Do A-Adrenergic Receptors Participate in Control of the Circadian Rhythm of IOP?
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Investigative Ophthalmology & Visual Science, Vol. 33, No. 11, October 1992 Copyright © Association for Research in Vision and Ophthalmology Do a-Adrenergic Receptors Participate in Control of the Circadian Rhythm of IOP? Yoshiaki Kiuchi, Takeshi Yoshiromi, and Douglas 5. Gregory The a2-adrenergic antagonists, yohimbine and rauwolscine, and the a,-adrenergic antagonist, bunazo- sin, were used to explore the role of a-adrenergic receptors in the regulation of the circadian rhythms of intraocular pressure and aqueous flow in New Zealand white rabbits. Blockade of a2-adrenergic recep- tors with yohimbine or rauwolscine produced small decreases in intraocular pressure during both light and dark phases. Rauwolscine had no effect on aqueous flow during the light or dark, but it increased the concentration of norepinephrine in the aqueous during both light and dark. These observations are difficult to reconcile with earlier suggestions that increased sympathetic input to the eye increases intraocular pressure and aqueous flow during the dark. The role of a2-adrenergic receptors in the control of the circadian rhythm of intraocular pressure is unclear. Blockade of a,-adrenergic receptors * with bunazosin produced a dose-dependent reduction of IOP during the dark phase of the circadian cycle, a smaller reduction during the light phase, and no reduction during either light or dark in rabbits after superior cervical ganglionectomy or preganglionic section of the cervical sympathetic trunk (de- centralization). Bunazosin decreased pupil diameter during the dark phase but had no effect on aqueous flow. Because it is unlikely that a,-adrenergic blockade increased outflow facility or uveoscleral out- flow, the mechanism for the role of a,-adrenergic receptors in the control of the circadian rhythm of intraocular pressure in rabbits remains to be identified. Invest Ophthalmol Vis Sci 33:3186-3194, 1992 Rabbits have circadian rhythms of intraocular pres- approximately half the range of the circadian rhythm sure (IOP) and aqueous flow; both IOP and flow are of IOP. Blockade of /?-adrenergic receptors with timo- lowest during the light phase and highest during the lol (TIM) during the dark produced small decreases of dark phase.1"7 Superior cervical ganglionectomy IOP (<3 mmHg)9 and aqueous flow (< 10%)" and (CGX) or preganglionic section of the cervical sympa- reduced the dark phase increase of aqueous cAMP.12 thetic trunk (decentralization, DX) blunted the dark Because the effects of TIM on IOP and aqueous flow phase increases in IOP,4'8"10 aqueous flow,11 aqueous were not large enough to explain the entire dark- norepinephrine (NE) concentration,1012 and aqueous phase increases of either IOP or flow or even the dark cyclic adenosine monophosphate (cAMP).12 There- phase increases that require intact sympathetic inner- fore, we and others4'8"13 have argued that the increases vation to the eye, it seemed likely that NE stimulation in IOP and aqueous flow observed during the dark of a-adrenergic receptors also may play a role in the phase of the circadian cycle in rabbits result from ele- regulation of the dark-phase increases of IOP and vated sympathetic input to the eye during the dark. aqueous flow in rabbits. Recently, a study was pub- The dark phase increases of IOP and aqueous flow lished of the effects of a-adrenergic agents on the in- appear to be mediated partly by stimulation of fi- creases in IOP and aqueous flow between late light adrenergic receptors by NE. Both CGX and DX de- phase and early dark phase.13 creased IOP 5 mmHg early during the dark phase, Although the major effect of CGX or DX on IOP in rabbits was to decrease IOP during the dark, both pro- cedures produced small increases of IOP early in the light phase.48 Furthermore, CGX increased aqueous From the Department of Ophthalmology and Visual Science, flow during the light, and although the changes were Yale University School of Medicine, New Haven, Connecticut. not statistically significant, there was a tendency to- Supported by Public Health Service (Bethesda, MD) grants EY00785 and EY05078, the Connecticut Lions Eye Research ward increased flow during the light after DX." Both Foundation, Inc. (New Haven, CT), and Research to Prevent surgical procedures decreased aqueous NE during the Blindness, Inc. (New York, NY). light phase.12 Although blockade of /3-adrenergic re- Submitted for publication: November 15, 1991; accepted April ceptors with TIM decreased IOP and aqueous flow 8, 1992. during the dark, it had no effect on IOP9 or aqueous Reprint requests: Douglas S. Gregory, Department of Ophthal- mology and Visual Science, Yale University School of Medicine, flow" during the light phase. Therefore, it is reason- PO Box 3333, New Haven, CT 06510. able to think that input from the sympathetic nerves 3186 Downloaded from iovs.arvojournals.org on 10/02/2021 No. 11 a-ADRENERGIC RECEPTORS AND CIRCADIAN IOP RHYTHM / Kiuchi er ol 3187 to the eye has two effects on IOP and flow in rabbits. were treated with physiologic saline. We applied BNZ In addition to increasing IOP and aqueous flow dur- (50 /xl) at 00:00 or 12:00 CT; IOP was recorded at the ing the dark (in part by stimulating 0-adrenergic re- same time intervals as in the experiments with YOH ceptors), sympathetic input may decrease both IOP and RWL. Our data are expressed as the average dif- and flow by a different mechanism during the light. ference between IOP in the treated (and contralateral) For this reason, we treated rabbits entrained to alter- eye on the day of treatment and the average IOP in nating 12-hr periods of light and dark with yohimbine both eyes on the day the animals were not treated with (YOH) and rauwolscine (RWL), a2-adrenergic antago- BNZ. Concentrations of BNZ, YOH, and RWL were nists, and bunazosin (BNZ), an a,-adrenergic antago- expressed as percent of the base drug, ie, in grams of nist,14"16 during both the light and dark phases of the base per deciliter. circadian cycle to explore the possibility that a-adren- ergic receptors participate in control of the circadian Pupillary Diameter rhythms of IOP and aqueous flow. This was estimated by comparing the pupillary di- ameter of the rabbits to semicircles of known diame- Materials and Methods ter on a clinical examination card after unilateral ap- plication of 0.3% BNZ at 13:00 CT (one dose of 50 /*1) Animals and Animal Surgery or at 12:30 and 12:45 CT (two doses of 25 ^1 each). All experimental procedures using animals adhered Pupillary diameter was measured during the dark by to the ARVO Resolution on the Use of Animals in the light of the same dim red light used for IOP mea- Research. Male New Zealand white rabbits (weight surement. Illuminance was measured at the same po- range, 2-3 kg) were maintained in a 12-hr light-dark sition as the rabbits' eyes during pupillary diameter cycle for at least 2 wk before their use in all experi- measurements with lights on and off (20-36 and 0.2- ments. Animals subjected to bilateral CGX or bilat- 0.3 foot candles, respectively). Illuminance was mea- eral DX4'8 were allowed to recover in a room with a sured with a J16 Digital Photometer fitted with a lighting schedule of of alternating 12-hr light-dark pe- J6511 illuminance probe, which has a spectral sensi- riods. We confirmed CGX and DX 2-3 wk after sur- tivity comparable to human cone photoreceptors gery as previously described.12 (Tektronix, Beaverton, OR). IOP Measurements Aqueous Flow Measurements We measured IOP as previously described9 during Aqueous flow rates were estimated using modifica- the dark using the light of a Bright Lab Jr. red light tions of the intravitreal depot method17 and the cor- (Delta 1, Dallas, TX), which produces visible light in neal depot method.18 the far red.3 A crossover protocol was used for IOP Intravitreal depot method: Flow measurements us- experiments with YOH HC1 (Sigma, St. Louis, MO) ing the intravitreal depot method were done as previ- and RWL HC1 (Atomergic, Plainview, NY) each at a ously described7" using a crossover protocol. We ap- concentration of 0.3% in water. We applied 50 n\ of plied BNZ (50 y\ of 0.1% unilaterally) topically to one the drug topically to one eye of one half of each group half of the rabbits at 12:00, 14:00, and 16:00 CT; the of animals; contralateral eyes were treated with water. other half received saline in both eyes. On the follow- The other half of the group received 50 /ul of water to ing day, animals previously treated with saline re- both eyes. No less than 3 days later, animals previ- ceived unilateral BNZ, and those previously treated ously treated with YOH or RWL were treated with with BNZ received saline in both eyes. Fluorescence water, and those previously treated with water were was measured with a scanning fluorophotometer treated with YOH or RWL. For experiments using a (Fluorotron Master; Coherent, Palo Alto, CA) at concentration of 0.1% of drug, the 0.3% solution was 11:00, 13:00, 15:00, 17:00, and 19:00 CT. We applied diluted to 0.1 % with saline. Contralateral eyes were BNZ topically three times to ensure that, if aqueous treated with one part water and two parts saline, and flow was reduced by BNZ, it would be reduced long they were used as controls. Both YOH or RWL were enough to maximize the probability that the change applied either at 02:00 circadian time (CT, ie, lights could be detected and also to reproduce the experi- on at 00:00 CT) or at 14:00 CT (lights off at 12:00 mental protocol used earlier" to measure aqueous CT).