvement of prostaglandins in the tone regulation of retinal arterioles displays considerable species variation, 4,15 but despite this, no functional pharmacologic differences have hitherto been shown in the tone regulation in porcine and human retinal arterioles.…”

“…Furthermore, the effect of the PGE rec antagonist on ATP-induced vasodilation was not found in adenosine-induced vasodilation, which does not depend on the perivascular retina. 2 It has been shown that PGE receptors exist in ocular tissue, 6,7 and that PGE may induce vasodilation after intravitreal injection in minipigs, 5 an effect that can be reversed by indomethacin. 17 Furthermore, intravenously administered PGE 1 and PGE 2 increase retinal perfusion in rats 18 although this effect cannot be reproduced with PGE 1 in humans.…”

“…The existence of DP receptors in human retinal vessels makes it likely that ligands to these receptors have a physiological role for regulating retinal vascular tone. 7 However, the dual effect of PGD 2 found on arterioles with the perivascular retina with vasoconstriction at low PGD 2 concentrations and vasorelaxation at high concentrations may be due to a different effect on one EP receptor 7 or a mixed effect on several EP receptors with different receptor specificity at low and high concentrations of the ligand. 20 -23 In previous studies PGF 2␣ has been found to induce vasoconstriction which can be antagonized by a calcium channel blocker.…”

“…1 The exact nature of this COX product remains to be elucidated, but the presence of specific prostaglandin receptors in the retina suggest a physiological role of ligands to these receptors in retinal physiology including the regulation of vascular tone. [5][6][7] The purpose of the present study was to investigate how ATP-induced vasodilation is influenced by the prostaglandins (PG) PGE 2 , PGF 2␣ , PGD 2 , and PGI 2 and thromboxane A 2 (TXA 2 ), which have affinity for the prostaglandin receptors that have been identified in retinal tissue. Porcine retinal arterioles were mounted in a wire myograph, the effect of prostaglandins on relaxed and precontracted arterioles was studied, and the specificity of the observed effects was tested with the application of specific antagonists.…”

Morphologic characteristics of the human ciliary muscle

“…The prostaglandin receptor FP could also be identified [60,87,90,94,[98][99][100][101]; however, it is located mainly in the inner portion of the ciliary muscle [91,92,97]. Beside these two groups, the TP receptor [90] and the DP receptor [93,95,102,103] were described for the human ciliary muscle; IP receptors were not mentioned.…”