benzofurans and Ocular-Hypotension

In rabbit's aqueous humor, norepinephrine, epinephrine, dopamine and serotonin were detected simultaneously by a high performance liquid chromatography with electrochemical detection. Furthermore, the changes in catecholamine levels in aqueous humor were evaluated after topical application of moxonidine, an imidazoline1/alpha 2 receptor agonist, in the presence and absence of efaroxan. The level of norepinephrine in aqueous humor was reduced by moxonidine treatment. However, under the same set of conditions, there were no significant changes in the levels of dopamine, epinephrine or serotonin. Pretreatment with efaroxan antagonized moxonidine-induced suppression of norepinephrine levels. In other in vivo experiments, moxonidine caused a decrease in intraocular pressure which was antagonized by pretreatment with efaroxan. In the superior cervical ganglion preparation, norepinephrine release was increased 5-fold by the presence of a high K+ medium. The K(+)-evoked norepinephrine secretion was reduced by 55% by moxonidine. Pretreatment with efaroxan blocked the moxonidine-induced inhibition of norepinephrine release. It is concluded that inhibition of norepinephrine release from the superior cervical ganglion and suppression of aqueous norepinephrine levels contribute to the moxonidine-induced lowering of intraocular pressure. Moreover, the antagonism of moxonidine's in vivo and in vitro effects by efaroxan suggests the involvement of imidazoline1 receptors, but does not preclude activity on alpha 2 adrenoceptors.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Aqueous Humor; Benzofurans; Dopamine; Female; Imidazoles; Intraocular Pressure; Male; Norepinephrine; Ocular Hypotension; Rabbits; Superior Cervical Ganglion

To examine ocular actions by rilmenidine, an imidazoline1 and alpha 2 adrenoceptor agonist.. Intraocular pressure was measured in normal and sympathetically denervated rabbits by pneumatonometry. Electrically stimulated 3H-norepinephrine release from sympathetic nerves was determined in isolated, perfused rabbit iris-ciliary bodies. cAMP levels were evaluated in rabbit iris-ciliary bodies by radioimmunoassay. Ca2+ concentrations were measured in rabbit transformed nonpigmented ciliary epithelial cells by fluorescence ratio microscopy.. Topical, unilateral administration of rilmenidine produced hypotensive responses in normal rabbits which were antagonized by either bilaterally administered efaroxan, an imidazoline receptor antagonist or rauwolscine, an alpha 2 receptor antagonist. Sympathectomy also eliminated the ocular hypotensive response. Rilmenidine (0.001, 0.01, 0.1, 1 microM) caused 5 +/- 1%, 18 +/- 5%, 35 +/- 10%, and 48 +/- 9% inhibition, respectively, of 3H-norepinephrine overflow whereas 10 microM efaroxan or rauwolscine caused enhancement of norepinephrine release by 102 +/- 23% or 86 +/- 25%, respectively. Furthermore, pretreatment with efaroxan or rauwolscine partially antagonized the inhibition of norepinephrine release induced by rilmenidine. In other experiments, rilmenidine (1 microM) inhibited isoproterenol-stimulated cAMP accumulation in rabbit iris-ciliary bodies by 43 +/- 9% which was antagonized by 10 microM efaroxan or rauwolscine. Rilmenidine induced large increases in [Ca2+]i in rabbit nonpigmented ciliary epithelial cells which were effectively antagonized by efaroxan or rauwolscine.. These in vivo and in vitro data suggest that the ocular hypotensive activity induced by rilmenidine is due, in part, to suppression of sympathetic neuroeffector function in the rabbit ciliary body and that alpha 2 adrenergic receptors and/or imidazoline1 receptors are involved.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Benzofurans; Calcium; Ciliary Body; Cyclic AMP; Female; Imidazoles; Imidazoline Receptors; Intraocular Pressure; Iris; Male; Norepinephrine; Ocular Hypotension; Oxazoles; Rabbits; Receptors, Adrenergic, alpha-2; Receptors, Drug; Rilmenidine; Sympathectomy; Sympathetic Nervous System; Yohimbine

1) Moxonidine (MOX), injected icvt into the anterior lateral ventricle of NZW rabbits, induced bilateral, ocular hypotension (> 7.0 mmHg) that persisted for two hrs. 2) Oxymetazoline (OXY), injected icvt into the anterior lateral ventricle of NZW rabbits, induced bilateral ocular hypotension (> 7.0 mmHg) that peaked at two hrs. 3) Unilateral topical application of OXY induced maximal, bilateral ocular hypotension (> 12 mmHg), at 3 hrs, in both the contralateral and ipsilateral eyes, that persisted more than 12 hrs. 4) The putative imidazoline (I1) antagonist, efaroxan, injected icvt into the anterior lateral ventricle, inhibited significantly the ocular hypotension produced by icvt MOX, icvt OXY, and unilateral topical OXY. 5) Imidazoline (I1) receptors, located in the CNS, play a role in MOX- and OXY-induced ocular hypotension, as suggested by the ability of the putative imidazoline (I1) receptor antagonist efaroxan, to inhibit icvt MOX-, icvt OXY- and topical OXY-induced ocular hypotension.

Topics: Administration, Topical; Animals; Aqueous Humor; Benzofurans; Brain; Catheters, Indwelling; Imidazoles; Imidazoline Receptors; Injections, Intraventricular; Intraocular Pressure; Male; Ocular Hypotension; Oxymetazoline; Pupil; Rabbits; Receptors, Drug