ABSTRACTAlpha-2 (α2) and DA2 agonists lower intraocular pressure (IOP) in laboratory animals and man. Like β-blockers, α2 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 α2 and DA2 receptors on sympathetic neurons are separate entities by utilizing selective agonists and antagonists. In addition to their prejunctional actions, α2 agonists act postjunctionally in the iris root/ciliary body (IRCB). Moreover, utilizing selective postjunctional α2 adrenoceptor antagonists, heterogeneity can be demonstrated between ocular pre- and postjunctional adrenoceptors. Stimulation of postjunctional α2 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 α2 agonists should have a broader spectrum of action in the eye than β-receptor antagonists.Three bioassays were used in the activity analysis of α2 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 (α2 or DA2). In this system, it has been demonstrated that α2 agonists have inhibitory properties, but DA2 agonists are inactive. The composite ocular activity of α2 or DA2 agonists was tested by topical administration of graduated doses to eyes of rabbits and monkeys. In these experiments, IOP was measured over a 4 to 6 hour period to assess the in vivo efficacy of the compounds.Following topical administration, systemic distribution of the agents may evoke responses in the CNS. α2 Agonists generally cause suppression of sympathetic neuron function centrally and peripherally. In contrast, central stimulation of DA2 receptors enhances sympathetic outflow and vasopressin release which counteracts peripheral inhibition of sympathetic neurons. Collectively, these results suggest that α2 and DA2 agonists have multiple sites of action on separate receptors. Alpha-2 receptor agonism at CNS sites and ocular sites yield a pluripotential, synergistic action. In contrast, DA2 receptor action at central and ocular sites can be mutually antagonistic. Clinically, it would be advantageous to have α2 and DA2 agonists that have their predominant site of action
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