Alpha 2 and DA2 Agonists as Antiglaucoma Agents: Comparative Pharmacology and Clinical Potential

Abstract

Alpha-2 (alpha 2) and DA2 agonists lower intraocular pressure (IOP) in laboratory animals and man. Like beta-blockers, alpha 2 and DA2 agonists appear to lower IOP by reducing aqueous inflow. These agents share a common mode of action on sympathetic nerve terminals, where they modulate the release of neurotransmitters. However, one can demonstrate that peripheral prejunctional alpha 2 and DA2 receptors on sympathetic neurons are separate entities by utilizing selective agonists and antagonists. In addition to their prejunctional actions, alpha 2 agonists act postjunctionally in the iris root/ciliary body (IRCB). Moreover, utilizing selective postjunctional alpha 2 adrenoceptor antagonists, heterogeneity can be demonstrated between ocular pre- and postjunctional adrenoceptors. Stimulation of postjunctional alpha 2 adrenoceptors in the IRCB can inhibit the cellular responses to endogenous neurotransmitters and hormones that are coupled positively to adenylate cyclase. Based upon these observations, one can predict that alpha 2 agonists should have a broader spectrum of action in the eye than beta-receptor antagonists. Three bioassays were used in the activity analysis of alpha 2 and DA2 agonists. Prejunctional (neuronal) activity was determined in the cat nictitating membrane preparation in which frequency-related (2-8 Hz), neuronally induced contractions were inhibited by these compounds. Postjunctional activity was assayed on isolated rabbit IRCB tissue where cAMP levels were stimulated by either isoproterenol or VIP in the absence and presence of the test agonist (alpha 2 or DA2). In this system, it has been demonstrated that alpha 2 agonists have inhibitory properties, but DA2 agonists are inactive.(ABSTRACT TRUNCATED AT 250 WORDS)