63 (1985) 351-354 ACTA OPHTHALMOLOGICA

Effect of a- and P-receptor active drugs on corneal thickness

C. B. Nielsen and P. J. Nielsen

Department of Ophthalmology (Head: N. Ehlers). Arhus Kommunehospital. University of Arhus, Arhus, Denmark

Abstract. Phenylephrine (10 mg/ml), phentolamine (10 mglrnl), isoprenaline (0.5 mg/rnl) and tirnolol (5 mg/ ml) were applied topically to one eye of volunteers with normal corneas, the other eye serving as a control. One drop of each drug was given twice a day for 3 or 4 days. Tho1 was fond to increase corneal thickness in both the rnidicated and the control eye. A significantly greater effect was noted on the eye receiving the drug directly. When isoprenaline was given for 3 days, a slight signif- icant decrease in corneal thickness was found in both the medicated and the control eye, with the two eyes exhibit- ing a similar CCT change. The present results are suggestive of endothelial p-receptor importance in the regulation of corneal thickness.

Key words: central corneal thickenss - a-recoptors - &receptors.

The regulation of the 'pump-leak' function of the endothelial membrane is important for corneal thickness and visual acuity (Mishima 1982). Infor- mation on how this membrane works might extend the therapeutic spectrum and include, for instance, pharmacologic treatment of oedematous corneas. Corneal thickness after cataract surgery is de- creased by the prostaglandin-inhibiting drug naproxen (Nielsen 1982). Furthermore, the carbo- nic anhydrase inhibitor acetazolamide was found to increase corneal thickness after cataract extraction in cases where endothelial guttae were present (Nielsen 1980).

The intracellular messenger c-AMP has been demonstrated in most mammalian cells where ex- tracellular stimuli, e.g. hormonal, regulate intracel- M a r function (Robison et al. 1971). If extracellular information, e.g. via some humoral aqueous consti- tuents, influences the endothelial function and

corneal thickness, then the c-AMP system working via a- and P-recoptors might be suggested as a possible mediator. Dikstein (1973) did not find any effect of c-AMP on corneal thickness regulation in vitro, and experiments with adrenaline (a- and P-stimulating) and theophyllamine (inhibiting the breakdown of c-AMP) also failed to demonstrate any effect on corneal thickness in vivo with the cornea in a steady state (C. B. Nielsen, unpublished data).

The present study was performed to investigate whether other drugs with specific effect on a- and P-receptors wouls affect corneal thickness.

Material and Methods

Nineteen volunteers from the eye clinic's staff (age 30-45) were studied.

The a-stimulating drug phenylephrine (meta- oxedrin (DAK) 10mg/ml) was given to 8 volun- teers for 3 days, and the P-stimulating drug isopre- naline (isoprenalin (DAK) 0.5 mg/ml) was given to 6 volunteers for 3 days. Nine individuals received phentolamine (a-receptor blocking) (Regitin" (Ciba) 10 mg/ml) for 3 days and 9 persons were medicated with timolol (p-receptor blocking (Ti- macar@ (MSD) 5mg/ml) for 4 days. At least 4 weeks passed between each period of medication because some of the volunteers were medicated by more than one drug.

Due to the working conditions of the staff, it was possible only with the first study (timolol) to extend the period of medication to a full working week (Monday to Friday), the others being reduced to 4

35 1

days (3 days of medication). One drop of each drug was given twice a day to one eye chosen by the volunteer with the fellow eye serving as a control. The study was masked to the observer as to which eye was medicated.

Central corneal thickness was measured by a Haag-Streit pachometer (Ehlers & Sperling 1977) using the technique (alignment A) described by Olsen et al. (1980). Before each series of measure- ments, it was checked that the pin-lights were in the correct position, that the slit-width was set at ‘8’ on the scale and that the ocular was set at 0 diopters. Furthermore, the background light was dimmed. The pachometer was reset to zero and the slit focus removed from the center of the cornea between each of the three readings taken to the nearest 5 lm. Corneal thickness was recorded each day at noon starting with a pte-medication value. A possi- ble effect of the drugs might be weak and to reduce a potential observer induced effect on the day to day variation of the thickness readings, it was decided to let 2 observers make individual CCT measurements and then consider the calculated mean value to be the recorded central corneal thickness. No previous values were known to the

observers when the CCT measurements were done.

Intraocular pressure was recorded by applana- tion tonometry before and at the end of each medication period.

Resu I ts

After medication with timolol a statistically signifi- cant difference between medicated and control eye was found on day 1 (P < 0.02, t-test) (Fig. 1) with greater thickness of the medicated eye on all other days, although statistically insignificant. Compared to the pre-medication value, an increase in corneal thickness of about 10 pm is noted for the medi- cated eye (P < 0.001 for day 1 and 4, P < 0.01 for day 2 and 3, t-tests) and about 5 pm for the control eye (significantly increased on day 1, 2 and 4, P < 0.05, t-test) (Fig. 2).

After medication with isoprenaline, a decreasing corneal thickness is seen, reaching a significantly lower value than before medication on dag 3 (P < 0.01 for medicated eye, P < 0.05 for control

A CCT urn

la

5

1 2 3 4 DAY

Fig. 1. The difference in central corneal thickness between medicated (timolol) and control eye.

352

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0

- 1 c

I C

(

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11

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- 1 t 1. 2. 3. 4. 0.Y

Accr p

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Fig. 2. The change in central corneal thickness after the 4 drugs. Closed and open circles describe treated and control eye.

eye). A close correspondence between the thickness change in medicated and control eye is seen after isoprenaline.

Phenylephrine and phentolamine did not induce any statistically significant changes in corneal thick- ness.

At the end of the 4 days of treatment with timolol, the IOP in the medicated eye was reduced by 3.2 f 0.5 mmHg (X k SEM) (P < 0.001, paired t-test) in contrast to a reduction in the fellow eye of 1.3 k 0.8 mmHg (X k SEM) not significantly dif- ferent from zero.

There was no significant change in IOP values at the end of treatment with isoprenaline, phenyl- ephrine and phenotlamine.

A few of the volunteers complained of slight stinging after application of the phentolamine eye- drops and 8 out of 9 exhibited slight injection, miosis and ptosis at the end of the period.

There was no subjective nor objective sign of any irritative effect of isoprenaline, phenylephrine or timolol. Slight mydriaisis was seen after phenyl- ephrine.

Discussion

The study was designed to reveal a possible differ- ence between a medicated eye and the fellow control eye. This was possible after 1 day of instilla-

353 23 Acta Ophthal. 63.3

tion of timolol with insignificantly increased rela- tive values on all other days. Compared to the pre-medication value, however, a significant in- crease was seen in both treated and control eye. This supports some functional importance of the c-AMP system for endothelial function as sugges- ted by Wikehart & Fletcher (1979) after demon- stration of relatively great amounts of c-AMP in corneal endothelial tissue. Walkenbach et al. (1981) found endothelial c-AMP dependent protein ki- nase, a mediator of c-AMP regulated effects in cells, and Walkenbach & LeGrand (1982) further demonstrated, using the human cornea, that the synthesis of endothelial c-AMP could be increased by the a- and p-receptor stimulating drugs epin- ephrine, isoprenaline and phenylephrine. In the present study, isoprenaline excerted a slight de- creasing effect on the corneal thickness, although the close correspondence between the thickness readings taken from medicated and control eyes points to cautious interpretation of the data. On the other hand, the significant effect on the fellow eye after timolol and isoprenaline may well express that the contralateral eye is not an optimal control due to a possible systemic effect of absorbed drug after instillation in the cul de sac. A nervously mediated, consensual reaction from the fellow medicated eye may also be suggested.

Increases in intraocular pressure may thin cor- neal stroma when the endothelium is intact (Ehlers 1970) or when the denuded endothelial side of the stroma is in contact with silicone oil (Ehlers 1982). Referring to the CCT and IOP values recorded in these experiments, it is not likely that small IOP changes as measured in the present study may account for the CCT changes.

A positive correlation between each individual's CCT and IOP, as measured by applanation tono- metry, was demonstrated by Kruse Hansen (1971). This correlation may be based on greater rigidity of a thicker cornea, thus giving a falsely high applanation reading. On the other hand, if the cornea becomes oedematous, it may become less rigid and thus give a falsely low IOP reading due to less resistance to applanation (Ehlers, unpublished experiments). Is some of the apparent timolol effect on IOP based on the IOP/CCT correlation?

fheceptors regulate a series of physiological parameters to adapt the organism to changing

demands. Further studies may reveal whether the presence and influence of endothelial &receptors may constitute a pathway for iatrogenic influence on corneal oedema.

References

Dikstein S (1973): Efficiency and survival of the corneal endothelial pump. Exp Eye Res 15: 639-644.

Ehlers N (1970): On corneal thickness and intraocular pressure. 11. A clinical study on the thickness of the corneal stroma in glaucomatous eyes. Acta Ophthalmol (Copenh) 48: 1107- 11 12.

Ehlers N (1982): Presented at 23. Meeting for Associa- tion for Eye Research. Aachen, West Germany.

Ehlers N & Sperling S (1977): A technical improvement of the Haag-Streit pachometer. Acta Ophthalmol (Copenh) 57: 258-268.

Kruse Hansen F (1971): A clinical study of the normal human central corneal thickness. Acta Ophthalmol (Copenh) 49: 87-89.

Mishima S (1982): Clinical investigations on the corneal endothelium. Am J Ophthalmol93: 1-29.

Nielsen C B (1980): The effect of carbonic anhydrase inhibition on central corneal thickness after cataract extraction. Acta Ophthalmol (Copenh) 58: 985-990.

Nielsen C B (1982): Prostaglandin inhibition and central corneal thickness after cataract extraction. Acta Oph- thalmol (Copenh) 60: 252-258.

Olsen T, Nielsen C B & Ehlers N (1980): On the optical measurement of corneal thickness. 11. The measuring conditions and sources of error. Acta Ophthalmol (Copenh) 58: 975-984.

Robison G A, Butcher R W & Sutherland E W (1971): Cyclic AMP. Academic Press. New York, London.

Walkenbach R J & LeCrand (1982): Adenylate cyclase acitivity in bovine and human corneal endothelium. Invest Ophthalmol Vis Sci 22: 120- 124.

Walkenbach R J, LeGrand R D & Barr R E (1981): Distribution of cyclic AMP-dependent protein kinase in the bovine cornea. Exp Eye Res 32: 45 1-459.

Wikehart D R & Fletcher R T (1979: Chclic nucleotides in rabbit corneal endothelial cells: Fresh tissue vs. tissue culture. Exp Eye Res 28: 285-289.

Received on March 8th. 1984.

Author's address:

C. B. Nielsen. Department of Ophthalmology, Arhus Kornmunehospital, DK-8000 Arhus C, Denmark.

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