Effects of unoprostone and endothelin 1 on L-type channel currents in human trabecular meshwork cells.
BACKGROUND
The trabecular meshwork (TM) is a smooth muscle-like tissue with contractile properties and by this mechanisms involved in the regulation of aqueous humor outflow. Isopropyl unoprostone (Rescula, Novartis Ophthalmics), a synthetic docosanoid, reduces intraocular pressure in glaucoma patients and normal subjects. In isolated TM strips, unoprostone reduces TM contractility in the presence of endothelin 1 (ET-1). However, the signal transduction pathway of unoprostone still remains unclear. Since L-type channel currents are known to influence the contractility of TM, we examined the effects of unoprostone and ET-1 on L-type channel currents of TM cells.


METHODS
The effects of unoprostone, ET-1 and the tyrosine kinase inhibitor herbimycin A on L-type channel currents of cultured human TM cells were investigated using the perforated patch configuration of the patch-clamp technique.


RESULTS
Application of ET-1 had no effect on L-type channel currents. Unoprostone led to a dose-dependent reduction of control currents. The effect of unoprostone is independent of ET-1. After preincubation of cells with herbimycin A, unoprostone had no effect on the L-type channel current amplitude. Human TM cells preincubated with herbimycin A showed a reduced current density compared with control cells. Both substances, unoprostone and herbimycin A, increased the inactivation time constant of L-type channel currents.


CONCLUSIONS
We conclude that unoprostone reduces the activity of L-type Ca2+ channels. This effect seems to be independent of ET-1. The signal transduction pathway seems to be mediated by tyrosine kinases.
Thieme
Hagen
H
Augenklinik und Hochschulambulanz, Berlin, Germany.
Steinhausen
Kirsten
K
Ottlecz
Anna
A
Lambrou
George N
GN
Strauss
Olaf
O
Wiederholt
Michael
M
Rosenthal
Rita
R
D016227:Benzoquinones; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002478:Cells, Cultured; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047029:Lactams, Macrocyclic; D018408:Patch-Clamp Techniques; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D014129:Trabecular Meshwork / Q000187:drug effects* / Q000378:metabolism
D016227:Benzoquinones; D020746:Calcium Channels, L-Type; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; C072630:isopropyl unoprostone; C020754:herbimycin; D015237:Dinoprost; D011505:Protein-Tyrosine Kinases