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1 From the Institut für Klinische Physiologie, and 2 Augenklinik Universitätsklinikum Benjamin Franklin, Freie Universität Berlin; and 3 Klinik und Poliklinik für Augenheilkunde, Charitè, Campus Virchow Klinikum, Humboldt Universität Berlin, Germany.
PURPOSE. Inhibition of protein kinase C (PKC) and rho-kinase (ROCK) may represent a new way of influencing outflow facility through isolated relaxation of the trabecular meshwork (TM). This work was performed to investigate the existence of calcium-independent contraction in this smooth-muscle–like tissue and its modulation by targeting the rho-guanosine triphosphatase (GTPase)–mediated pathway.
METHODS. Isometric tension measurements of bovine TM and ciliary muscle (CM)
were performed. Intra- and extracellular calcium buffering was
accomplished with EGTA and
1,2-bis(2-aminophenoxy)-ethane-N,N,N,N',N'-tetra-acetic
acid tetrakis/acetoxymethhyl ester (BAPTA-AM) followed by stimulation
of PKC with phorbolester (PMA) or 4
-phorbol. Calcium-independent
contraction was blocked using the highly specific ROCK inhibitor
Y-27632. Western blot analysis and immunoprecipitation was performed
using human TM cells.
RESULTS. In TM, carbachol induced partial contraction under conditions of
extracellular calcium depletion (22.1% ± 2.3% versus 100%, n
= 9). The membrane-permeable calcium chelator BAPTA-AM completely
blocked this response (1.1% ± 1.4% versus 100%, n = 9).
When calcium was completely blocked, PMA induced contraction in TM
(16.7% ± 5.9% versus 100%, n = 9) but not in CM (1.8%
± 2.5% versus 100%, n = 6). The inactive PMA analogue
4-phorbol did not induce contraction, indicating that activation of
PKC is involved in this contractile response. The ROCK inhibitor
Y-27632 completely blocked the calcium-independent PMA-induced
contraction in TM. Western blot analysis and immunoprecipitation
revealed the expression of the rho-A protein in human TM cells.
CONCLUSIONS. The data indicate that contrary to CM, the TM features calcium-independent contractile mechanisms linked to rho-A and PKC isoforms that do not require calcium for activation. ROCK inhibitors may allow specific modulation of the TM to enhance outflow facility, thus lowering intraocular pressure.
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