The cross-species A3 adenosine-receptor antagonist MRS 1292 inhibits adenosine-triggered human nonpigmented ciliary epithelial cell fluid release and reduces mouse intraocular pressure.
OBJECTIVE
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.
Yang
Hui
H
Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6085, USA.
Avila
Marcel Y
MY
Peterson-Yantorno
Kim
K
Coca-Prados
Miguel
M
Stone
Richard A
RA
Jacobson
Kenneth A
KA
Civan
Mortimer M
MM
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058918:Adenosine A3 Receptor Antagonists; D000287:Administration, Topical; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism*; D048429:Cell Size; D002478:Cells, Cultured; D002924:Ciliary Body / Q000187:drug effects* / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D051379:Mice; D043684:Receptor, Adenosine A3 / Q000378:metabolism
D058918:Adenosine A3 Receptor Antagonists; D004095:Dihydropyridines; C107728:MRS 1191; C506339:MRS 1292; D043684:Receptor, Adenosine A3; D000241:Adenosine