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 alpha(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 microg) 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 microg i.c.v.). 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 microg i.c.v.), 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 i.c.v. MOX observed in the SX eye might be mediated by changes in outflow resistance. Sedation was observed in all the rabbits treated with MOX (i.c.v.) 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.

Naphazoline-induced suppression of aqueous humor pressure and flow: involvement of central and peripheral alpha(2)/I(1) receptors.

The objective of this study was to examine the ocular hydrodynamic effects of topically and centrally administered naphazoline, alone and following pretreatment with pertussis toxin (PTX) and alpha(2)/I(1)receptor antagonists. Topically and intracisternally administered naphazoline was examined for its ability to alter intraocular pressure (IOP) of rabbits in the absence and presence of receptor antagonists (rauwolscine, efaroxan) and a G(i/o)ribosylating agent PTX. In addition, the topical effects of naphazoline on pupil diameter and aqueous humor flow rate were evaluated. Topical unilateral application of naphazoline (7.5, 25 and 75 micro g; 25 micro l) elicited an ipsilateral dose-dependent mydriasis (2, 4 and 5.5 mm) that peaked at 2 hr with a duration of up to 5 hr. The IOP decreases induced by naphazoline were bilateral and dose-dependent (3, 6 and 10 mmHg); the response peaked at 1 hr and lasted for up to 5 hr. Pretreatment with efaroxan (250 micro g) elicited significantly greater antagonism of the ocular hypotensive response to naphazoline than did rauwolscine (250 micro g) suggesting an involvement of imidazoline (I(1)) receptors. Intracisternal application of naphazoline (3.3 micro g) also produced bilateral reductions (6 mmHg) of IOP that were immediate (10 min post drug) and lasted for approximately 2 hr. In PTX-pretreated (2.5 micro g kg(-1), i.a.) rabbits, the ocular hypotensive effects of naphazoline by both routes (topically and centrally) were attenuated by 50--65%. In addition to producing ocular hypotension, topical application of naphazoline (75 micro g; 25 micro l) caused significant reduction, from 2.8 to 1.5 micro l min(-1), in aqueous humor flow. These in vivo data indicate that, regardless of route of administration, alteration of aqueous humor flow by naphazoline was induced by the activation of alpha(2)and I(1)receptors. The ocular hypotensive effects produced by central administration did not result in sedation, therefore, there is the suggestion that central alpha(2)adrenergic receptors were stimulated minimally by naphazoline. Thus, these data suggest that ocular hypotensive effects and suppression of aqueous humor flow rate by naphazoline are mediated, in part, by alpha(2)and/or central I(1)at both central (brain) and peripheral (eye) sites. Moreover, these data indicate that the receptors are linked to PTX-sensitive G((i/o))proteins.

8OH-DPAT-Induced ocular hypotension: sites and mechanisms of action.

The purpose of this study was to define the ocular actions of 8-OH-DPAT(DPAT), a 5-HT(1A)receptor agonist. The intraocular pressure responses to topically applied DPAT were dose related (25, 125, 250 microgram) and bilateral in normal rabbits but of relatively short duration. Ocular hypotension induced by topical, unilateral DPAT (125 microgram) in normal eyes did not occur in sympathetically denervated eyes. DPAT-induced ocular hypotension was inhibited by pretreatment with spiroxatrine, a 5-HT(1A)and alpha(2C)receptor antagonist, but not spiperone, a 5-HT(2A)receptor antagonist. In contrast, the hypotensive effect produced by unilaterally applied DPAT in the contralateral eye was abolished following pretreatment with rauwolscine, an alpha(2)-receptor antagonist, but the DPAT-induced ocular hypotension was not antagonized in the treated (ipsilateral) eye. Following central administration of DPAT (3 microgram) into the lateral ventricle, intraocular pressure was lowered bilaterally at 10 min and the effect lasted for 2 hr. In in vitro experiments, DPAT (0.1, 1, 10 micrometer) failed to alter norepinephrine release in rabbit iris-ciliary bodies. However, DPAT depressed basal cAMP levels in rabbit iris-ciliary bodies and also caused a dose-related (1, 10, 100 micrometer) inhibition of isoproterenol (1 micrometer)-stimulated cAMP accumulation by 26%, 58% and 82%, respectively. These findings indicate that: (1) based upon bilateral activity by the topical route, DPAT-induced ocular hypotension could result, in part, through activation of 5-HT(1A)receptors in the eye and 5-HT(1A)receptors and/or alpha(2C)adrenoreceptors in the central nervous system, (2) the activity of DPAT on 5-HT(1A)and/or alpha(2C)receptors was confirmed by antagonism of the ocular hypotensive response by spiroxatrine, (3) although there is no apparent prejunctional effect of DPAT on sympathetic nerves of iris-ciliary bodies, the accumulation of basal and isoproterenol-stimulated cAMP levels were depressed by DPAT, and (4) as a result of inhibition by rauwolscine, the ocular hypotensive effect of DPAT in the contralateral eye could involve an action on alpha(2)adrenoreceptors in the central nervous system.

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 alpha1 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.

Potential mechanisms of moxonidine-induced ocular hypotension: role of norepinephrine.

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.

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.

Ocular actions of an octahydrobenzo[f]quinoline: Ha117.

An octahydrobenzo[f]quinoline compound, Ha117, was examined for activity on: (1) intraocular pressure and in normal, sympathectomized and water loaded rabbits and aqueous flow rate in normal and sympathectomized rabbits, respectively; (2) contractions of the cat nictitating membrane elicited by electrical stimulation of cervical sympathetic nerves; (3) cAMP accumulation in the isolated rabbit iris root-ciliary body preparation. Ha117 lowered intraocular pressure and aqueous flow rate in normal but not in sympathectomized rabbits. Elevated intraocular pressure produced by water loading was suppressed by Ha117 and pretreatment with metoclopramide antagonized the inhibitory effect of Ha117. Neuronally mediated contractions of the nictitating membrane were inhibited in a dose-related fashion by Ha117, and inhibitory effects were antagonized by domperidone. Ha117 and an analog, Ha118, did not suppress isoproterenol- and vasoactive intestinal peptide-induced accumulation of cAMP in the rabbit iris root/ciliary body. In vivo results in rabbit and cat models suggest that the ocular hypotensive effect of Ha117 is mediated by an action on prejunctional dopamine (DA2) receptors. In vitro data in the rabbit iris root/ciliary body suggest that Ha117 and Ha118-induced lowering of intraocular pressure does not involve postjunctional suppression of cAMP accumulation.

Comparative effects of alpha-2 and DA-2 agonists on intraocular pressure in pigmented and nonpigmented rabbits.

Alpha-2 and DA2 adrenoceptor agonists produce ocular hypotension in cats, rabbits, monkeys and humans. In this study, the effects of topical, unilateral administration of medetomidine (MED), an alpha-2 agonist, and Ha-118 (HA), a DA2 agonist, were compared on intraocular pressure (IOP) in normal, unilaterally sympathectomized (SX), and ocular hypertensive (oral water loaded) Dutch Belted (DB) and New Zealand White (NZW) rabbits. MED (75 micrograms) produced bilateral ocular hypotensive effects in both DB and NZW normal rabbits; however, HA (250 micrograms) lowered IOP unilaterally in NZW rabbits only. MED (25 micrograms) inhibited the rise in IOP caused by oral water loading in both DB and NZW rabbits; HA, on the other hand, was effective only in NZW rabbits. Topical bilateral pretreatment with metoclopramide, a DA2 antagonist, inhibited the ocular antihypertensive effect of HA in NZW rabbits. The IOP lowering effects of MED were absent in the SX eyes of DB and NZW rabbits, but hypotensive responses to MED were present in normal (contralateral) eyes of both strains. In contrast, HA was effective only in the treated, normal eyes of SX NZW rabbits. These data support pharmacodynamic roles for alpha-2 and DA2 receptors in modulating IOP. The lack of activity by HA in DB rabbit eyes suggests a possible absence of DA2 receptors or excessive binding of HA to pigment in the anterior segment of DB rabbit eyes.

Medetomidine-induced alterations of intraocular pressure and contraction of the nictitating membrane.

The alpha-2 adrenoceptor agonist, medotomidine (MED), was examined for effects on: (1) intraocular pressure (IOP) in normal and sympathectomized (SX) rabbits; (2) IOP in normal rabbits pretreated with the alpha-2 antagonist idazoxan; (3) contractions of the cat nictitating membrane (CNM) elicited by nerve stimulation and intra-arterial (IA) norepinephrine. Unilateral topical administration of MED (7.5-75 micrograms) caused dose-dependent, bilateral IOP reduction in normal eyes, but MED (25 micrograms) had no appreciable hypotensive activity in SX eyes. The ocular hypotensive effect of MED (25 micrograms) was antagonized by treatment with idazoxan (100 micrograms, bilaterally), a relatively selective alpha-2 antagonist. MED and dexmedetomidine (DMED) also inhibited frequency-related contractions of CNM induced by electrical stimulation of the cervical sympathetic trunk. Rauwolscine (100 micrograms, IA) shifted the MED dose response in the CNM to the right indicative competitive antagonism, whereas SK&F 104078 (300 micrograms, IA), a relatively dose-selective postjunctional alpha-2 antagonist, had no effect on DMED suppression. These results show that MED lowers IOP in part, by interacting with alpha-2 adrenoceptors located on sympathetic nerve endings. An effect of MED on imidazoline sites may also be possible.

Ocular inhibitory effects of the dopamine DA2 agonist (Ha-118) in cats and rabbits.

1. Topical administration of the dopamine (DA2) receptor agonist, Ha-118, produced unilateral ocular hypotension and miosis in normal cats. 2. The ocular hypotensive and mitotic effects of Ha-118 were not observed in surgically sympathectomized cats indicating that an intact sympathetic pathway is necessary to demonstrate activity. 3. Ha-118 caused dose-dependent suppression of contractions of the cat nictitating membrane (CNM) elicited by electrical stimulation of the pre- and postganglionic sympathetic nerve trunks but not by exogenously administered noradrenaline suggesting that Ha-118 affected prejunctional but not ganglionic or postjunctional receptors. 4. Sulpiride antagonized Ha-118-induced inhibition of neuronally mediated contractions in the CNM suggesting an interaction at DA2 receptors. 5. Topical administration of Ha-118 inhibited the rise in intraocular pressure induced by oral water loading in rabbits. 6. Topical pretreatment with metoclopramide, a DA2 antagonist, inhibited the ocular antihypertensive effect of Ha-118 in rabbits. 7. These studies demonstrate that Ha-118 decreased intraocular pressure (IOP) and pupil diameter (PD) in the cat and that this activity can be correlated with suppression of peripheral sympathetic tone in the CNM.

Review: alpha 2 and DA2 agonists as antiglaucoma agents: comparative pharmacology and clinical potential.

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)