PURPOSETo test the putative role of A(3) adenosine receptors (ARs) in modulating intraocular pressure (IOP).METHODSIOP was monitored for up to 32 minutes in A3-knockout (A3AR-/-) and A3AR+/+ control mice by the servo-null approach. The IOP responses to adenosine, A3AR agonists and A3AR antagonists were studied singly or in combination in both strains.RESULTSIOP was significantly lower in A3AR-/- mice (12.9 +/- 0.7 mm Hg) than in A3AR+/+ control animals (17.4 +/- 0.6 mm Hg). The nonselective AR agonist adenosine produced a much smaller increase in IOP (2.2 +/- 0.8 mm Hg) in the knockout than in A3AR+/+ control mice (14.9 +/- 2.4 mm Hg). The A3-selective agonist IB-MECA did not affect IOP in A3-knockout mice, but raised it in A3AR+/+ mice. The highly selective A3AR antagonist MRS 1191 did not affect IOP in A3AR-/- mice, but lowered it in A3AR+/+ control mice. Preadministering MRS 1191 did not affect the small adenosine-triggered increase in IOP in A3AR-/- mice, but markedly attenuated adenosine's effects on IOP in A3AR+/+ control mice. MRS 1523, an A3AR antagonist less selective than MRS 1191 in rats, decreased IOP in both A3AR-/- and A3AR+/+ animals. As in black Swiss outbred mice and other mammalian species, reducing aqueous humor inflow with acetazolamide lowered IOP and administering water intraperitoneally increased IOP in both A3AR-/- and A3AR+/+ mice.CONCLUSIONSThe reduced IOP and altered purinergic responses of IOP in A3AR knockout mice support the conclusion that A3ARs contribute to the regulation of IOP.