Miller J. Ogidigben

Oxymetazoline: Potential Mechanisms of Inhibitory Effects on Aqueous Humor Dynamics

Oxymetazoline, an alpha 2 agonist, was active in lowering intraocular pressure in normal and sympathetically denervated rabbit eyes. Ocular hypotension was accompanied by decreased aqueous humor inflow. Topical pretreatment with rauwolscine, an alpha 2 antagonist, reduced the oxymetazoline-induced hypotensive effect more in contralateral than in ipsilateral eyes indicating the possible involvement of central alpha 2 adrenoceptors. Efaroxan, a relatively selective imidazoline antagonist, and diclofenac, a cyclooxygenase inhibitor, failed to inhibit the oxymetazoline-induced ocular hypotensive response. Oxymetazoline induced mydriasis in treated eyes at all doses. In in vitro studies, oxymetazoline inhibited isoproterenol-stimulated cAMP production in rabbit iris-ciliary bodies and cultured rabbit nonpigmented ciliary epithelial cells. The inhibition of cAMP accumulation induced by oxymetazoline was antagonized by rauwolscine or by BRL-44408, a relatively selective alpha 2A-adrenoceptor antagonist. These data indicate that oxymetazoline lowered intraocular pressure by activating alpha 2A receptors (ciliary epithelium) and that the ocular hypotensive effect was not totally dependent on intact sympathetic nerves. Results suggest that mechanisms involving centrally mediated effects of oxymetazoline are probable and this possibility is currently under investigation.

Lisuride Acts at Multiple Sites to Induce Ocular Hypotension and Mydriasis

Topically unilaterally applied lisuride caused dose-related lowering of intraocular pressure in ipsilateral (treated) but not in contralateral eyes of normal rabbits. The ocular hypotensive response induced by lisuride was antagonized by pretreatment with metoclopramide, a dopamine receptor antagonist, and was partially reduced by local sympathetic denervation. In contrast to the unilateral effect on intraocular pressure, lisuride caused mydriasis in both eyes. Mydriasis was of greater magnitude and more sustained in normal eyes compared to sympathetically denervated eyes. Additional in vivo experiments demonstrated that lisuride caused dose-related suppression of neuronally initiated contractions of cat nictitating membrane. In in vitro experiments lisuride caused dose-related inhibition of norepinephrine release from isolated rabbit iris-ciliary bodies. Pretreatment with Bay K 8644, a calcium channel activator, did not attenuate lisuride-induced inhibition of norepinephrine release in isolated rabbit iris-ciliary bodies. Because lisuride pretreatment caused no change in isoproterenol-stimulated cAMP accumulation in isolated iris-ciliary bodies, suppression of adenylate cyclase was unlikely. It is concluded that the ocular hypotensive effect of lisuride results, in part, from activation of prejunctional dopaminergic receptors on peripheral sympathetic nerves in the anterior segment of the eye but may also involve antagonism on peripheral postjunctional α1 adrenoceptors as well. Bilateral increases in pupil diameter antagonized by metoclopramide suggest a stimulatory action of lisuride on dopamine receptors in the central nervous system.

Central imidazoline (I 1 ) receptors modulate aqueous hydrodynamics

The purpose of this work is to determine the relative contributions of central imidazoline (I 1) receptors to the ocular hydrodynamic action of moxonidine. Moxonidine (MOX), an a 2 and I 1 receptor agonist, and efaroxan (EFA), a relatively selective I 1 antagonist, were utilized to study alterations in intraocular pressure (IOP) and aqueous flow in New Zealand white rabbits subjected to intracerebroventricular (i.c.v.) cannulation and sympathectomy. Intracerebroventricular administration of MOX (0.033, 0.33 and 3.33 µg) to normal rabbits produced dose-dependent, bilateral IOP decreases of 3, 6, and 8 mmHg, respectively. The ocular hypotensive response to MOX was immediate (10 min. post drug), lasted for one hour, and was inhibited by prior administration of efaroxan (3.33 µg icv). In unilaterally sympathectomized (SX) rabbits, the ocular hypotensive response induced by i.c.v MOX in the denervated eye was attenuated approximately 50%, but the duration of ocular hypotension in the surgically altered eye was longer than that of the normal eye. MOX (0.33 µg icv), caused a statistically significant decrease (2.24 to 1.59 ml/min.) in aqueous flow in normal eyes. In SX eyes, there was no change in aqueous flow by MOX, suggesting that IOP effect in icv MOX observed in the SX eye might be mediated by changes in outflow resistance. Sedation was observed in all the rabbits treated with MOX (icv) and was dose-dependent. These in vivo data support the suggestion that centrally located I 1 receptors modulate the early contralateral response to topically administered MOX and are involved in lowering of IOP and aqueous flow in rabbit. In addition, expression of the full ocular hypotensive effect of centrally applied MOX depends on intact sympathetic innervation. Ocular hypotension induced by MOX in the SX eye may involve an effect on uveoscleral outflow.

Pharmacological evidence of a role for prejunctional imidazoline (I(1)) receptors in ocular function.

Imidazoline and guanidiniun-substituted isoindoline compounds have been reported to demonstrate affinity for the putative imidazoline receptors (I 1) and alpha-2 (a 2) adrenoceptors. The purpose of this study was to determine the relative contribution of I 1 receptors to ocular actions of moxonidine (MOX) and brimonidine (BRIM) by utilizing relatively selective a 2 and I 1 antagonists. MOX, an a 2 /I 1 receptor agonist, BRIM, a selective a 2 agonist, efaroxan (EFA), an I 1 /a 2 antagonist and rauwolscine (RAU), a relatively selective a 2 antagonist, were utilized to study alterations in sympathetically evoked contractions of the cat nictitating membrane (CNM). MOX (1-10 µg) suppressed, dose dependently, contractions of the CNM elicited by electrically stimulating the cervical preganglionic sympathetic trunk. The suppressive effect of MOX was antagonized more effectively by EFA (333 µg) than by rauwolscine (333 µg). In contrast, RAU, but not EFA, completely reversed the suppressive effects of BRIM on electrically induced contractions of the CNM. In conclusion, these in vivo data suggest that I 1 receptors are involved in the pre-junctional (neuronal) modulation of contractions in the CNM (Supported by NIH grant EY06338).