Cat iris sphincter smooth-muscle contraction: comparison of FP-class prostaglandin analog agonist activities.
The pharmacologic characteristics of a number of FP-class prostaglandin (PG) analogs were determined by using the cat iris sphincter smooth-muscle-contraction assay. Cumulative concentration-response curves were generated for each compound. The relative agonist potencies (EC(50)) of the compounds were: cloprostenol (0.0012 +/- 0.0004 nM) >> travoprost acid (0.46 +/- 0.13 nM) = bimatoprost acid (0.99 +/- 0.19 nM) > (+/-)-fluprostenol (15.8 +/- 2.6 nM) = PGF(2alpha) (18.6 +/- 1.8 nM) > latanoprost acid (29.9 +/- 1.6 nM) > bimatoprost (140 +/- 45 nM) > S-1033 (588 +/- 39 nM) > unoprostone (UF-021; 1280 +/- 50 nM; n = 4-14). The maximum response induced by travoprost acid (122% +/- 2.3% maximum response relative to PGF(2alpha)) was significantly greater than that induced by all the other PG compounds (P < 0.001 - P < 0.02). Interestingly, the FP-receptor antagonist, AL-8810, behaved as a moderate efficacy partial agonist (EC(50) = 2140 +/- 190 nM; 63 +/- 4.3% maximum response relative to PGF(2alpha)), indicating that the cat iris contains an extremely well-coupled FP-receptor population, and/or the tissue contains an extremely high density of the FP-receptor and/or spare receptors. The cat iris contraction data were well correlated with other FP-receptor-mediated signal-transduction processes, including FP-receptor binding in bovine corpus luteum (r = 0.86), FP-receptor binding in human iris (r = 0.61), phosphoinositide (PI) hydrolysis in human ciliary muscle and trabecular meshwork cells (r = 0.77 - 0.86), PI turnover in rat and mouse cells (r = 0.73 - 0.76) and via cloned human FP-receptor (r = 0.9), and rat uterus contraction (r = 0.84). These data confirm the presence of functional FP-receptors in the cat iris sphincter, which are exquisitely well coupled and which respond to a variety of FP-class PG analogs with differing potencies.
Sharif
Najam A
NA
Ophthalmology Discovery Research, Alcon Research Ltd, Fort Worth, TX 76134, USA. naj.sharif@alconlabs.com
Kaddour-Djebbar
Ismail
I
Abdel-Latif
Ata A
AA
D000818:Animals; D002415:Cats; D002417:Cattle; D002924:Ciliary Body / Q000187:drug effects / Q000378:metabolism; D003338:Corpus Luteum / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D066298:In Vitro Techniques; D007498:Iris / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D011453:Prostaglandins / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011982:Receptors, Prostaglandin / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D014129:Trabecular Meshwork / Q000187:drug effects / Q000378:metabolism; D014590:Uterine Contraction / Q000187:drug effects
D010716:Phosphatidylinositols; D011453:Prostaglandins; D011982:Receptors, Prostaglandin