advertisement
Abstract #18350 Published in IGR 3-3
Mechanisms of action of unoprostone on trabecular meshwork contractility
Thieme H; Stumpff F; Ottlecz A; Percicot CL; Lambrou GN; Wiederholt MInvestigative Ophthalmology and Visual Science 2001; 42: 3193-3201
PURPOSE: This study was performed to clarify the possible mechanism behind the ocular hypotensive effect of unoprostone isopropyl (Rescula; Novartis Ophthalmics AG, Basel, Switzerland), a new docosanoid that has been shown to reduce intraocular pressure (IOP) in patients with ocular hypertension or primary open-angle glaucoma. To gain insight into the possible mode of action, the effects of unoprostone on ciliary muscle (CM) and trabecular meshwork (TM) contractility, intracellular calcium levels, and membrane channels were investigated. METHODS: The effects of unoprostone (M1 metabolite = free acid, 10-5 M) and endothelin (ET)-1 (10-9 M) on bovine TM (BTM) and ciliary muscle (CM) strips were investigated, by using a custom-made force-length transducer system. The effects of unoprostone and ET-1 (5 x 10-8 M) on intracellular Ca2+ mobilization in cultured human TM (HTM) were measured using fura-2AM as a fluorescent probe. Patch-clamp experiments were performed on HTM and BTM cells in order to investigate the unoprostone-dependent modulation of membrane currents. RESULTS: In isolated TM and CM strips, unoprostone almost completely inhibited ET-induced contractions (TM: 2.9 ± 4.3% versus 19.6 ± 5.7%, p < 0.05, n = 6; CM: 1.4 ± 1.6% versus 30.1 ± 5.3%, p < 0.01, n = 6; 100% = maximal carbachol-induced (10-6 M) contraction). However, neither carbachol-induced contraction nor baseline tension was affected by unoprostone. Furthermore, unoprostone had no effect on baseline intracellular calcium levels (baseline: 126 ± 45 nM versus unoprostone: 132 ± 42 nM, n = 8) in HTM cells. The endothelin-induced increase (679 ± 102 nM), however, was almost completely (p < 0.01) blocked by unoprostone (178 ± 40 nM). In patch-clamp recordings, unoprostone could be shown to double the amplitude of outward current (HTM: 200 ± 33%; n = 6; BTM: 179 ± 20%; n = 8). This effect was blocked by the specific inhibitor of maxi-K channels, iberiotoxin. CONCLUSIONS: This study presents evidence for direct interaction of unoprostone with the contractility of the TM and CM. This compound may lower IOP by affecting aqueous outflow, most probably conventional outflow pathways (i.e., TM) through inhibition of ET-dependent mechanisms. In addition, unoprostone interacts with the maxi-K channel. Although primarily Ca2+-sensitive signal-transduction pathways seem to be involved, effects of unoprostone on Ca2+-independent pathways and uveoscleral outflow cannot be excluded.
Dr H. Thieme, Institut für Klinische Physiologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Germany
Classification:
11.4 Prostaglandins (Part of: 11 Medical treatment)
