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ATP Is Released Into the Rabbit Eye by Antidromic Stimulation of the Trigeminal Nerve

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ATP Is Released Into the Rabbit Eye by Antidromic Stimulation of the Trigeminal Nerve ATP is released into the rabbit eye by antidromic stimulation of the trigeminal nerve Eugenio Maul and Marvin Sears Antidromic stimulation of the trigeminal nerve produces an irritative response in the rabbit eye characterized by ipsilateral miosis, hyperemia, elevated intraocular pressure, and a disruption of the blood-aqueous barrier. The latter is a bilateral effect. The mediator or mediators in- volved in this response of the eye are unknown. Increased ATP levels in aqueous humor could be found after trigeminal stimulation. Treatment of rabbits with dipyridamole further in- creased ATP levels in aqueous humor after stimulation, confirming the findings of Holton that stimulation of sensory nerves causes a release of ATP. Intravitreal injections of ATP could not reproduce the ocular irritative response; however, an iridial hyperemia of long latency and an increase in aqueous humor protein levels were produced. The mechanism of this part of the reaction requires further study. Key words: adenosine triphosphate, trigeminal nerve, aqueous humor, antidromic stimulation, irritative response, ocular hyperemia, dipyridamole Antidromic stimulation of the trigeminal mitter receptor mechanism.4 The substance nerve produces an irritative response in the or substances released by trigeminal nerve rabbit eye characterized by ipsilateral miosis, stimulation have not been identified. The hyperemia of the iris and conjunctiva, in- purpose of this study was to learn whether traocular hypertension, and a disruption of adenosine triphosphate (ATP) is released into the blood-aqueous, barrier.u 2 This last effect the rabbit eye by trigeminal nerve endings is also present in the contralateral eye.3 after antidromic stimulation and whether The irritative response produced by stimu- ATP could stimulate an irritative response. lation of this neural pathway suggested that the effects were the consequence of a trans- Material and methods Animals. New Zealand, male, albino rabbits From the Department of Ophthalmology and Visual Sci- weighing 2 to 3 kg were used. When required, ence, Yale University School of Medicine, New Ha- general anesthesia was induced with sodium pen- ven, Conn. tobarbital, 15 mg/kg intravenously. This study was supported in part by U.S. Public Health Experimental groups. The trigeminal nerve was Service EY-00237, the Connecticut Lions Eye Re- exposed and mechanically stimulated as previ- search Foundation, Inc., and New Eyes for the ously described.3 One, 5, 10, and 20 min after Needy, Inc. Dr. Maul received support from New stimulation, the aqueous humor of both eyes was Eyes for the Needy, Inc., during the tenure of his obtained by paracentesis and set on crushed ice. glaucoma fellowship. Submitted for publication Jan. 16, 1978. Animals with exposure of the trigeminal nerve but Reprint requests: Dr. Marvin Sears, Department of not stimulated served as controls. Aqueous humor Ophthalmology and Visual Science, Yale University of anesthetized unstimulated rabbits and normal School of Medicine, 333 Cedar St., New Haven, rabbits under topical anesthesia was obtained at Conn. 06510. the same time. ATP concentration was deter- 256 0146-0404/79/030256+07$00.70/0 © 1979 Assoc. for Res. in Vis. and Ophthal., Inc. Downloaded from iovs.arvojournals.org on 09/30/2021 Volume 18 Number 3 ATP released by antidromic stimulation 257 mined in all aqueous humor samples within min- final concentrations of 10"8M, 10"6M, and 10-*M. utes of finishing the experiment. The pupillary diameter was measured with a Six rabbits were pretreated with 250 £ig/kg in- caliper after addition of ATP to the bath. At the travenous dipyridamole 30 minutes before trigem- end of the experiment acetylcholine was added to inal stimulation. Three rabbits were treated with two and norepinephrine to the remaining two intraperitoneal dipyridamole, 1 mg/kg, divided preparations, and pupil diameter was again re- into two doses, administered 3 and 1 hr before corded. the nerve stimulation. (Dipyridamole was kindly Intravitreal administration of nucleotides. Ten supplied by Boehringer Ingelheim, N. Y.) Aque- microliters of a solution containing 28 nmol ATP, ous humor of these last two groups was obtained adenosine diphosphate (ADP), or adenosine mon- by paracentesis 1 min after stimulation and as- ophosphate (AMP) were administered to three sayed for ATP concentration. groups of rabbits. The solution was injected with a ATP measurement in neural tissue. Normal 30-gauge needle through the pars plana into the rabbits were sacrificed with an overdose of sodium vitreous under topical anesthesia. Ten microliters pentobarbital. The jugular veins were sectioned of saline were injected to the contralateral eye, and the head of the animal was then washed out of which served as a control. The animals were ob- blood with ice-cold saline perfusion through the served in a single-blind fashion for a 36 hr period; carotid arteries. The trigeminal nerve and Gasse- the pupil diameter and iris conjunctival hyperemia rian ganglion were excised and wet weighed sepa- were clinically recorded. Aqueous humor was ob- rately. The tissue pieces were mechanically ho- tained at 30 min and 8, 18, 24, and 36 hr after drug mogenized in ice-cold water, boiled for 10 min, administration, and protein concentration deter- then centrifuged for 15 min at — 10° C and mined with refractometry of a 50 fx\ sample.4 800 X g, in a Sorvall centrifuge. The supernatant Rabbits after paracentesis were eliminated from was assayed for ATP concentration. the group under observation. ATP assay. ATP concentration in the test sam- Statistical analysis. The significance of the re- ples was determined with the firefly (Photinus sults was calculated with the t test for sample spiralis) luciferin-lucinferase system. The samples means or, where specified, with the modified were boiled for the recovery of ATP because the Wilcoxon-White test for samples of different size.7 enzyme is inhibited by a number of substances, All data are given as the mean ± standard error of including various quenching agents.1 The light the mean. rate was measured with a Packard Tricarb liquid scintillation spectrometer at tritium setting, 65% Results gain, 3 sec after mixture of the test sample with ATP in aqueous humor of normal rabbits. the crude luciferase preparation. A standard curve Fourteen samples were assayed: the ATP for ATP from 2 to 50 pM was obtained with each present was 4.50 ± 0.7(14) nmol/L. There ATP assay. was no significant difference in ATP between In addition, internal standards were used, the test sample was divided into two halves, a known paired samples of aqueous humor nor in that amount of ATP was added to one half before boil- of normal aqueous humor obtained from rab- ing, and the same amount was added to the other bits under topical or general anesthesia. half after boiling. ATP in aqueous humor of rabbits with uni- ATP concentration in whole blood was deter- lateral stimulation of the trigeminal nerve. mined in eight rabbits. ATP measurements were When the trigeminal nerve of one side was also done in aqueous humor of four animals 1 min stimulated the irritative response previously after disruption of the lens with a needle through reported could be observed. ATP concentra- the pars plana. tion in aqueous humor measured 1 min after Effect of ATP on the iris preparation. Four stimulation was higher than in controls. In- irises of normal rabbits were mounted between terestingly, ATP of the contralateral side was two plexiglass rings like a diaphragm and set into a 10 ml chamber at 25° C filled with buffered solu- also higher than in controls. The mean for tion according to the method of Farnebo and controls was 3.8 ± 0.7 nmoles/L (11). One Hamberger,6 and oxygen 95% was bubbled into minute after stimulation the aqueous humor the solution. The pupil was allowed to stabilize for of the stimulated side was 16.2 ± 3 nmol/L a 30 min period, then ATP was added to reach (15) in the treated side (p < 0.01) and 14.7 ± Downloaded from iovs.arvojournals.org on 09/30/2021 Invest. Ophthalmol. Visual Sci. 258 Maul and Sears March 1979 n=l5 Table I. ATP content of neural tissue 20 n=l5 Trigeminal nerve Gasserian ganglion E n=6 (fig/gm-) 5 10 37.7 31 28.5 27.7 C ST CL ST CL ST CL ST CL 37.7 19.4 I 5 10 20 MIN. AFTER STIMULATION Fig. 1. ATP concentration in aqueous humor 3 (15) in the contralateral side. The ATP of (nmol/L) of the control (C), stimulated side (ST), aqueous humor 5, 10, and 20 min after stimu- and contralateral side (CL) 1, 5, 10, and 20 min- lation was significantly lower (Fig. 1). utes after unilateral stimulation of the trigeminal ATP in aqueous humor of rabbits pre- nerve. Mean ± S.E.M. treated with dipyridamole after unilateral n«3 stimulation of the trigeminal nerve. When in- travenous dipyridamole, 250 /u-g/kg, was n=3 administered 30 min before stimulation, the 40 i- ATP level in aqueous humor of the stimu- lated side was 10.4 ± 5 nmol/L (6), and that 30 of the contralateral side was 8.85 ± 3.7 (6). E n°l5 These measurements were not different from n=l5 .5 20 n = 6 those in the stimulated group that did not a. T n«6 < receive the drug. When dipyridamole was 10 administered intraperitoneally, 1 mg/kg, ATP 1 min after stimulation was 36.9 ± 12 nmol/L (3) in the stimulated side and 24.8 ± ST CL 3T CL ST CL 14 (3) in the contralateral side, values sig- C (DIP250>ifl/kg) (DIP lOOO^fl/kg) nificantly higher than in the stimulated group TRIGEMINAL STIMULATION (Fig. 2) without dipyridamole treatment Fig. 2. ATP concentration in aqueous humor of (p < 0.01, Wilcoxon-White test).
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