Karen Bowman

Effects of adrenergic agonists upon regional ocular blood flow in normal and ganglionectomized rabbits.

Abstract Radioactive microspheres were used to measure changes in regional ocular blood flow 30–45 min after the topical application of epinephrine, norepinephrine, phenylephrine, and isoproterenol, to both normal and ganglionectomized rabbits. In normal animals, epinephrine (4%), phenylephrine (8%), and norepinephrine (4%), in order of decreasing potency, caused significant reductions in blood flow to the iris and ciliary processes. Isoproterenol (4%) had no significant effect in these tissues. Ganglionectomized eyes received much lower drug concentrations (0·1% in all cases), and displayed a different order of responsiveness: phenylephrine caused a larger reduction in flow than epinephrine, and norepinephrine failed to provoke statistically significant change. None of the drugs affected choroidal blood flow in either normal or ganglionectomized animals, but retinal blood flow in ganglionectomized eyes was significantly reduced by phenylephrine or isoproterenol administration. Additional experiments, addressing epinephrines effects at 3 hr after administration, demonstrated a restoration of flow to the ciliary processes and an increased iridial blood flow in both normal and ganglionectomized animals. This was accompanied by an increased flow to the choroid, and a reduced retinal blood flow in the ganglionectomized state.

A comparison of topical cannabinoids on intraocular pressure

A comparison has been made of the relative efficacy of a series of naturally occurring cannabinoids, related to Δ9-tetrahydrocannabinol, on the reduction of the rabbit intraocular pressure. Mineral oil was compared to sesame oil as a vehicle for some compounds. Some compounds which in sesame oil did not evoke a fall in intraocular pressure were found to do so when mineral oil was the vehicle, illustrating more efficacious drug delivery to the eye. Of the drugs tested Δ8-THC was the most potent in reducing intraocular pressure. It was found that some drugs which have been shown to have greatly reduced psychoactive effects in man, relative to Δ9-THC, reduced rabbit intraocular pressure. Such drugs appear to merit testing under clinical conditions.

Cannabinoid penetration and chronic effects in the eye.

Abstract The penetration of topically applied 14 C-labelled Δ 9 -tetrahydrocannabinol (THC) from various vehicles into the eye has been measured, and a low viscosity light mineral oil proved to be most efficient. Further delineation of oils was made on the basis of the physiological intraocular pressure decrease in response to topical THC and the least viscous oil (11 cP) proved most efficacious. Both 9- and 60-day studies were made with both an oil soluble and water soluble cannabinoid related to THC. Drops were applied topically, 2 × 50 μl per day, and the intraocular pressure response noted daily in the 9-day study and approximately once weekly in the 60-day study. The intraocular pressure always fell by about 20% at the dose levels employed here in response to the drugs and no tolerance was noted. The water soluble derivative produced a greater intraocular pressure reduction in ganglionectomized eyes.

Cannabinoid action on the eye as mediated through the central nervous system and local adrenergic activity

Abstract The newer cannabinoid derivatives (SP-1 and SP-106) have been compared to Δ 9 -tetrahydrocannabinol (THC) for their efficacy in reducing the intraocular pressure of normal and ganglionectomized eyes. All compounds have a lesser effect in the ganglionectomized eye compared to that in the normal eye, but SP-106 produces a proportionately greater effect than SP-1 and THC over a 60-day test period with twice daily administration of the drugs. The THC effect in a ganglionectomized and preganglionectomized eye is the result of local activity in the eye, whether drug reaches the eye through topical or systemic routes. This effect can also be completely inhibited using a β-adrenergic antagonist, and an α-adrenergic antagonist blocks the THC-induced effect on total outflow facility. These results indicate that cannabinoids act in the eye through both local sympathomimetic activity whether the drug reaches the eye via a topical or systemic route, as well as acting through a site proximal to the superior cervical sympathetic ganglion, presumably in the central nervous system.

Intracellular potential and pH of rabbit corneal endothelial cells

Rabbit corneal endothelial pH and electrical potential have both been determined using tracer distribution techniques. Intercellular pH was measured using the dimethyloxazolidine-dione method and intracellular potential was measured using tetraphenylphosphonium bromide. Intracellular pH was determined as 7.10 in an ambient solution of pH 7.5. The only solution variations which altered intracellular pH were variations in the external solution pH, bathing in sodium-free or bicarbonate-free solution, incubation for 3 hours with 10(-6) or 10(-4) M ouabain or for 1 hour with 10(-4) M ouabain or in a high (60 mM) bicarbonate solution. The data indicate a close correlation between sodium and bicarbonate needs for the endothelium which corresponds with known effects of these ions on transendothelial ion fluxes. Intracellular potentials were measured of -34 mV, which were stable in the face of all environmental perturbations except 1 mM acetazolamide and 10(-6) M ouabain exposure for 3 hours. These newer techniques may be employed to provide some clues into the mechanism of endothelial transport systems.

Water soluble marihuana-derived material: Pharmacological actions in rabbit and primate

Further studies have been made with water soluble marihuana-derived material (MDM). Neither adrenergic, cholinergic, aldosterone, dopamine or serotonin antagonism affected the fall in intraocular pressure induced by MDM. Partial blockade was obtained with galactose, glucose, or mannose, but not arabinose, when the latter were given at intravenous concentrations of 1 gm/animal and MDM was given at 25 micrograms animal, suggesting that these sugars may be involved at the active site of the MDM glycoproteins. Dexamethasone was without effect on either intravenous or intravitreal MDM indicating that the MDM effect is not a non-specific response to a protein. A similar plant glycoprotein, larch arabinogalactan, at 200 micrograms/animal was without effect on intraocular pressure. Aqueous humor flow rate was increased 3 hours after MDM administration, a period corresponding to the intraocular pressure increase caused by MDM, and fell to 20% of control values when the fall in intraocular pressure occurred. Blood flow through the iris was increased at both one and six hours after intravenous MDM injection indicating a vasodilation which could contribute to the initial increase in intraocular pressure. Intravitreal injection of MDM in rabbit and rhesus monkey caused a fall in intraocular pressure only after a 24 hour delay: the unilateral response indicated that systemic metabolism was not required for activity and the delay was likely caused by the diffusion time to the ciliary processes from the mid-vitreal injection site. The changes in beta-receptors, adenylate cyclase and carbonic anhydrase in the ciliary processes are minimal indicating a possible vascular mechanism of action of MDM.

Marihuana-derived material: distribution and effects after systemic administration

Studies have been made in an attempt to elucidate the mode of action of water-soluble marihuana-derived material (MDM). MDM lowers intraocular pressure (IOP) at systemic dose levels greater than 5 micrograms/rabbit by reducing aqueous humor inflow. Blood pressure, body temperature, and PO2 remain constant despite the wide variation in IOP caused by high dose levels of MDM, viz. an initial hypertensive phase followed by a hypotensive phase. Blood PCO2 and pH, however, both decrease with 1 mg MDM/rabbit indicating an acidosis which may partially explain some of the fall in IOP caused by MDM at this high dose level. Low doses of MDM (50 micrograms/animal), however, induce no such changes in systemic chemistry, illustrating the absence of an MDM effect which can explain the greater than 50% fall in IOP. Repeated injections of MDM on a weekly basis indicate a sequentially reduced effect on IOP. MDM, when incubated in vitro for 6 hours with saline, aqueous or vitreous, always induced a fall in IOP; incubation in these media for 24 hours, however, reduced the capacity to induce an IOP decrease. When aqueous or vitreous was removed from animals which had received intravitreal injections of MDM 24 hours previously (thus, at a time when the IOP in these animals was low) and was reinjected intravitreally into fresh recipient rabbits, the IOP fell in the recipients with aqueous, but not vitreous. Only when high doses of MDM (greater than or equal to 2 mg) were given systemically to a donor rabbit was any evidence obtained of a fall in IOP in recipient rabbits at short times after the donor injection (less than 10 min); at greater times after the donor injections whole blood or serum from donor rabbits failed to elicit a fall in IOP in recipient animals. These data indicate that, in vivo, MDM is bound or metabolized rapidly in rabbits when MDM is given systemically.

Corneal epithelial healing rates after topical nucleotides

Discrete 28mm2 epithelial lesions in paired rabbit corneas were treated four times daily with either vehicle alone or 10(-2)M or 10(-3)M Db cAMP in the presence or absence of either theophylline (10(-2)M) or epinephrine (5.5 x 10(-3)M). Cyclic GMP was also used either alone or with pilocarpine (1%). The lesion size was determined photographically at various intervals over 48 hours. No treatment regimen at the concentrations of cyclic nucleotides used had any influence on the rate of epithelial regrowth.

CORNEAL ENDOTHELIAL PERMEABILITY FOLLOWING STORAGE IN MOIST CHAMBER AND MK MEDIUM

Rabbit corneal endothelial permeability to sucrose and dextran was determined after storage in moist chamber or MK medium. When compared to fresh rabbit corneas there was no statistically significant difference in endothelial permeability to these two solutes after both types of storage for periods up to ten days.

Interaction between ophthalmic drugs and intraocular lenses

We evaluated the in vitro interaction between commonly used ophthalmic drugs and a series of intraocular lenses to determine if the lenses could act as a drug reservoir in the eye. Lenses examined included anterior and posterior chamber lenses as well as iris plane lenses. Assessment of lens uptake was made by immersing the lens for nine days in a radioactive drug solution with a concentration equal to that found in the anterior chamber one hour after drug administration. No evidence of drug uptake was found for any lens immersed in epinephrine, norepinephrine, dexamethasone, or chloramphenicol.