Anders Bill

Ocular and optic nerve blood flow at normal and increased intraocular pressures in monkeys (Macaca irus): a study with radioactively labelled microspheres including flow determinations in brain and some other tissues

The effects of moderate increments in the intraocular pressure on blood flow rates in the various tissues of the eye were studied in monkeys. Blood flow rates were determined with radioactively labelled microspheres, 15 μm in diam. One eye had its spontaneous intraocular pressure while the other eye had its pressure stabilized at a higher level. The mean values for the intraocular pressures in the two eyes were 13 and 41 cm H2O respectively. In eyes with spontaneous intraocular pressure mean blood flow through the retina, the iris, the ciliary body, and the choroid were 25, 17, 89, and 607 mg/min respectively. Blood flow through the ciliary processes was 222 and through the ciliary muscle 153 g/min/00 g tissue respectively. In eyes with increased intraocular pressure there were statistically significant reductions in blood flow through the choroid and through the prelaminar part of the optic nerve by 29 and 30% of the mean blood flow through control eyes respectively. The changes in blood flow through the retina, the iris, the ciliary processes and the ciliary muscle were not statistically significant. They ranged from a reduction by 8% to an increase by 19% in eyes with increased intraocular pressure. The results suggest that even moderate increments in intraocular pressure cause clear reductions in the blood flow through the choroid and through the prelaminar part of the optic nerve, while blood flow through the retina outside the optic disc and through the different parts of the anterior uvea is efficiently autoregulated. It is suggested that the susceptibility of the optic disc to increments in intraocular pressure is due to the deficient autoregulation of blood flow through the optic disc, which in turn might be explained by the choroidal origin of the optic disc vessels which interferes with normal autoregulatory mechanisms. Determinations were also made of blood flow through various parts of the brain and some other organs. Two different doses of microspheres were used to determine blood flow rates in the brain and in the eye. The larger dose seemed to reduce blood flow by 25% or more in the brain and in the iris, while no such effect was seen in the retina, the choroid or the ciliary body.

Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2α-1-isopropylester in the cynomolgus monkey

The effects of topical application of a single dose of prostaglandin F2 alpha, administered as the isopropylester, on the intraocular pressure (IOP), aqueous humor flow (AHF), conventional, and uveoscleral outflow were studied in cynomolgus monkeys under pentobarbital anesthesia. 1 microgram PGF2 alpha decreased the IOP by 2.9 +/- 0.6 mmHg (3 hr after the application) as compared with the vehicle-treated control eye. The mean AHF during the whole experiment was slightly higher in the experimental than in the control eye, 1.34 +/- 0.11 microliters min-1 compared with 1.16 +/- 0.09 microliters min-1. The uveoscleral outflow was significantly increased in the PGF2 alpha-treated eye, 0.98 +/- 0.12 microliters min-1 compared with 0.61 +/- 0.10 microliters min-1 for the control eye. The conventional outflow was lower in the experimental eye throughout the experiment. Topical application of 10 micrograms pilocarpine at the time when the fall in IOP was expected prevented the drop in the IOP. Simultaneously the increase in the uveoscleral outflow was abolished. After systemic pretreatment with atropine, 1 mg (kg body weight)-1 i.v., there was no significant difference in IOP, AHF, conventional or uveoscleral outflow between the PGF2 alpha-treated, and the control eye. The results of the present investigation suggest that PGF2 alpha decreases the intraocular pressure by increasing the uveoscleral outflow. The mechanism behind the increase in the uveoscleral outflow remains to be established. Relaxation of the ciliary muscle as well as enlarged intramuscular spaces and loss of extracellular material may contribute to the effect.

Uveoscleral drainage of aqueous humour in human eyes

The anterior chamber contents of 12 human eyes were mixed in vivo with [131I] albumin in isotonic saline. At various times after mixing the radioactive solution was washed out of the eye and the eye was enucleated (in ten cases because of a malignant melanoma), frozen, and analysed for radioactive material. The frozen eye was sectioned and autoradiographs made. The labelled albumin passed into the iris and the ciliary body including the ciliary processes, the suprachoroid and the sclera. This indicates that there is uveoscleral drainage of a queous humour in man as has been demonstrated previously in monkeys. In eyes treated with atropine uveoscleral flow was 4–27% of the total outflow; in eyes treated with pilocarpine it was 0–3% and in two eyes receiving neither of the drugs for 48 hr it was 4 and 14%, respectively.

Pressures in the juxtacanalicular tissue and Schlemm's canal in monkeys

A micropuncture technique involving the use of microcannulas with tip diameters less than 5 microns was used to measure the pressure in Schlemms canal and in the meshwork at distances approximately 7 and 14 microns from the inner wall of Schlemms canal. In one set of experiments where the spontaneous intraocular pressure (IOP) was 12.2 +/- 0.5 cmH2O and the Schlemms canal pressure (PSc) was 7.6 +/- 0.7 cmH2O, the pressure at 7 microns from the inner wall of Schlemms canal was found to be 8.9 +/- 0.7 cmH2O and at a distance of 14 microns, 11.0 +/- 0.5 cmH2O--that is, 1.3 +/- 0.2 and 3.4 +/- 0.3 cmH2O respectively, higher than the PSc. In another set of experiments, the spontaneous IOP and PSc were also measured and then the IOP was increased by means of an external reservoir and measured once again. Spontaneous IOP was 16.0 +/- 1.3 cmH2O and the PSc was 11.5 +/- 1.4 cmH2O before the IOP was increased. After the IOP was increased to 20.2 +/- 1.2 cmH2O, the PSc was 11.7 +/- 1.6 cmH2O. When the microcannula was introduced into the juxtacanalicular tissue to locations at about 7 and 14 microns from the inner wall of Schlemms canal the pressure measured at 7 microns was 16.9 +/- 1.3 and at 14 microns it was 18.9 +/- 1.4 cmH2O--that is, 5.2 +/- 0.8 and 7.2 +/- 1.0 cmH2O respectively, higher than the PSc. The results indicate that at the spontaneous IOP about 75% of the resistance between the anterior chamber and Schlemms canal is located within 14 microns from the canal with some 50% being located within the region 7 and 14 microns from the canal. After a small increase in IOP, the tissue causing most of the outflow resistance became relocated to a region within 7 microns from the canal.

SCANNING ELECTRON MICROSCOPIC STUDIES OF THE TRABECULAR MESHWORK AND THE CANAL OF SCHLEMM - AN ATTEMPT TO LOCALIZE THE MAIN RESISTANCE TO OUTFLOW OF AQUEOUS HUMOR IN MAN

Chamber angle tissue from human eyes was investigated with scanning electron microscopy. The uveal and corneoscleral parts of the trabecular meshwork are described. The endothelial cells of the inner wall of Schlemms canal arc long and slender and, at most places, are oriented along the lumen of the canal. The average projected surface of a cell towards the canal is about 480 μm2. The total number of endothelial cells in the inner wall of the canal is about 23,000. The cells have pores with diameters up to 3(5) μm. The total number of pores is about 20,000. Calculations show that if all the observed pores exist in vivo, the resistance to outflow in the paths through the endothelial cells is a small fraction of the total resistance to outflow.

Conventional and uveo-scleral drainage of aqueous humour in the cynomolgus monkey (Macaca irus) at normal and high intraocular pressures.

[ 131 I]Albumin and [ 125 I]-γ-globulin were used to mark the bulk flow of aqueous humour in young cynomolgus monkeys. In living animals, at a normal intraocular pressure of about 11 mmHg, the net formation of aqueous humour was 1·24 ± 0·13 μl/min. The rate of drainage by way of uveo-scleral routes was 0·44 ± 0·06 μl/min and by way of conventional routes was 0·80 ± 0·11 μl/min. At an intraocular pressure artificially raised to 22 mmHg by an extra inflow, the outflow from the anterior chamber by way of uveo-scleral routes was 0·63 ± 0·08 μl/min and by way of conventional routes was 4·18 ± 0·12 μl/min. It is suggested that, in the pressure region investigated, a change in intraocular pressure produces almost the same change in tissue pressure in the uvea and in the suprachoroid and that this explains why the outflow by way of uveo-scleral routes was so alike at the different pressures investigated. After death, at an intraocular pressure artificially raised to 14 mmHg by an inflow of about 5 μl/min, the mean outflow from the anterior chamber by way of uveo-scleral routes was 1·25 ± 0·17 μl/min.

The pressures in the episcleral veins, Schlemm's canal and the trabecular meshwork in monkeys: Effects of changes in intraocular pressure

The pressures in the episcleral veins, Schlemms canal and the trabecular meshwork were studied with a micropuncture technique using cannulas with tip diameters of less than 5 microns. The pressure in Schlemms canal, Psc, was 14.3 +/- 1.0 cmH2O at spontaneous intraocular pressure, IOP, 19.2 +/- 0.9 cmH2O. The outflow pressure from the anterior chamber to Schlemms canal was 4.9 +/- 0.7 cmH2O. The relationship between pressures was IOP = 0.73 Psc + 8.7. When the intraocular pressure was increased stepwise from the spontaneous level to 30 cmH2O there was an increase in pressure in Schlemms canal of 1.7 +/- 0.6 cmH2O, (P less than 0.05). The total outflow resistance and the resistance between the anterior chamber and Schlemms canal were 3.27 +/- 0.43 and 2.92 +/- 0.50 cmH2O min microliter-1 respectively for the intraocular pressure interval between the spontaneous pressure and a level 4-11 cmH2O higher. In the intraocular pressure range from 20 to 30 cmH2O the corresponding figures were 2.89 +/- 0.45 and 2.69 +/- 0.42 cmH2O min microliter-1 and for the pressure range 25-35 cmH2O, 2.48 +/- 0.58 and 2.31 +/- 0.59 cmH2O min microliter-1. The difference between the total outflow resistance and that between the anterior chamber and Schlemms canal was about 10% of the total at intraocular pressures below 35 cmH2O. Stepwise increments in IOP increased the trabecular meshwork pressure by 0.88 cmH2O for each cmH2O increase in IOP in the interval of 30-50 cmH2O. The total outflow resistance and the resistance between the anterior chamber and the tip of the microcannula was 3.91 +/- 1.53 and 1.94 +/- 0.99 cmH2O min microliter-1 respectively for the intraocular pressure interval between the spontaneous pressure and 30 cmH2O. In the interval between 30 and 45 cmH2O the corresponding figures were 2.16 +/- 0.66 and 0.20 +/- 0.13 cmH2O min microliter-1. The episcleral venous pressure at the spontaneous intraocular pressure was 14.1 +/- 1.0 cmH2O in seven animals with minimal trauma, and 12.3 +/- 0.8 cmH2O in animals after cannulation of Schlemms canal. The outflow pressure from the anterior chamber to the episcleral veins was 4.4 +/- 1.2 cmH2O in animals with minimal trauma and 7.1 +/- 0.8 cmH2O after cannulation of Schlemms canal. The relationship between pressures was IOP = 0.68EVP + 11.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of norepinephrine, isoproterenol and sympathetic stimulation on aqueous humour dynamics in vervet monkeys

An attempt was made to analyze what types of adrenergic receptors are involved in the mechanisms for aqueous humour production and drainage and to determine the maximum effects of these receptors. The parameters determined were: mean arterial blood pressure, intraocular pressure, rate of aqueous flow via Schlemms canal, rate of flow through uvcoscleral routes and gross facility of outflow. The recipient venous pressure was calculated. Isoproterenol, 0·1 and 1·0 μg/ml, perfused through the anterior chamber increased the rate of aqueous humour production and the gross facility of outflow and tended to increase the rate of uveoscleral drainage of aqueous humour. A dose of 10 μg/ml produced more variable results than the lower doses. Norepinephrine perfused through the anterior chamber at a dose of 1 or 10 μg/ml had no significant effect on the gross facility of outflow or the rate of aqueous formation. Neither isoproterenol nor norepinephrine had statistically significant effects on the intraocular pressure and the recipient venous pressure. Stimulation of the cervical sympathetic nerves to the eye gave a probably significant increase in the rate of aqueous humour formation. After beta-receptor blockade with propranolol, 5 mg/kg, neither the effects on the rate of aqueous formation nor those on the facility of outflow could be elicited. The results suggest that there are adreuergic beta-receptors in the ciliary processes and in the chamber angle of the monkey eye which stimulate the secretion of aqueous humour and increase the facility of outflow, respectively. The average effect of maximum adrenergic beta-receptor stimulation was to increase the rate of aqueous formation by about 30% and to raise the facility of outflow by about 55%.

The effects of pilocarpine and neostigmine on the blood flow through the anterior uvea in monkeys. A study with radioactively labelled microspheres

15 μm microspheres labelled with 85Sr were used to determine the rate of blood flow through the various parts of the eye in monkeys. Pilocarpine or neostigmine had been applied on the cornea of one eye while the other eye served as control. Both pilocarpine and neostigmine increased blood flow through the iris, the ciliary processes and the ciliary muscle by 100–200%, while the blood flow through the choroid and the retina was unchanged. Atropine, but not hexamethonium, abolished the effect of neostigmine. The results suggest that the increase in blood flow is mediated through vascular muscarinic receptors.

Basic physiology of the drainage of aqueous humor

The drainage of aqueous humor is discussed on the basis of previously reported results and results included in this communication. Water, solutes and small particulate material such as cell fragments are drained from the anterior chamber with a bulk flow of aqueous humor into the iridocorneal angle. In primates most of the fluid passes through the uveal, corneo-scleral and endothelial meshwork into the canal of Schlemm to be drained through collector channels into intrascleral, episcleral and conjunctival veins. There is also a drainage of fluid through the interstitial tissue spaces of the ciliary muscle into the supraciliary and supra-choroidal spaces. From these spaces fluid may pass through the sclera via spaces between the collagen fibrils in the sclera and through loose connective tissue along nerves and blood vessels piercing the sclera. Exchange by ultrafiltration, diffusion and active transport between the anterior chamber fluid and the surrounding tissues modifies the composition of the anterior chamber fluid but causes practically no net movement of fluid. The structures between the anterior chamber and Schlemms canal may be regarded as a self-cleaning filter. These structures and the inner wall of Schlemms canal also have rectifying properties restricting retrograde flow under conditions of a reversal of the normal pressure gradient. The flow from the anterior chamber into Schlemms canal is pressure dependent. Artificial increments in intraocular pressure (IOP) also affect the routes: opening of more transcellular routes in the inner wall of Schlemms canal and washout of ground substance tend to reduce the outflow resistance. Moderate increments in IOP have practically no effect on uveoseleral flow. The uveal meshwork is an anterior extension of the connective tissue of the ciliary muscle. Contraction of the muscle causes a rearrangement of the filtering tissue in such a way that the resistance to outflow via Schlemms canal is reduced. At the same time uveoscleral flow is almost stopped due to compression of the interstitial spaces within the muscle. Experiments with cytochalasin B, epinephrine and EDTA indicate that agents not likely to cause contraction of the ciliary muscle may also cause marked effects on the outflow resistance.