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Impressum
Pressure lowering properties of Unoprostone by influencing the conventional outflow pathway.
1,2Thieme H., 3Lambrou G. E., 2Foerster M. H., 1Wiederholt M.
1Institut für Klinische Physiologie und 2Augenklinik, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12203 Berlin; 3Novartis Ophthalmics AG, Basel, Switzerland
Introduction: Unoprostone, a new Docosanoid not binding to prostaglandin
receptor sites, has been shown to reduce intraocular pressure in patients
with POAG and ocular hypertension by an unknown mechanism. The trabecular
meshwork (TM) an the Ciliary muscle (CM) influence IOP by contractile
mechanisms. Therefore the effect of Unoprostone on contractility was investigated.
Methods: Isometric contraction measurements of trabecular meshwork
and ciliary muscle strips were performed in response to Unoprostone, Carbachol
and Endothelin-1. Patch clamp investigations in human and bovine TM-cells
as well as calcium measurements on human TM cells were performed.
Results: Unoprostone blocks the Endothelin-induced contraction
of TM and CM strips. There was no effect on the carbachol-induced contraction.
In patch clamp investigations Unoprostone opened the contractilityinfluencing
Maxi-K channel. Unoprostone did not change basal intracellular calcium
levels in human TM cells, however the endothelin induced calcium rise
was completely blocked off. (679 +/- 102 nM vs. 132 +/- 18.nM, p<0,01).
Discussion: Endothelin is found in higher concentrations in aqueous
humor of POAG patients and is probably involved in the pathogenesis of
this disease. Probably Unoprostone lowers IOP by an endothelinantagonising
effect in TM an CM tissue leading to relaxation. This results either from
interaction of Unoprostone with the Maxi K channel which indirectly leads
to a lowered intracellular calcium level. Furthermore calcium sensitive
signal transduction pathways are involved including Endothelin. An additional
effect of Unoprostone on calcium-independent pathways cannot be excluded.