The Cross-Species A₃ Adenosine-Receptor Antagonist MRS 1292 Inhibits Adenosine-Triggered Human Nonpigmented Ciliary Epithelial Cell Fluid Release and Reduces Mouse Intraocular Pressure

Abstract

Purpose: Antagonists to A₃ adenosine receptors (ARs) lower mouse intraocular pressure (IOP), but extension to humans is limited by species variability. We tested whether the specific A₃AR antagonist MRS 1292, designed to cross species, mimicks the effects of other A₃AR antagonists on cultured human nonpigmented ciliary epithelial (NPE) cells and mouse IOP. Methods: NPE cell volume was monitored by electronic cell sorting. Mouse IOP was measured with the Servo-Null Micropipette System. Results: Adenosine triggered A₃AR-mediated shrinkage of human NPE cells. Shrinkage was blocked by MRS 1292 (IC₅₀ = 42 ± 11 nM, p < 0.01) and by another A₃AR antagonist effective in this system, MRS 1191. Topical application of the A₃AR agonist IB-MECA increased mouse IOP. MRS 1292 reduced IOP by 4.0 ± 0.8 mmHg at 25-μ M droplet concentration (n = 10, p < 0.005). Conclusions: MRS 1292 inhibits A₃AR-mediated shrinkage of human NPE cells and reduces mouse IOP, consistent with its putative action as a cross-species A₃ antagonist.

KEYWORDS:

• A₃ adenosine receptors
• aqueous humor inflow
• Cl⁻ channels
• intraocular pressure
• MRS 1292