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.

Pharmacological evidence for heterogeneity of ocular alpha 2 adrenoceptors.

Previous studies have shown that ocular alpha 2 adrenoceptors are located prejunctionally on sympathetic neurons and postjunctionally on cells in the iris/ciliary body. While the activation of alpha 2 adrenoceptors at each site has been postulated to alter aqueous humor dynamics, little is known about the pharmacological characteristics of these receptors or their role in the modulation of anterior segment function. The purpose of the current study was to determine the possible heterogeneity of ocular alpha 2 adrenoceptors using relatively selective alpha 2 adrenoceptor agonists and antagonists to examine ocular pre- and postjunctional alpha 2 adrenoceptors. Prejunctional alpha 2 effects were evaluated by means of the cat nictitating membrane (CNM) preparation. Postjunctional alpha 2 effects were evaluated by means of the cAMP assay in rabbit iris root/ciliary body. In the CNM, the administration of UK-14, 304 (UK) produced a dose-related inhibition of neuronally mediated contractions. Pretreatment with the alpha 2 antagonist rauwolscine caused a 1 to 2 log unit right shift in the dose-response curve of UK in the CNM. However, pretreatment with alpha 2 antagonist SKF 104078 had no demonstrable effect on UK-induced inhibition of neuronally mediated contractions of the CNM. In the rabbit iris root/ciliary body, UK produced a concentration-dependent inhibition of cAMP accumulation on isoproterenol- and VIP-induced cAMP production. Pretreatment of iris root/ciliary bodies with SKF 104078 or rauwolscine reversed the inhibitory effect of UK on isoproterenol- and VIP-induced accumulation of cAMP. These data provide the first evidence that the pre- and postjunctional alpha 2 adrenoceptors represent pharmacologically distinct subpopulations of receptors in the eye.(ABSTRACT TRUNCATED AT 250 WORDS)

Hymenopteran venom stimulates adenylate cyclase in cultured human cells through a histamine receptor.

We have examined the effect of venom sac extract (VSE), prepared from two hymenopteran species, on intracellular cyclic AMP (cAMP) accumulation in a cultured human cell line. VSE prepared from the oriental hornet (Vespa orientalis) and from the paper wasp (Polistes carolina) induced an increase in accumulation of cAMP in human, transformed, non-pigmented, ciliary epithelial cells. The effect of V. orientalis VSE on intracellular cAMP was dose-dependent. Blocking the response of adenylate cyclase-linked beta-adrenergic receptors was without effect on this cellular response to VSE. On the other hand, the response to VSE prepared from both species was suppressed almost totally by the H2-histamine receptor-specific antagonist, cimetidine. The findings are discussed in the light of earlier observations that described a significant reduction in intraocular pressure in vertebrate animals treated with V. orientalis VSE.

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)

The role of cyclic AMP in the control of elasmobranch ocular tapetum lucidum pigment granule migration.

We have studied the effect of adding cAMP to dogfish ocular tapetum lucidum tissue maintained in vitro. Normally, under conditions of dark-adaptation, tapetal pigment granules attain an aggregated state, exposing highly reflective cellular plates (which contain crystalline guanine) to incident illumination. The reflected light from these plates is believed to function in the visual process by increasing photoreceptor photon capture under low light conditions. Upon illumination, the pigment granules attain a dispersed state, occluding the reflective surfaces. We found that this occlusion may be mimicked in dark-adapted tissue in vitro by adding cAMP, or by the use of agents believed to increase intracellular cAMP concentrations such as forskolin and IBMX. Additionally, aggregation of pigment in light-adapted tissue transferred to darkness is inhibited by such agents. The results of this and previously published studies indicate that the processes of pigment aggregation and dispersal in vivo are under the control of the neural retina through the probable mediation of either hormonal or direct neural communication.

CNPase activity in the vertebrate retina, retinal pigmented epithelium, and choroid.

The activity of the enzyme 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase, E.C.3.1.4.37) has been studied in the retina of three vertebrate species. Activity was highest in the goldfish, followed by Xenopus laevis and Rana pipiens. Also, high activity levels were found in goldfish retinal pigment epithelium and choroid, but not in the other two species. When added to in vitro culture systems, 2',3'-cyclic nucleotides were found to have no effect on goldfish cone retinomotor movement, but caused a marked inhibition of Rana pipiens rod outer segment disc membrane shedding. It is suggested that CNPase may play a role in cellular processes requiring membrane structural reorganization.

Frog rod outer segment shedding in vitro: histologic and electrophysiologic observations.

Rod outer segment shedding in the frog, Rana pipiens, has been studied using an in vitro eyecup method. Control experiments have shown that shedding responses in vitro are comparable to those in vivo and, like the situation in vivo, shedding in isolated eyecups requires a dark period followed by light onset. We found an initial, rapid and light-evoked component of the shedding response to be critically dependent upon bicarbonate concentration, supporting the initial discovery of a bicarbonate requirement for Xenopus rod shedding by Besharse et al. In Rana, in vitro shedding occurs in the presence of 20 mM aspartate, suggesting that functional integrity of the inner retina is not a prerequisite for rod shedding. Additionally, shedding was found to be suppressed completely in the presence of the local anesthetic MS-222 and the phosphodiesterase inhibitor IBMX. In the case of IBMX, electrophysiologic recording indicated changes in photoreceptor sensitivity in the presence of the drug. Such changes may play a role in the observed inhibition of shedding.

Simple sugars inhibit rod outer segment disc shedding by the frog retina.

To investigate the hypothesis that sugar molecules might act as markers for ROS disc phagocytosis, frog eyecups were incubated in a normally permissive medium for ROS disc shedding with and without added simple sugars. L-fucose, alpha-methyl-D-mannopyranoside and D-mannose all significantly reduced the numbers of packets of ROS discs found in the retinal pigment epithelium. D-fucose, L-mannose, D-fructose, D-galactose, D-glucose and sucrose were without significant effect at the same concentration. Ultrastructural examination of the retinas indicates that the sugars were effective on the disc shedding process rather than on phagocytosis of already shed disc packets.