Endothelin–antagonism: mechanisms of action of prostaglandin F2a on trabecular meshwork contractility

Abstract

Abstract: : Purpose: Prostaglandin F2α (PGF2α) and its analogues are known to reduce intraocular pressure (IOP) in glaucoma patients by enhancement of uveoscleral flow. The trabecular meshwork (TM) is actively involved in the regulation of IOP via contractile mechanisms. Endothelin–1 (ET–1) is probably involved in the pathogenesis of glaucoma and induces contraction of TM via the endothelin receptor A while PGF2α has no influence on TM contractility. The involvement of PGF2α in the ET–1 evoked contraction of TM was examined. Methods: The effects of PGF2α and PGF2α receptor (FP–receptor) antagonists on ET–1 induced contraction of isolated bovine TM strips were investigated. Western blot analysis was used to identify the FP receptor on protein level. Results: ET–1 (10–9 M) induced contraction of TM (22.9 ± 5.9 % vs 100 % carbachol (10–6 M) induced contraction, n=6). In the presence of PGF2α (10–6 M) the contraction elicited by ET–1 was reduced to 4.1 ± 2.1 % (n=17, p<0.001). The ET–1 (10–8 M) induced contraction of TM (69.2 ± 10.5 %, n=7) was not significantly reduced when PGF2α was applied in the presence of the FP–receptor antagonist PGF2α dimethylamide (10–6 M) (55.3 ± 4.1 %, n=7). In membrane lysates of cultured human TM cells the FP–receptor protein was verified at 64 kDa. Conclusions: PGF2α inhibits the ET–1 induced contraction of TM. The effect of PGF2α is mediated via the FP receptor, because PGF2α failed to inhibit the ET–1 induced contraction of TM in the presence of the FP receptor antagonist. The reduction of IOP by PGF2α could be due to its antagonistic action on the ET–1 effect on TM. The inhibiting action of PGF2α on ET–1 might be attributed to a heterologous desensitization of the ET–AR induced by the activation of the FP receptor or an interference in intracellular signaling pathways of the two receptors downstream of phospholipase C. (Supported by Deutsche Forschungsgemeinschaft DFG Th751/4–1). CR: None

Keywords: trabecular meshwork • outflow: trabecular meshwork • receptors