Pharmacoydnamics of Beta-Blocker Modulation of Aqueous Humor Production

Abstract

A conscious rabbit model with microdialysis sampling of endogenous aqueous humor ascorbate was developed in order to assess the pharmacodynamics of beta-blocker modulation of aqueous humor production. CMA/20 microdialysis probes were implanted in the anterior chamber of each eye of rabbits (n =6). After a 2 week recovery period, an i.v. bolus of14C-ascorbate (20 μCi) was administered. Blood samples and aqueous humor microdialysis probe effluent were collected and analysed for endogenous and14C-ascorbate to estimate the basal rate of ascorbate blood to aqueous humor secretion (Ro). After a 1 hr washout, each rabbit received a series of three doses of3H-propranolol (750–3000 μ g, 16.5 μCi mg−1) every 60 min into the lower cul-de-sac of each eye. Probe effluent was analysed for endogenous ascorbate and3H-propranolol; ascorbate and propranolol in the iris/ciliary body, vitreous and aqueous was determined at the end of the experiment. Nonlinear least-squares regression analysis of the concentration-time profiles for aqueous humor ascorbate was performed to estimate the change in aqueous humor flow. The average basal aqueous humor ascorbate secretion rate was ∼48 μg hr−1. Propranolol (1500 μg) produced significant increases in aqueous humor ascorbate, this observation is consistent with a reduction in aqueous humor production (∼47%). Analysis of intraocular tissue ascorbate indicated that propranolol inhibited ascorbate secretion at the 3000 μg dose, the highest dose examined in this study; this inhibition was not observed at the 750 μg or 1500 μg doses. Changes in aqueous humor production precipitated by the administration of beta-adrenergic antagonists can be estimated by measuring changes in aqueous humor ascorbate concentrations in the conscious rabbit. Microdialysis sampling of aqueous humor for endogenous ascorbate provides a relevant analytic tool to estimate modulatory effects of anti-glaucoma drugs on aqueous humor production.