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.