The subdivision of adrenoceptors (alpha, beta, dopamine) into several classes, each having subtypes (alpha1, alpha2, beta1, beta2, DA1, DA2), has led to an increased understanding of the sympathoadrenal system and to the development of drugs which stimulate or inhibit these discrete subtypes of receptors. In the eye, dopamine (DA2) and alpha (alpha2) agonists can lower intraocular pressure (IOP) in cats, rabbits and monkeys, as well as in normal and glaucomatous humans. The overall objectives of this research project are: 1) to investigate the physiological, pharmacological and pathophysiological significance of alpha2 and DA2 receptors in the anterior segment of the eye and 2) to determine the consequences of alpha2 and DA2 agonist-induced changes in CNS and neuroendocrine activity on ocular function. In order to accomplish these objectives, alpha2 and DA2 agonists will be evaluated in terms of: a) hetero-geneity of alpha2 and DA2 receptors at pre/postjunctional sites in anterior segment; b) effects of alpha2 and DA2 neuronal receptors on catecholamine and cotransmitter release; c) biochemical messengers utilized by alpha2 and DA2 receptors at the neuroeffector junction; d) effects of alpha2 and DA2 agonists on neuroendocrine function; e) relative importance of central versus peripheral and pre- versus postjunctional alpha2 and DA2 receptors in modulating aqueous flow, iris function and intraocular pressure (IOP). Local effects of alpha2 and DA2 agonists on the neuroeffector junction will be studied utilizing cat nictitating membrane and iris/ciliary body preparations. Systemic effects will be determined by analyzing alpha2 and DA2 agonist-induced changes in neuroendocrine function (prolactin, vasopressin, atrial natriuretic peptide) following topical administration. Alpha-2 and DA2 agonists will be evaluated for alteration of IOP in cats, rabbits and bush babies and aqueous flow in rabbits and bush babies before and after the administration of centrally and peripherally acting alpha2 and DA2 antagonists. Data from these neuropharmacological and neuroendocrinological models will result in a better understanding of the functional contribution of alpha2 and DA2 receptors to the modulation of ocular hydrodynamics. In addition, this project should expand and improve the use of alpha2 agonists as antiglaucoma agents and provide a rational basis for the inclusion of dopamine (DA2) agonists in the medical therapy of glaucoma.
Showing the most recent 10 out of 17 publications
