Edwin U. Padillo

Inhibition of Vitreoretinal VEGF Elevation and Blood–Retinal Barrier Breakdown in Streptozotocin-Induced Diabetic Rats by Brimonidine

PURPOSE To determine whether long-term brimonidine (BRI) treatment prevents the hyperglycemia-induced increase in vitreoretinal vascular endothelial growth factor (VEGF) expression and breakdown of the blood-retinal barrier (BRB) in streptozotocin (STZ)-induced diabetic rats. METHODS Brown Norway/Long-Evans rats were divided into three groups with similar distributions of blood glucose and body weight. Two groups received a single intravenous injection of STZ (65 mg/kg) and the remaining control group received vehicle. Drug treatment administered via miniosmotic pumps was initiated 1 or 6 weeks later. The STZ-induced diabetic rats were treated with BRI (1 mg/kg/d) or vehicle (VEH) and control nondiabetic rats were treated with VEH for 4 weeks. Vitreoretinal VEGF protein, vitreal glutamate, and BRB breakdown were then measured. RESULTS At 5 weeks after STZ treatment, STZ-treated diabetic rats demonstrated significantly elevated vitreoretinal VEGF expression, vitreal glutamate concentrations, and BRB leakage compared with nondiabetic control rats. Chronic BRI treatment had no effect on vitreal glutamate concentrations in diabetic animals but significantly decreased vitreoretinal VEGF expression and BRB breakdown to levels similar to those observed in control rats. BRI also significantly reduced BRB breakdown in aged diabetic rats at 10 weeks after STZ treatment. CONCLUSIONS BRI produced marked decreases in vitreoretinal VEGF and inhibition of BRB breakdown in diabetic rats. The mechanism for these effects may involve attenuation of retinal NMDA receptor activity by BRI. The results suggest that BRI would be useful for treatment of ocular diseases associated with BRB leakage, such as diabetic macular edema and retinopathy.

Adrenergic and Imidazoline Receptor-Mediated Responses to UK-14,304-18 (Brimonidine) in Rabbits and Monkeys

Brimonidine is a relatively selective alpha-2 adrenoceptor agonist that is being developed for the treatment of glaucoma. Because brimonidine is chemically related to clonidine and has affinity for the nonadrenergic imidazoline receptor, its ocular effects may be unrelated to alpha-2 receptor activation. The objective of this study was to determine the pharmacology of the intraocular pressure (IOP) response to brimonidine in rabbits and monkeys and the side effects (miosis, cardiovascular depression) in monkeys. Conscious albino rabbits and cynomolgus monkeys were pretreated topically with the following receptor antagonists: rauwolscine (alpha-2), idazoxan (alpha-2, imidazoline), SKF 105854 (vascular postjunctional alpha-2), and prazosin (alpha-1). Intraocular pressure, pupil size, or blood pressure/heart rate was monitored noninvasively for 6 hours following dosing. Binding experiments were performed using [3H]brimonidine in membrane preparations from rabbit iris/ciliary body and from monkey cerebral cortex and brain stem. In rabbits, the ocular hypotensive response to brimonidine was unilateral and was inhibited by rauwolscine > idazoxan >> SKF 105854 = prazosin; this ranked order of potency correlated with displacement of [3H]brimonidine in the rabbit iris/ciliary body. In monkeys, brimonidine decreased IOP bilaterally and suppressed cardiovascular function suggesting a CNS site of action. Intraocular pressure and cardiovascular responses to brimonidine were inhibited by idazoxan >> rauwolscine > SKF 105854 = prazosin; a similar profile was obtained for displacement of [3H]brimonidine in monkey brain tissue. Both rauwolscine and idazoxan inhibited the miotic response to brimonidine in monkeys. Taken together, these results indicate that brimonidine stimulates an ocular alpha-2 adrenoceptor to decrease IOP in the rabbit and a CNS imidazoline receptor to decrease IOP, blood pressure, and heart rate in the cynomolgus monkey. The miotic response in the monkey is mediated by an alpha-2 adrenoceptor. The alpha-1 and vascular postjunctional alpha-2 adrenoceptors do not appear to play a role in mediating these responses.

Analogs of UK 14,304: Structural features responsible for α2 adrenoceptor activity

Abstract Factors influencing the potency of UK 14,304 analogs including conformational preorganization and arrangement of hydrogen bond acceptors on the aromatic core are described. The previously reported importance of twist of the iminoimidazoline ring relative to the core for enhanced α 2 activity is supported.

Analogs of UK 14,304 as α2-adrenoceptor agonists. Twist and agent polarity as design elements

Abstract Tetrahydroquinoxaline analogs of UK 14,304 were prepared. These agents proved to be highly polar, potent, and selective α 2 -adrenoceptor agonists. This study suggested that agents bearing a twist of the imidazoline ring relative to the quinoxaline nucleus prove more potent than planar analogs.