Blood-retina barrier permeability is independent of trace substance lipid solubility in retinitis pigmentosa and in the healthy eye.

Differential ocular spectrofluorometry was used to assess the passive permeability of the blood-retina barrier in healthy subjects and in patients with retinitis pigmentosa by determination of the rate of inward leakage of fluorescein and fluorescein glucuronide after intravenous injection of fluorescein. In five healthy subjects we found permeabilities of 1.3 (0.6-2.8) nm/s [log-mean (range)] for fluorescein and 1.3 (0.6-3.1) nm/s for fluorescein glucuronide. Six patients with retinitis pigmentosa all had a markedly increased blood-retina barrier leakage, with inward permeabilities of 8.2 (3.4-25) nm/s for fluorescein and 8.2 (5.6-27) nm/s for fluorescein glucuronide. Since no detectable difference was found between the permeabilities of the two tracers the passive permeability of the blood-retina barrier appears to be independent of the 18-fold difference in lipid solubility between the two tracers, both in retinitis pigmentosa and in healthy subjects. Presumably, the structural substrate for leakage of small hydrophilic molecules through the blood-retina barrier is a water-filled pore, since diffusion through lipid cellular membranes would favor fluorescein over its more water soluble glucuronide.

Fluorescein transport across the human blood-retina barrier in the direction vitreous to blood. Quantitative assessment in vivo.

Inward and outward movement of flourescein across the human blood-retina barrier was studied in five healthy volunteers, using a differential spectrofluorometry method that eliminates the contribution of fluorescein glucuronide to the total fluorescence in the vitreous and in plasma. The inward permeability across the blood-retina barrier, which is presumed to be passive, and the diffusion coefficient in the vitreous for fluorescein was calculated from data obtained 1 h after intravenous injection of fluorescein. The rate of elimination of fluorescein from the vitreous across the blood-retina barrier was estimated from data obtained 7 to 12 h after injection of fluorescein. The calculations were based upon the free plasma fluorescein decay curve and the preretinal fluorescein gradient in the vitreous. The mean inward permeability of fluorescein was 1.39 x 10(-7) cm/sec (range: 0.70-2.06 x 10(-7) cm/sec), whereas the mean outward permeability was 1.51 x 10(-5) cm/sec (range: 1.14-1.73 x 10(-5) cm/sec). We have thus found that the movement of fluorescein across the blood-retina barrier is highly asymmetric, the outward transport being more than 100 times faster than the passive inward leakage. This could indicate the presence of an active pumping mechanism in the blood-retina barrier, responsible for fluorescein transport in the direction from the vitreous to the blood.

Probenecid inhibition of the outward transport of fluorescein across the human blood-retina barrier.

The effect of probenecid on the outward transport of fluorescein from vitreous to blood was studied in 13 insulin-dependent diabetic patients with background retinopathy in a randomised double-masked placebo controlled cross-over study. Fluorescein and fluorescein glucuronide was separated in the vitreous and in plasma by differential spectrofluorometry. The data for fluorescein were analysed using a simplified mathematical model of the eye. The inward permeability was estimated from data obtained 1 h after injection and the outward transport from data obtained 7 h after injection. During placebo treatment the mean inward permeability was 3.75 x 10(-7) cm/sec and the mean outward permeability was 2.25 x 10(-5) cm/sec. During probenecid treatment the mean inward permeability was 3.34 x 10(-7) cm/sec and the mean outward permeability was 1.44 x 10(-5) cm/sec. Thus, we found no significant change in inward permeability (p = 0.5879), whereas a significant decrease of 36% was found in the outward permeability of fluorescein (p = 0.0171). The demonstration that the outward permeability, which is more than 100-fold higher than the inward permeability in the healthy eye, is significantly decreased by probenecid, demonstrates that active transport is involved in movement of fluorescein across the blood-retina barrier from the vitreous to the plasma.

Interferon alpha-2a treatment of patients with subfoveal neovascular macular degeneration. A pilot investigation.

It has recently been suggested that interferon alpha-2a has a beneficial effect on exudative age-related macular degeneration (AMD). So far, results are controversial, and masked, placebo controlled, randomized studies with well-defined inclusion criteria are required to assess the effect of interferon alpha-2a. In preparation for such a study we performed a pilot investigation that included 5 patients with subfoveal neovascularizations. All patients received interferon alpha-2a (Roferon-A, Hoffmann La-Roche) 1.5 mio, IU subcutaneously every second day for 8 weeks. Improved visual acuity was subjectively observed by 4 patients and objectively by 3 patients. Two patients showed decreased central visual field defect. Fluorescein angiography and fundus photography showed ambiguous changes. Amsler chart and contrast sensitivity also showed heterogenous results. Even though the treatment with interferon alpha-2a may show some positive effect, our results are not unequivocal and serve to underline the need for controlled studies before the effect of interferon alpha-2a on neovascular AMD can be reliably assessed.

Blood-retina barrier permeability in diabetes during acute ACE-inhibition.

We assessed the acute effect of ACE-inhibition (captopril) on blood-retina barrier (BRB) permeability in 10 hypertensive insulin-dependent diabetic patients with background retinopathy in a double-masked placebo controlled cross-over study. All patients underwent ophthalmological examination, fundus photography, fluorescein angiography, vitreous fluorometry, and continuous blood pressure recording within 3 h of the drug/placebo administration. The decrease in mean arterial blood pressure, from placebo treatment 149/92 +/- 17/7 to captopril treatment 132/83 +/- 14/7 mmHg (mean +/- SD), P less than 0.01 was not accompanied by a significant decrease in BRB permeability, which was 2.51 (1.24-9.15) with placebo and 3.02 (1.25-13.93).10(-7) cm/s during captopril treatment (geometric mean and-range), NS. Our study suggests that abnormal leakage through the BRB in hypertensive insulin-dependent diabetic patients with background retinopathy is caused predominantly by structural changes in the retinal vessels whereas hydrostatic forces play a minor role.