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Abstract #9919 Published in IGR 5-3
Human ciliary muscle cell responses to FP-class prostaglandin analogues: phosphoinositide hydrolysis, intracellular Ca2+ mobilization and MAP kinase activation
Sharif NA; Crider JY; Husain S; Kaddour Djebbar I; Ansari HR; Abdel Latif AAJournal of Ocular Pharmacology and Therapeutics 2003; 19: 437-455
Phospholipase C induced phosphoinositide (PI) turnover, intracellular Ca2+ ([Ca2+]i) mobilization and mitogen-activated protein (MAP) kinase activation by FP-class prostaglandin analogues was studied in normal human ciliary muscle (h-CM) cells. Agonist potencies obtained in the PI turnover assays were: travoprost acid ((+)-fluprostenol; EC50 = 2.6 ± 0.8 nm) > bimatoprost acid (EC50 = 3.6 ± 1.2 nm) > (±)-fluprostenol (EC 50 = 4.3 ± 1.3 nm) >> prostaglandin F2ALP (PGF2ALP) (EC50 = 134 ± 17 nm) > latanoprost acid (EC50 = 198 ± 83 nm) > S-1033 (EC 50 = 2930 ± 1420 nm) > unoprostone (EC50 = 5590 ± 1490 nm) > bimatoprost (EC50 = 9600 ± 1100 nm). Agonist potencies in h-CM cells correlated well with those previously obtained for the cloned human ciliary body-derived FP receptor (r = 0.96, p < 0.001) and that present on h-TM cells (r = 0.94, p < 0.0001). Travoprost acid, PGF2ALP and unoprostone also stimulated [Ca2+]i mobilization in h-CM cells with travoprost acid being the most potent agonist. MAP kinase activity was stimulated in the h-CM cells with the following rank order of activity (at 100 nm): travoprost acid > PGF 2ALP > latanoprost acid > PGD2 > bimatoprost > latanoprost = bimatoprost acid = fluprostenol > PGE2 = S-1033 > unoprostone > PGI2. The PI turnover, [Ca2+]i mobilization and MAP kinase activation induced by several of these agonists was blocked by the FP receptor antagonist, AL-8810 (11β-fluoro-15-epiindanyl PGF2ALP) (e.g., Ki = 5. 7 μm versus PI turnover). These studies have characterized the biochemical and pharmacological properties of the native FP prostaglandin receptor present on h-CM cells using three signal transduction mechanism assays and a broad panel of FP-class agonist analogues (including free acids of bimatoprost, travoprost and latanoprost) and the FP receptor antagonist.
Dr. N.A. Sharif, Alcon Research, Ltd., 6201 South Freeway, Fort Worth, TX 76134-2099, USA
Classification:
11.4 Prostaglandins (Part of: 11 Medical treatment)
