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. 2005 Sep;30(9):747-54.
doi: 10.1080/02713680590953147.

The cross-species A3 adenosine-receptor antagonist MRS 1292 inhibits adenosine-triggered human nonpigmented ciliary epithelial cell fluid release and reduces mouse intraocular pressure

Hui Yang  1 , Marcel Y Avila, Kim Peterson-Yantorno, Miguel Coca-Prados, Richard A Stone, Kenneth A Jacobson, Mortimer M Civan
Affiliations

The cross-species A3 adenosine-receptor antagonist MRS 1292 inhibits adenosine-triggered human nonpigmented ciliary epithelial cell fluid release and reduces mouse intraocular pressure

Hui Yang et al. Curr Eye Res. 2005 Sep.

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-microM 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.

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Conflict of interest statement

Disclosure of interest: R.A.S., K.A.J., and M.M.C. are co-inventors on patent applications and issued patents assigned to the University of Pennsylvania and NIH dealing with the use of A3 adenosine-receptor antagonists as agents in treating glaucoma. K.A.J. is a co-inventor of MRS 1292 on a patent assigned to the National Institutes of Health. The other authors have no commercial conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Purinergic regulation of inflow. NaCl is thought to be taken up from the stroma by Na+-K+-2Cl− symports and Na+/H+ and Cl−/HCO3− antiports of the PE cells, to permeate gap junctions into the NPE cells and to be released into the aqueous humor by Na+,K+- activated ATPase and Cl− channels of the NPE cells. ATP released by PE cells can trigger production of cAMP, which acts directly on maxi-Cl− channels to enhance Cl− return to the stroma, thereby reducing net secretion., ATP-stimulated recycling is enhanced by the anti-estrogen tamoxifen. At the opposite tissue surface, ATP released by NPE cells can be metabolized to adenosine that, by stimulating A3-regulated Cl− channels, can increase net secretion.,,
FIGURE 2
FIGURE 2
Chemical structures of the physiologic agonist adenosine, the full agonist IB-MECA, and the current nucleoside derivative MRS 1292, an antagonist of A3ARs.
FIGURE 3
FIGURE 3
A3AR antagonists inhibit adenosine-triggered shrinkage of cultured human NPE cells. Cells were suspended in isotonic (Iso) solution containing gramicidin (Gram). Adenosine (10 μM) triggered shrinkage. Both the novel A3AR antagonist MRS 1292 (100 nM) and the established antagonist MRS 1191 (100 nM) prevented that shrinkage (N = 10, passages 10–14). Cells were pretreated with the antagonists for 2 min before initiating the measurements. Solid curves are nonlinear least-square fits to Eq. (1): control (Δv∞ = 1.2 ± 0.1%; τ = 4.5 ± 1.7 min), adenosine (Δv∞ = 4.2 ± 0.2%; τ = 3.8 ± 0.6 min), and adenosine + MRS 1292 (Δv∞ = 1.9 ± 0.2%; τ = 11.7 ± 2.6 min). The symbols Δv∞ and τ symbolize the steady-state shrinkage and the time constant of that shrinkage, respectively. Cells exposed to adenosine and MRS 1191 did not display exponential shrinkage and their volumes could not be fit to Eq. (1) so that the data points are connected by interrupted lines.
FIGURE 4
FIGURE 4
Concentration-response relationship of MRS 1292. The cell shrinkages were measured after 60 min of exposure, as in the experiments of Figure 3, and corrected for the shrinkage displayed by the parallel control aliquots of cells. The curve was generated from an exponential two-parameter fit of the results.
FIGURE 5
FIGURE 5
Effects of topical control physiologic saline (n = 6), the antagonist MRS 1292 (at a droplet concentration of 25 μM, n = 10), and of the agonist IB-MECA at droplet concentrations of 14 nM (n = 5), 140 nM (n = 6), and 1,400 nM (n = 4) on IOP of living mice. Values are means ± SEs.
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