Kinin Modulation of Conventional Outflow Facility in the Bovine Eye

Abstract

The aim of this study was to investigate the effects of bradykinin on conventional outflow facility in relation to kinin effects on matrix metalloproteinase (MMP) secretion. Conventional outflow facility was measured in isolated bovine segments perfused at a constant pressure of 10 mmHg. Experiments were also performed in primary cultures of bovine trabecular meshwork cells to assess bradykinin effects on the secretion of MMP-9 assessed by western blot. Administration of bradykinin (10(-7) M) to perfused anterior segments produced a 50% increase in outflow facility above basal levels. The effect was slow to develop, requiring 100 min for a significant increase in facility and 4 h for the peak response to be observed. Pretreatment of anterior segments with the B(2) kinin receptor antagonist, HOE-140 (10(-6) M), or with the nonselective MMP inhibitor, GM6001 (10(-5) M) blocked the response to bradykinin (10(-7) M). Treatment of cultured trabecular meshwork cells with bradykinin (10(-7) M) for 120 min stimulated secretion of MMP-9 into the extracellular media, and this response was inhibited by HOE-140 (10(-6) M). These results demonstrate that bradykinin activates B(2) kinin receptors to increase conventional outflow in the perfused bovine eye and provide evidence that secretion and activation of MMPs within the conventional pathway may mediate the effect.

Endogenous bioactive lipids and the regulation of conventional outflow facility

“…Currently unknown is whether EP 2 specifically mediates the secretion of MMPs and ECM turnover in TM cells. There is increasing evidence suggest that the resistance to aqueous humor drainage through TM drainage tissue is in part dependent on the composition of ECM in this tissue [21,23]. For example, outflow facility increases upon exogenous introduction of MMPs into conventional tract [23] or by altering endogenously produced MMPs by conventional outflow cells [71,72].…”

“…Secondly, changes in ECM turnover and remodeling in the JCT region appear to contribute to the regulation of outflow through the conventional tract. For example, a number of treatments known to alter matrix metalloproteinase (MMP) expression/secretion by TM cells change outflow facility [20][21][22]. Moreover, direct inhibition of MMP activity in the conventional outflow pathway with tissue inhibitors of metalloproteinases or several families of synthetic MMP inhibitors decrease outflow facility [23].…”

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

“…MMP proteins are often upregulated in glaucomatous AH; however, the activity of these proteins is reduced in comparison to cataract controls, likely reflective of MMP:TIMP imbalance [92,[96][97][98]. Perfusion of ocular tissues with MMPs or MMP-activating compounds results in increased outflow facility, possibly the most convincing demonstration of ECM involvement in regulating outflow resistance [99][100][101][102]. Furthermore, recent studies on ECM characteristics, such as stiffness resulting from crosslinking, or caveolin-mediated matrix endocytosis, also highlight ECM influence on outflow facility [103,104].…”

Plasma Kallikrein and Diabetic Macular Edema

“…Bradykinin, via its B2R, stimulates outflow facility in perfused anterior segments [47], suggesting that the KKS may regulate aqueous outflow and intraocular pressure. More information is needed to characterize the significance of this pathway to the physiologic control of intraocular pressure.…”