Effect of 5-methylurapidil, an α(1a)-adrenergic antagonist and 5-hydroxytryptamine(1a) agonist, on aqueous humor dynamics in monkeys and rabbits

Purpose. To evaluate the effects of 5-methylurapidil (5-MU) on intraocular pressure (IOP) and aqueous humor dynamics in female cynomolgus monkeys and albino rabbits. Methods. IOP was measured by pneumatonometer prior to and up to 6 hours after AM administration of 5-MU to one eye of each of 8 normal monkeys and to the laser-induced glaucomatous eye of 8 monkeys. During single-dose and 5-day multiple-dose testing, pupillary diameter (PD) was measured at the same time and same intervals as IOP measurements in the normal monkeys. Outflow facility and aqueous humor flow rates were measured in 8 normal monkeys before and after treatment. Uveoscleral outflow was measured in 8 rabbits before and after treatment. Results. In normal monkeys, unilateral topical application of 2 x 25 μl of 1% or 2% 5-MU significantly (p < 0.05) reduced pupil size and IOP bilaterally as compared to baseline measurements. The reduction in IOP (mean ± SEM, mmHg) was up to 2.8 ± 0.7 (1% 5-MU) and 4.4 ± 0.5 (2% 5-MU) in the treated eyes, and 2.3 ± 0.8 (1%) and 3.0 ± 0.7 (2%) in the contralateral eyes. In glaucomatous monkeys, the maximum reduction in IOP was 6.5 ± 1.0 mmHg (1%) and 7.5 ± 0.8 mmHg (2%). The ocular hypotensive effect increased over time with twice-daily administration for 5 days. Compared with baseline values, outflow facility and aqueous flow rates in the treated eyes of normal monkeys were increased (p < 0.01) by 51% and by 11%, respectively. Uveoscleral outflow was unaltered (p > 0.3) in rabbits compared with baseline values. Mild corneal edema, corneal punctate erosions, and conjunctival discharge occurred in some eyes treated with either 1% or 2% 5-MU. Conclusions. 5-Methylurapidil, an antagonist at the α(1A)-adrenergic receptor subtype and an agonist at the 5-HT(1A) receptor subtype, lowers IOP predominantly by increasing outflow facility and may have potential for the therapy of glaucoma.