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Z. Wang, C. W. Do, M. Y. Avila, K. Peterson, R. A. Stone, Z. G. Gao, L. S. Jeong, K. A. Jacobson, M. M. Civan; A Novel Cross-Species Antagonist to A3 Adenosine Receptors Lowers Mouse Intraocular Pressure Measured Non-Invasively. Invest. Ophthalmol. Vis. Sci. 2008;49(13):356. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To determine whether novel selective, putative cross-species antagonists of A3 adenosine receptors (ARs) lower intraocular pressure (IOP) in the living mouse. The 5 antagonists tested are modifications of Cl-IB-MECA, an effective A3-selective agonist across species.
IOP was measured with a micropipette by the invasive Servo-Null Micropipette System (SNMS) and by non-invasive pneumotonometry before, during and after topical drug application. Bovine nonpigmented ciliary epithelial (NPE) cell volume was measured by calcein fluorescence.
The 5 agonist-based, A3AR antagonists separately lowered mouse SNMS-measured IOP by 3-5 mmHg rapidly, within several minutes of application. No effect was detected pneumotonometrically with 4 of the compounds over 30 min of observation, consistent with the slower, smaller responses previously observed following topical application of A3AR agonists and the A3AR antagonist MRS1191. LJ1251 uniquely lowered IOP measured both by pneumotonometry (by 4.2 ±0.7 mmHg after 30 min, N=6, P<0.002) and by SNMS (by 4.9 ±1.7 mmHg, N=6, P<0.05). LJ1251 (150 nM) blocked the shrinkage of native bovine NPE cells (N=8) triggered by 0.3 mM adenosine alone (N=14) (P<0.05, ANOVA).
With enhanced intraocular delivery by measuring IOP invasively, 5 derivatives of the A3AR agonist Cl-IB-MECA lowered IOP. Measured non-invasively, only LJ1251 rapidly reduced IOP after topical application, and acted across species as a bovine A3AR receptor antagonist. We conclude that LJ1251 is a particularly promising A3AR antagonist for further study because of its apparent more ready permeation of the mouse ocular coats.
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