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Abstract #10839 Published in IGR 6-2
Human ciliary muscle cell responses to FP-class prostaglandin analogs: 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: 437-55
Phospholipase C induced phosphoinositide (PI) turnover, intracellular Ca2+ ([Ca2+]i) mobilization and mitogen-activated protein (MAP) kinase activation by FP-class prostaglandin analogs 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 (EC50 = 4.3 ± 1.3 nM) >> prostaglandin F2α) (PGF2α)) (EC50 = 134 ± 17 nM) > latanoprost acid (EC50 = 198 ± 83 nM) > S-1033 (EC50 = 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, PGF2α 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 > PGF2α > 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 (11 β-fluoro-15-epiindanyl PGF2α) (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 analogs (including free acids of bimatoprost, travoprost and latanoprost) and the FP receptor antagonist, AL-8810.
Molecular Pharmacology Unit, Alcon Research, Ltd., Fort Worth, TX 76134-2099, USA. naj.sharif@alconlab.com
Classification:
11.4 Prostaglandins (Part of: 11 Medical treatment)
