Pharmacologic trabeculocanalotomy. Facilitating aqueous outflow by assaulting the meshwork cytoskeleton, junctional complexes, and extracellular matrix.
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Animals↗
Biomedical subjects
P L Kaufman
Publications and source records attributed to P L Kaufman.
Age-related loss of ciliary muscle mobility in the rhesus monkey. Role of the choroid.
Ciliary muscle topography was studied in rhesus monkey eyes (aged 6 to 29 years) bisected meridionally through cornea and optic nerve head. Half of each eye was incubated in atropine sulfate, the other in pilocarpine hydrochloride, and both were then processed for histologic study. Several ciliary muscle sections from the original cut margin and the middle of the half eyes were traced and compared quantitatively. In sections from the middle, where the attachments of the muscle were presumably intact, the pilocarpine effect on ciliary muscle topography was lost with age. In sections near the cut margin, where some of the posterior attachments were disrupted and the choroid had detached from the sclera, the pilocarpine effect persisted with age. These findings suggest that loss of ciliary muscle movement with age is caused by decreased compliance of its posterior attachment.
Aging↗
PhXA34-induced ocular hypotension.
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Humans↗
The effect of 12(R)-hydroxyeicosatetraenoic acid on aqueous humor dynamics in the rabbit and cynomolgus monkey.
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12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
The effect of topical PGF2 alpha on uveoscleral outflow and outflow facility in the rabbit eye.
Prostaglandin F2 alpha (PGF2 alpha) is a powerful ocular hypotensive agent in rabbit, cat, dog, monkey and human. In cynomolgus monkeys, the intraocular pressure (IOP) lowering is due to increased uveoscleral outflow (Fu). Because the anatomy of the rabbit outflow apparatus differs significantly from that of the primate, we sought to determine whether the mechanism of the PGF2 alpha-induced IOP fall was the same. PGF2 alpha tromethamine salt (PGF2 alpha-TS) (50 micrograms) applied to one eye of 14 conscious rabbits produced a significant IOP fall of 7.4 +/- 0.9 mmHg (P less than 0.001). In untreated control eyes, Fu determined from the quantity of intracamerally perfused [125I]albumin found in the ocular and periocular tissues accounted for 5-8% of total aqueous outflow. In 15 unilaterally PGF2 alpha-treated rabbits, after 4-6 hr dosing Fu was 49 +/- 14% higher in the treated than in the contralateral control eyes. Total outflow facility of outflow from the anterior chamber to the general circulation were measured concurrently in 11 rabbits using a two-level constant pressure perfusion and isotope accumulation technique. Both facilities tended to be higher in the treated eyes than in the controls, with a strong correlation between drug-induced changes in total facility and changes in facility of flow to blood (r = 0.85, P less than 0.001). In eight rabbits treated unilaterally with 50 micrograms PGF2 alpha-TS, the fluorophotometrically determined aqueous formation rate was probably not decreased relative to control eyes. Protein levels in the aqueous humor were approximately eight-fold higher in PG-treated vs. control eyes, suggesting a drug-induced compromise of the blood-aqueous barrier.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Topical↗
Inhibition of outflow facility and accommodative and miotic responses to pilocarpine in rhesus monkeys by muscarinic receptor subtype antagonists.
The muscarinic receptor subtype antagonists 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), 11-[(2-[diethylamino)methyl]-1- piperidinyl)acetyl]-5,11-dihydro-6H-pyrido[2,3- b][1,4]benzodiazepine-6-one (AF-DX 116) and pirenzepine were used to inhibit the outflow facility and accommodative and miotic responses to near-maximal intracameral doses of pilocarpine in the living rhesus monkey eye. The pharmacologic M3 antagonist 4-DAMP was the most potent inhibitor of all three responses, with IC50 values of 41.7 nM for outflow facility (vs. 40.9 microM pilocarpine), 19.8 nM for accommodation (vs. 40.9 or 81.8 microM pilocarpine) and 3.2 nM for miosis (vs. 4.1 microM pilocarpine). The M1 antagonist pirenzepine was at least 30-fold less potent, with IC50 values of 2.2 microM for outflow facility, 1.4 microM for accommodation and 0.1 microM for miosis. The M2 antagonist AF-DX 116 was the least potent by far, with IC50 values of 15.5 microM for outflow facility, 14.2 microM for accommodation and 1.5 microM for miosis. The results suggest that these three functional responses to pilocarpine are all mediated through an M3 receptor subtype.
Accommodation, Ocular↗
Superior cervical ganglionectomy in monkeys: surgical technique.
Seven cynomolgus monkeys underwent a histologically confirmed left superior cervical ganglionectomy (SCGx). Unilateral ocular sympathetic denervation persisting for at least 2 yr was confirmed by ipsilateral ptosis, miosis, supersensitivity of pupillary dilation to topical phenylephrine, and profound pupillary hyporesponsiveness to topical hydroxyamphetamine. Intraocular pressure 8-9 and 23-27 months postoperatively were identical in the denervated and contralateral control eyes. This model should facilitate studies of aqueous humor physiology and pharmacology.
Administration, Topical↗
Outflow facility and its response to pilocarpine decline in aging rhesus monkeys.
Refractive error and total outflow facility were determined by Hartinger coincidence refractometry and two-level constant-pressure perfusion, respectively, in 17 rhesus monkeys, aged 5 to 29 years. Maximum accommodative response to corneal (iontophoretic) carbachol hydrochloride, baseline outflow facility, and the facility response to strong but submaximal intracameral doses of pilocarpine hydrochloride all declined with age. The correlation between accommodative response to carbachol and facility response to pilocarpine was slightly stronger than that between age and facility response. Since the ciliary muscle plays a major role in controlling both outflow facility and accommodation, and since histologic and videographic techniques demonstrate an age-related decline in rhesus ciliary muscle excursion induced by topical pilocarpine or electrical stimulation of the Edinger-Westphal nucleus, the present data support the hypothesis that an age-related decline in ciliary muscle mobility is associated, perhaps causally, with an age-related decline in facility and facility responsiveness to cholinergic drugs.
Accommodation, Ocular↗
New developments in the drug treatment of glaucoma.
This article reviews standard treatment modalities for patients with glaucoma and describes 3 classes of drugs which are undergoing development: apraclonidine (aplonidine, ALO 2145), an alpha 2-adrenergic agonist which has been released for clinical use; topical carbonic anhydrase inhibitors, a modification of the systemic carbonic anhydrase inhibitors currently in use; and prostaglandins (PGs), a new class of drugs with topical ocular hypotensive activity. Standard treatment modalities include parasympathomimetic agents such as pilocarpine, carbachol, and phospholine iodide, which lower intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork. A newer form of pilocarpine as a gel produces a longer action. Adrenergic agonist medications, such as epinephrine (adrenaline) and its prodrug dipivefrine (dipivalyl epinephrine), function by increasing uveoscleral outflow and trabecular outflow facility. A decrease in aqueous formation by the ciliary processes is thought to be the mechanism of action of beta-adrenoceptor antagonists, but the physiological basis for this action has not been clearly demonstrated. A newer beta-blocker, betaxolol, has relatively selective beta 1-blocking activity. Carbonic anhydrase inhibitors are nonbacteriostatic sulphonamide derivatives which decrease aqueous formation by the ciliary body. Almost 50% of patients taking these medications are unable to tolerate them because of their adverse effects, and there is thus much interest in the development of a topical carbonic anhydrase inhibitor with the potential for fewer adverse effects. MK 507 is the most recent and most potent compound in the series of topically active carbonic anhydrase inhibitors. Apraclonidine hydrochloride is a derivative of clonidine hydrochloride, an alpha 2-adrenergic agonist. Clonidine has previously been shown to lower IOP significantly, but has the potential to produce marked lowering of both systolic and diastolic blood pressures. Its major ocular effect appears to be a decrease in aqueous production. The structural modification to apraclonidine decreases corneal absorption and the drug's ability to cross the blood-brain barrier, minimising the risk of centrally mediated cardiovascular side effects. Apraclonidine may also influence secondary avenues of aqueous outflow, such as uveoscleral outflow, and may also affect conjunctival and episcleral vascular flow. It produces a mean decrease in IOP of 25% for as long as 12 hours. Adverse effects include blanching of the conjunctiva, minimal mydriasis and eyelid retraction. This drug has been approved in the US for use in prevention of elevated IOP after argon laser trabeculoplasty and iridotomy, and has potential uses in preventing an IOP rise after YAG laser posterior capsulotomy and cataract surgery in patients already on other antiglaucomatous medications.(ABSTRACT TRUNCATED AT 400 WORDS)
Adrenergic alpha-Agonists↗
Parasympathetic denervation of the ciliary muscle following panretinal photocoagulation.
Cynomolgus monkeys underwent unilateral panretinal scatter photocoagulation (PRP) and/or nasal and temporal horizontal retinal meridional photocoagulation (HRMP) with xenon arc or argon or krypton laser light. Shortly thereafter, in the PRP-treated eyes, accommodative responsiveness to topical eserine and electrical stimulation of the Edinger-Westphal nucleus (EWN) was diminished, accommodative responsiveness to intramuscular (i.m.) pilocarpine was enhanced, and the number of muscarinic receptors in the ciliary muscle was reduced compared to the contralateral controls. In most instances, these parameters returned to normal over 6-12 wks and the abnormalities could be induced again by another round of PRP. However, in some PRP-treated eyes, accommodative responsiveness to EWN stimulation and topical eserine remained subnormal permanently (greater than 1 yr). Shortly after HRMP alone, accommodative responses to i.m. pilocarpine, topical eserine, and central stimulation did not differ markedly in the treated and control eyes. Morphologic studies 1 to 78 wk following PRP revealed that myelinated and unmyelinated nerves within the entire circumference of the choroid and ciliary muscle were severely damaged early on. The number of unmyelinated nerves between the individual ciliary muscle fibers was drastically reduced, those which remained were swollen or deteriorated, and agranular synaptic vesicles were rarely seen. Thereafter, the nerves in the choroid and ciliary muscle gradually regenerated. Following HRMP, only the choroidal nerves which passed through the photocoagulated areas and the ciliary muscle nerves in the corresponding meridians showed signs of deterioration, and there was minimal effect on the physiologic responses examined. These findings collectively indicate that intraocular parasympathetic denervation of the ciliary muscle is produced by PRP, although all nerve types are likely damaged.
Accommodation, Ocular↗
Accommodation and ciliary muscle muscarinic receptors after echothiophate.
Twice daily topical administration of echothiophate for 2 weeks to the eyes of living cynomolgus monkeys produced profound subsensitivity of the accommodative response to pilocarpine and an approximately 50% decrease in the number of specific binding sites for 3H-quinuclidinyl benzilate (3H-QNB) in the ciliary muscle without a change in their affinity. When echothiophate treatment was discontinued, functional cholinergic sensitivity and the number of QNB binding sites both returned to normal over a similar 4-8 week period. Most animals had a modest overshoot of both functional sensitivity and number of binding sites for at least several weeks thereafter. The treated to control eye ratios for the number of binding sites and accommodative response to pilocarpine were correlated and the plot of log treated to control binding site ratio versus treated to control accommodation ratio resembled a dose-response curve. Similarly, the treated versus control eye differences for the two parameters were correlated, with the regression line passing through the 0-0 axis intercept. Collectively, these findings suggest that agonist-induced modulation of functional cholinergic sensitivity in the parasympathetically innervated (as opposed to denervated) ciliary muscle occurs by a muscarinic receptor-mediated mechanism. This system appears to provide a useful model to study the regulation of ciliary muscle cholinergic sensitivity.
Accommodation, Ocular↗
Dose-related effects of prostaglandin F2 alpha isopropylester on intraocular pressure, refraction, and pupil diameter in monkeys.
Topical application of Prostaglandin F2 alpha (PGF2 alpha) to the eye reduces intraocular pressure (IOP) in all mammalian species studied thus far, including humans. The L-isopropylester derivative is currently the one most commonly used in experimental and clinical studies. Dose-response relationships were determined between PGF2 alpha-IE and IOP, pupillary diameter, and refraction in ketamine-anesthetized ocular normotensive cynomolgus monkeys. Single doses of 10 and 30 micrograms had smaller and less consistent but longer lasting IOP-lowering effects than repeated doses (twice daily for 3 days) of 1-5 micrograms. For repeated dosing in this manner, the just-maximal dose is probably between 2-5 micrograms, producing a approximately 70% reduction in IOP to a final IOP of approximately 5 mm Hg. Continuing treatment for up to 18 days did not further enhance the efficacy of twice daily treatment with a submaximal 1-microgram dose. Partial reversal of anesthesia-induced tonic accommodation occurred with single 10- and 30-micrograms doses and with repeated 1-microgram doses, but additional myopia of 0.5-1.5 diopters was induced with repeated higher doses. These physiologic findings and previous morphologic data are consistent with a proposed dual PG action on the ciliary muscle, one involving a short-onset long-lasting direct effect on the muscle fibers (causing relaxation and narrowing of the muscle bundles) and the second involving a slowly developing but shorter duration dissolution of the intermuscular connective tissues.
Accommodation, Ocular↗
Cytochalasin B potentiates epinephrine's outflow facility-increasing effect.
Total outflow facility was determined in both eyes of cynomolgus monkeys by two-level constant pressure perfusion. After a baseline measurement, one eye of the experimental animal received intracameral cytochalasin B (CB); the other eye received vehicle without CB. Twenty minutes later both eyes received intracameral epinephrine (EPI), and 30 min later the outflow facility was again determined. Doses of CB and EPI which were subthreshold when given singly produced significant facility increases when given concurrently. Subthreshold doses of CB given concurrently with a maximal dose of EPI produced significantly larger facility increases than a maximal dose of EPI given alone. A maximal dose of CB produced a larger facility increase than a maximal dose of EPI. Maximal doses of CB and EPI given concurrently produced a larger facility increase than did a maximal dose of EPI alone and had about the same effect as a maximal CB dose given alone. Since CB's facility-increasing effect is likely due to "disruption" of actin filaments in the endothelial cells of the trabecular meshwork and Schlemm's canal and since CB potentiates the facility-increasing effect of EPI, EPI may also act by "disrupting" actin filaments and consequently altering endothelial cell shape.
Actins↗
Effects and interactions of epinephrine, norepinephrine, timolol, and betaxolol on outflow facility in the cynomolgus monkey.
Total outflow facility was determined in cynomolgus monkeys by two-level constant pressure perfusion. Topical epinephrine increased facility by 30% to 35% three to four hours after dosing, whether given as a single 600-micrograms dose or as twice daily 600-micrograms doses for three days. A single 5.5-micrograms intracameral dose of epinephrine or norepinephrine increased facility by 65% to 70% three to four hours after dosing. A single 180-micrograms topical dose of timolol or betaxolol had no effect on facility three to four hours later. Timolol pretreatment prevented the facility-increasing effect of both topical epinephrine and intracameral norepinephrine, but betaxolol pretreatment prevented neither. These findings indicate that no cumulative facility-increasing effect of epinephrine, beyond the acute (three hour) facility-increasing effect, develops within three days; there may be a facility-decreasing effect of large topical epinephrine doses on the vascular structures external to the trabecular meshwork; there is no, or only subthreshold, facility-affecting ambient beta-adrenergic tone in the meshwork; and the facility-increasing effect of both epinephrine and norepinephrine is mediated by beta 2-adrenergic receptors in the trabecular endothelium.
Administration, Topical↗
Correlation of visual function and retinal leukocyte velocity in glaucoma.
Twelve subjects with glaucoma or ocular hypertension underwent measurement of visual fields (Humphrey perimeter and the Henson CFS2000 perimeter), contrast sensitivity (Vistech wall charts), and perimacular leukocyte velocity (Oculix BFS-1000 blue field entoptic technique). Significant positive correlations were seen between asymmetry of visual function and asymmetry of retinal leukocyte velocity in the study population. The eye with the higher velocity of retinal leukocyte flow tended to have better visual function as measured by Humphrey mean deviation (P less than .05), Henson Score (P less than .06), and Vistech contrast sensitivity score at 6 cycles/degree (P less than .001). An association of borderline significance was found between the asymmetries of intraocular pressure and retinal leukocyte velocity (P = .06). No significant intraocular pressure:visual field correlations were found on asymmetry analysis, although the inverse relationship between intraocular pressure and contrast sensitivity was significant (P less than .05). Significant correlations were obtained between visual field scores derived from the Henson data and Humphrey parameters mean deviation (P less than .001) and corrected pattern standard deviation (P less than .05) on both asymmetry and single eye analysis.
Adult↗
In vivo videography of the rhesus monkey accommodative apparatus. Age-related loss of ciliary muscle response to central stimulation.
Fourteen rhesus monkeys, aged 1 to 24 years, underwent permanent implantation of a bipolar stimulating electrode into the Edinger-Westphal nucleus and complete unilateral or bilateral iridectomy. Slit-lamp Scheimpflug videography of the lens and slit-lamp goniovideography of the lens equator, zonule, and ciliary body allowed direct real-time observation and video recording of the movements of these structures during centrally stimulated accommodation and during disaccommodation. Scalloping of the lens capsule at the zonular insertion sites was clearly visible during disaccommodation and even during accommodation when the zonules were folded. During accommodation, the lens became axially thicker, the ciliary ring narrowed, and, at high levels of accommodation, the zonular fibers slackened and even folded and the lens moved downward. With increasing age and concomitantly decreasing accommodative amplitude, these excursions all diminished, so that in the oldest animals, they were very minimal or absent. Maximum centrally stimulated accommodative amplitude declined with age on a time scale similar to that for cholinomimetic drug-induced accommodation in the rhesus monkey and voluntary accommodation in the human.
Accommodation, Ocular↗
Ciliary neuromuscular morphology in cynomolgus monkeys after ciliary ganglionectomy.
Cynomolgus monkeys underwent unilateral ciliary ganglionectomy (CG) and/or posterior ciliary neurectomy (PCN). The ciliary muscle was functionally denervated, as evidenced by loss of choline acetyltransferase activity, loss of the accommodative response to topical eserine and electrical stimulation of the Edinger-Westphal nucleus, and supersensitivity of the accommodative response to pilocarpine. Light and electron microscopy carried out 3-28 days after CG/PCN revealed degeneration of myelinated and unmyelinated nerve fibers as evidenced by axonal swelling and shrinkage, mitochondrial degeneration, axoplasmic condensation and vacuolization, and activated, phagocytosing Schwann cells. By 1-3 months after CG/PCN, few non-myelinated axons remained between the muscle bundles, larger nerve bundles were disordered and deteriorated, and Schwann cells filled with lipid and cellular debris were prominent. Beyond 6 months (6-37 months), most eyes were reinnervated by functional criteria. Concurrently, the ciliary neuromuscular morphology appeared virtually normal, exhibiting many non-myelinated axons containing numerous agranular synaptic vesicles and large mitochondria; however, remnants of degenerated axons were still present. In two eyes remaining functionally denervated, many of the unmyelinated axons between the ciliary muscle bundles were swollen or empty, with small, degenerated mitochondria and only rare synaptic vesicles, and were often ensheathed by thickened, condensed Schwann-cell cytoplasm. The muscle fibers were atrophic and separated from each other as well as from the ensheathed nerve fibers. Thus, following CG/PCN, the morphologic and functional evidence of parasympathetic denervation and reinnervation of the ciliary muscle is pathophysiologically and temporally consistent.
Acetylcholinesterase↗
Ciliary muscle choline acetyltransferase and acetylcholinesterase after ciliary ganglionectomy.
Choline acetyltransferase (ChAT; EC 2.3.1.6) and acetylcholinesterase (AChE; EC 3.1.1.7) activities were measured in cynomolgus monkey ciliary muscle 1 month and 6 or more months after ciliary ganglionectomy (CG) or post-ganglionic ciliary neurectomy (PCN). ChAT activity was undetectable and AChE activity was elevated 1 month after CG or PCN, while both averaged about 30% of normal levels 6 or more months after denervation. Four out of six eyes reinnervated by functional criteria 6-12 months after CG or PCN. In one of the two remaining eyes permanently denervated, ChAT was absent from the ciliary muscle. In the other, ChAT activity was about 50% of normal, similar to the reinnervated eyes, but the regenerated cholinergic nerves were not approximated to the ciliary muscle fibers.
Acetylcholinesterase↗