Isoproferenol Stimulates Aqueous Flow in Humans With Horner's Syndrome

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1 Investigative Ophthalmology & Visual Science, Vol. 29, No. 4, April 1988 Copyright Association for Research in Vision and Ophthalmology Isoproferenol Stimulates Aqueous Flow in Humans With Horner's Syndrome Rhondi S. Larson and Richard F. Brubaker Topical 1 percent isoproterenol in the presence of the phosphodiesterase inhibitor theophylline was tested for its ability to stimulate the rate of aqueous humor flow through the anterior chamber of the normal and the partially adrenergically denervated human eye (Horner's syndrome). Both the affected eye and the unaffected eye were observed to have lower flows at night than during the day. Isoproterenol had no significant effect on flow during the day in normal eyes or in Horner's syndrome, but during sleep this /?-adrenergic agonist increased flow in the normal eye by 34% and in the Horner's eye by 50%. We interpret the results as indicating that #-adrenergic activity in the human eye can stimulate aqueous formation under some conditions. However, the observed stimulation could have been due to something other than increased /8-adrenergic activity in the ciliary epithelium. Invest Ophthalmol Vis Sci 29: ,1988 The j8-adrenergic antagonist is the class of pharmacologic agents which exhibits the greatest inhibitory effect on aqueous flow in the human eye of topically applied drugs. Yet timolol, a j8 r j8 2 -adrenergic antagonist which is widely prescribed for the treatment of glaucoma, has no effect on aqueousflowduring sleep when the rate of flow is spontaneously low. 1 It has been postulated that endogenous adrenergic activity during the day stimulates aqueous formation and this stimulus subsides during sleep. 2 Such a hypothesis can explain both the spontaneous day/night cycle of flow and the effectiveness of /3-adrenergic blockers during the daytime only. This hypothesis would be supported by evidence that topically applied /3- adrenergic agonists increase the rate of aqueous flow during sleep. It has been shown that the mixed a,/3-adrenergic agonist epinephrine stimulates flow in normal human subjects, 3 " 6 and that this effect is blocked by the /3-adrenergic antagonist timolol. 4 However, a similar study failed to demonstrate any effect of isoproterenol. 2 Subsequently, it has been shown that the epinephrine effect is more pronounced when the subject is asleep. 1 From the Department of Ophthalmology, Mayo Clinic and Foundation, Rochester, Minnesota. Supported by NIH Grant EY-00634, Research to Prevent Blindness, Inc., New York, New York and the Mayo Foundation, Rochester, Minnesota. Submitted for publication: April, 198; accepted November 5, 198. Reprint requests: Richard F. Brubaker, MD, Department of Ophthalmology, Mayo Clinic, Rochester, MN This study was conducted to determine if the effect of isoproterenol could be measured under conditions more likely to maximize a 0-adrenergic response. The experiment was run under three conditions, each of which was expected to enhance any effect of this /3- adrenergic agonist: (1) during sleep, when endogenous adrenergic activity should be lowest; (2) in subjects with unilateral terminal neuron Horner's syndrome, in whom there should be adrenergic supersensitivity in one eye; (3) in the presence of a phosphodiesterase inhibitor, in order to amplify the cellular effects of j8-adrenergic stimulation. Materials and Methods Subjects were selected from the diagnostic indices of the Mayo Clinic who had recently been diagnosed as having postganglionic Horner's syndrome in one eye, confirmed by pupillography. Eligible subjects were invited by letter to participate in the experiment. Twelve subjects, after following federal guidelines for written informed consent, completed the study (Mayo Institutional Review Board Approval #142-N-86, April 25, 1986). Each subject initially underwent an eye examination consisting of measurement of corrected visual acuity, pupillary responses, confrontation visual fields, extraocular motility, applanation tonometry, slit-lamp examination and ophthalmoscopic examination. The volume of the anterior chamber of both eyes of each subject was measured photogrammetrically. At the end of the study described in the following paragraphs, each subject underwent Lowenstein- 621

$Clinical data for the subjects Subject, sex, age (yrs) Eye eye AC Vol (»\) IOP (mmhg) Eye Homer's eye AC Vol(nl) IOP (mmhg) % Homer's 01, M, 66 02, M, 45 03, M, 61 04, F, 68 05, M, 56 06, M, 68 0, M,$

2 622 INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / April 1988 Vol. 29 Table 1. Clinical data for the subjects Subject, sex, age (yrs) Eye eye AC Vol (»\) IOP (mmhg) Eye Homer's eye AC Vol(nl) IOP (mmhg) % Homer's 01, M, 66 02, M, 45 03, M, 61 04, F, 68 05, M, 56 06, M, 68 0, M, 50 08, M, 60 09, M, 5, M, 36, M, 46, M, ' These four subjects studied previously by Wentworth and Brubaker. Loewenfeld pupillography before and after the instillation of one percent hydroxyamphetamine in order to confirm the diagnosis of third neuron Horner's syndrome. Pupillographic tracings were recorded in the dark and with background illumination of 0.05 footcandles. The responses of the pupil to stimulation by light and a loud noise were studied. The degree of the sympathetic lesion (% Horner's) was estimated as follows in response to hydroxyamphetamine: /. Horner's eye dilation\ nn, x % Horner's =1, _,.,. X 0 (1 \ normal eye dilation / The pupil of one eye of all subjects was normal on these pupillographic tracings. The other had the typical pupillographic signs of Horner's syndrome including: (1) anisocoria; (2) lag of pupillary dilation after a single light stimulus; and (3) the absence of psychosensory dilation (Table I). 8 The study consisted of fluorophotometric determinations of two separate day/night cycles of aqueous humorflow.on thefirstday/night cycle, theflowwas studied without addition of any drugs; on the second, the subject was treated with an oral phosphodiesterase inhibitor (theophylline) and topical one percent isoproterenol eye drops. The rate of flow was calculated for the sleep cycle from measurements of fluorescence made at 2400 (before going to sleep) and 0600 (after waking up). No measurements were made while the subject was asleep. Flow was calculated for the awake cycle from measurements of fluorescence made hourly from 0600 to 00. The rate of flow of aqueous humor was calculated by a modification 9 of Method 2 of Jones and Maurice. Briefly, flow is calculated from the rate of disappearance of fluorescein from the combined cornea and anterior chamber relative to the concentration in the anterior chamber. Loss offluoresceinby diffusion is assumed to be equivalent to ten percent of the normal rate of loss and is subtracted from all calculated rates of fluorescein clearance. Loss of fluoresbe negligible. Flow is given by the equation Flow = (C c (2)-V c -C c (l)-v c ) + (C(2).V a -C a (l).v a ) C a -(t(2)-t(l)) - diffusional loss (2) C a is calculated for the interval on the assumption that the loss offluoresceinfrom the anterior chamber is a first order process. c a = In C(2) (3) On the second day, theophylline (Brethine, Geigy, Ardsley, NY) was given orally. In addition, 1 percent isoproterenol ophthalmic solution was given to both eyes. (See Table 2 for dosage schedule.) The isoproterenol solution was formulated at the Rochester Methodist Hospital pharmacy under IND exemption #28,395. The stability of the solution was measured using high pressure liquid chromatography. At 0 on 1, 2 percent fluorescein was given by topical instillation in each eye. Excess fluorescein was immediately irrigated from the cornea and conjunctival sac. Corneal and anterior chamber concentrations of fluorescein were measured 1 hr later to insure that an adequate concentration of fluorescein had been achieved. Subjects were instructed to avoid excess fluid intake, caffeine and other extraneous

3 No. 4 ISOPROTERENOL STIMULATES AQUEOUS FLOW / Lorson ond Druboker 623 drugs, heavy exercise and direct exposure to bright sunlight during the course of the study. Otherwise, subjects were normally active during the daytime segment and were encouraged to sleep during the nighttime segment. Meals and comfortable, safe sleeping quarters were provided. The daytime and nighttime segments of the study were run contiguously beginning with fluorophotometric measurements of the corneal stroma and anterior chamber 5 hr after the instillation of fluorescein, ie, at 2200 (Table 2). Measurements of fluorescence were then taken at 2300, 2400, and hourly from 0600 to 00 on 2. The subject was sleeping between 2400 and 0600 during which no measurements were made. Flow was calculated for the period of sleep from the 2400 and the 0600 measurements and for the period of wakefulness from the hourly measurements from 0600 to 00. This sequence was repeated on the second day/ night cycle with the addition of oral theophylline and topical isoproterenol. Theophylline sustained release capsules (Brethine, Geigy) (5 mg/kg) were administered to each subject at 2300 on 2 and 000 on 3. Isoproterenol ophthalmic solution was instilled at 2400 on 2 and at 000 and 00 on 3. Prior to each instillation of isoproterenol, proparacaine was instilled to improve ocular penetration, to mask the burning sensation of the drug, and to prolong the contact time of the drug with the eye. A second instillation was carried out 5 min after the initial instillation. Table 2. Horner's study schedule Time I Eye exam Pupillography (no drugs) Instill fluoro Meas cone Dinner Sleep 2 Breakfast Instill fluoro Dinner Drug#l Drug #2, sleep Sleep 3 Drug #1, #2 Breakfast Drug #2 Pupillography with 1% Paradrine Study complete Drug #1 = oral theophylline; drug #2 = isoprotcrcnol ophthalmic. The t-test for paired samples was used to test statistical significance. A P value of <0.05 was considered statistically significant. The variance of the technique Table 3. Aqueous humor flow Baseline measurements Measurements with fi-stimulation, asleep ( ) Dav, awake ( ) Ni^lit, asleep ( ) Dav. awake ( ) Subject Homer 's Homer "v Homer's Homer's * () t S.D * Outlier, omitted from statistical analysis. t Concentration of fluorescein too high in cornea to be measured accurately. Note. flow calculated from measurement of fluorescence at 2400 and 0600; day flow calculated from measurements of fluorescence hourly from 0600 to 00.

4 624 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / April 1988 Vol. 29 Table 4. /night aqueous humor flow, /il/min (day , awake) (night , asleep) eyes SD Homer's eyes SD Baseline flow * If ^-stimulated flow *t ft 0.91 % Increase stimulated over baseline All daytime rates were significantly different (P <, 0.05) from corresponding nighttime rates. * Statistically significant difference (P = 0.031) between night stimulated and unstimulated. t Statistically significant difference (P = 0.006) between night stimulated and unstimulated. % Statistically significant difference (P = 0.018) between stimulated Homer's and normal eyes at night. No other differences were statistically significant. employed in this study to measure flow has been estimated from previous studies to be 0.20." A sample size often subjects provides a 90% chance of detecting a 35% change of flow. Results The rate of flow in the normal eyes of the subjects during the day, 0600 to 00, was 2. ± 0.1 jul/min, somewhat lower than has been measured for other groups of normal eyes employing the same technique. The flow measured simultaneously in the fellow eye with Horner's syndrome was 2.43 ± The difference was not statistically significant (P = 0.18). During sleep (2400 to 0600), the rate of flow was 38% lower in the normal eye, 1.31 ±0.31 ^1/min (P = 0.003) and 38% lower in the Horner's eye, 1.51 ± 0.65 /ul/min (P = 0.001) (see Tables 3 and 4). On the second cycle of testing, during /3-adrenergic stimulation the flow in both eyes during the day (0600 to 00) was 14-22% higher than it had been the previous day, ± 0.94 /A/min in the normal eye and 2. ± 0.85 in the Horner's eye. The effect of /3-adrenergic stimulation in the day was not statistically significant, similar to what has been reported previously for isoproterenol. 2 Under conditions of /?- adrenergic stimulation, theflowduring sleep was 32% lower in the normal eye, 1.5 ± 0.62 /il/min (P = 0.006) and 18% lower in the Horner's eye, 2.2 ± 0.91 (P = 0.001) than during the day. However, as compared to the flow during the baseline sleep measurement, the flow under conditions of/3-adrenergic stimulation and sleep was 34% higher in the normal eye (P = 0.031) and 50% higher in the Horner's eye (P = 0.006). Discussion The results of this study confirm previous observations " that the rate of flow through the anterior chamber is less rapid during sleep than during the day. This difference in the diurnal and nocturnal rate, almost a factor of two, was observed in eyes with postganglionic Horner's syndrome showing that a full complement of adrenergic innervation to the eye is not required for this cycle to occur. There was no correlation between the percent Horner's syndrome as measured by the hydroxyamphetamine test and the day-night difference in flow. However, it is not known whether ciliary process denervation parallels iris denervation. Isoproterenol and theophylline in combination increased the rate of aqueous flow in the normal eye. and in the denervated eye during sleep. Thisfindingis consistent with the hypothesis that spontaneous /3- adrenergic activity is much lower in the eye during sleep and the effect of the ^-agonist is unmasked. Under these conditions, the response of the denervated eye is greater than the response of the fellow eye, which can be explained by denervation hypersensitivity due perhaps to less rapid removal of the topically applied catecholamine. The lack of stimulation of flow during the day is in accord with a previous experiment in which the effect of isoproterenol on flow was studied by similar techniques. 2 The lack of an effect during the day could also have been due to adrenergic desensitization caused by the initial exposure of the eye to isoproterenol during the previous sleep cycle. Key words: isoproterenol, Horner's syndrome, aqueous flow, human eye, adrenergic agonist, adrenergic denervation Acknowledgments The authors would like to thank D. D. Saggau, MD, N. J. Moyer, and L. Kullerstrand for their invaluable expertise and assistance in this study. References 1. Topper JE and Brubaker RF: Effects of timolol, epinephrine and acetazolamide on aqueous flow during sleep. Invest Ophthalmol Vis Sci 26:, 1985.

No. 4 ISOPKOTERENOL STIMULATES AQUEOUS FLOW / Larson and Drubaker 625 2. Brubaker RF and Gaasterland D: The effect of isoproterenol on aqueous humor formation in humans.

5 No. 4 ISOPKOTERENOL STIMULATES AQUEOUS FLOW / Larson and Drubaker Brubaker RF and Gaasterland D: The effect of isoproterenol on aqueous humor formation in humans. Invest Ophthalmol Vis Sci 25:35, Townsend DJ and Brubaker RF: Immediate effect of epinephrine on aqueous formation in the normal human eye as measured byfluorophotometry.invest Ophthalmol Vis Sci 19:256, Higgins RG and Brubaker RF: Acute effect of epinephrine on aqueous humor formation in the timolol-treated normal eye as measured by fluorophotometry. Invest Ophthalmol Vis Sci 19:420, Nagataki S and Brubaker RF: Early effect of epinephrine on aqueous formation in the normal human eye. Ophthalmology 88:28, Schenker HW, Yablonski ME, Podos SM, and Linder L: Fluorophotometic study of epinephrine and timolol in human subjects. Arch Ophthalmol 99:, Johnson S, Passmore JA, and Brubaker RF: The fluorescein distribution volume of the anterior chamber. Invest Ophthalmol Vis Sci :633, Thompson H and Pilley S: Pupillary dilatation lag in Homer's syndrome. Br J Ophthalmol 59:31, Brubaker RF: Clinical evaluation of the circulation of aqueous humor. In Clinical Ophthalmology, TD Duane, editor. Philadelphia, Harper and Row, 1986, pp Jones Rand Maurice D: New methods of measuring the rate of aqueous flow in man with fluorescein. Exp Eye Res 5:208, Carlson KH, McLaren JW, Topper JE, and Brubaker RF: Effect of body position on intraocular pressure and aqueous flow. Invest Ophthalmol Vis Sci 28:46, Dixon W and Massey F, Jr (editors): Introduction to Statistical Analysis. New York, McGraw Hill, 1969, p. 5.. Ericson L: Twenty-four hourly variations in the inflow of the aqueous humor. Acta Ophthalmol 36:381, Reiss GR, Lee DA, Topper JE, and Brubaker RF: Aqueous humor flow during sleep. Invest Ophthalmol Vis Sci 25:6, Topper JE and Brubaker RF: Effects of timolol, epinephrine, and acetazolamide on aqueousflowduring sleep. Invest Ophthalmol Vis Sci 26:, Wentworth WO and Brubaker RF: Aqueous humor dynamics in a series of patients with third neuron Homer's syndrome. Am J Ophthalmol 92:40, 1981.

Aqueous Flow in Humans After Adrenalectomy

Aqueous Flow in Humans After Adrenalectomy Todd L. Maus,* William F. Young, Jr.,"\ and Richard F. Brubaker* Purpose. This study was performed to determine if the circadian rhythm of aqueous humor formation