Brimonidine Evokes Heterogeneous Vasomotor Response of Retinal Arterioles: Diminished Nitric Oxide–Mediated Vasodilation When Size Goes Small

Abstract

Purpose: : Brimonidine, an α₂–adrenergic receptor (AR) agonist, has been employed in the treatment of glaucoma due to its beneficial effects on intraocular pressure reduction and neuroprotection. In addition, some studies have implicated that brimonidine might influence ocular blood flow; however, its effect on the retinal microcirculation has not been characterized. Herein, we examined the vasomotor action of brimonidine on varying branching orders of retinal arterioles in vitro and determined the contribution of the α₂–AR subtype and the role of endothelium–derived nitric oxide (NO) in this vasomotor response.

Methods: : First– and second–order porcine retinal arterioles were isolated, cannulated and pressurized for functional studies. Videomicroscopic techniques were employed to record diameter changes in response to brimonidine. RT/PCR was performed for detection of α–AR and endothelial NO synthase (eNOS) mRNA in retinal arterioles.

Results: : All first–order arterioles (82±2 µm i.d.) dilated dose–dependently to brimonidine (0.1 nM to 10 µM) with 10% dilation at the highest concentration. Second–order arterioles (50±1 µm i.d.) responded heterogeneously with either dilation or constriction. The incidence and magnitude of vasoconstriction were increased with increasing brimonidine concentration. Administration of NO synthase inhibitor L–NAME abolished the brimonidine–induced vasodilation in first–order arterioles. Regardless of vessel size, vasomotor responses (i.e., vasodilation and vasoconstriction) of retinal arterioles were sensitive to the α₂–AR antagonist rauwolscine. Consistent with the functional data, α_2A–AR mRNA and eNOS mRNA were detected in retinal arterioles.

Conclusions: : The data demonstrate that brimonidine at clinical doses evokes a consistent NO–dependent vasodilation in first–order retinal arterioles but a heterogeneous response in second–order arterioles. These vasomotor responses are mediated by the activation of α₂–AR. It appears that brimonidine, depending upon the concentration, may cause heterogeneous flow distribution in the retinal microvascular network.

Keywords: neuroprotection • signal transduction: pharmacology/physiology • nitric oxide