Cat Iris Sphincter Smooth-Muscle Contraction: Comparison of FP-Class Prostaglandin Analog Agonist Activities

Abstract

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 (EC₅₀) 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_2α (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_2α ) 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 (EC₅₀ = 2140 ± 190 nM; 63 ± 4.3% maximum response relative to PGF_2α), 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.