Download Effects of stimulation of the ocular sympathetic nerves on IOP

Effects of Stimulation of the Ocular Sympathetic
Nerves on IOP and Aqueous Humor Flow
Carlos Delmonte,* Stephen P. Barrels, John H. K. Liu, and Arthur H. Neufeld
Ocular sympathetic nerves were stimulated chronically in awake rabbits using electrodes unilaterally
implanted on the cervical sympathetic trunk. IOP was measured by pneumatonometry and aqueous
inflow was measured by fluorophotometry. In each animal, continuous trains of 1 msec pulses were
delivered by means of a portable electrical stimulator. Experiments were spaced by 1 week recovery
periods. Stimulation was varied over a range of amplitudes (5-15 V) and frequencies (3-12 Hz).
Continuous sympathetic stimulation produced an immediate sharp decrease in IOP followed by a
gradual rise to pre-stimulation values which were attained 60-90 min after onset. A rebound increase
in IOP occurred when stimulation was terminated. The magnitude of the initial IOP drop, the delay in
the return to pre-stimulation IOP, and the rebound rise in IOP subsequent to termination of electrical
stimulation were proportional to the stimulation frequency. Maximal effects were observed at 12 Hz,
and stimulation with 8-10 Hz for 180 min caused a sustained reduction in anterior chamber aqueous
humor flow. Topical 2% phentolamine 1 hr before stimulation markedly reduced IOP and abolished
the acute IOP changes observed in untreated stimulated animals. Topical 1% timolol did not affect
either the initial IOP drop or the rebound; however, the IOP recovered during stimulation to values
greater than pre-stimulation IOP. We conclude that in rabbits the 0-adrenergic effect of prolonged
sympathetic nerve stimulation is to decrease aqueous flow. Chronic electrical stimulation in awake
animals provides an experimental model for studying the role of the ocular sympathetic nerves. Invest
Ophthalmol Vis Sci 28:1649-1654,1987
IOP. Henderson and Starling4 first noticed a decrease
of IOP in anesthetized cats and dogs following sympathetic stimulation, an observation later confirmed
by others in the rabbit.5"7 In an extensive study,
Langham and Rosenthal8 reported that in the rabbit
sympathetic stimulation for periods up to 30 min
reduced IOP, aqueous humor formation and blood
flow to the ciliary processes, whereas the drainage of
aqueous humor remained unaffected. All these studies, however, were performed in anesthetized animals, using manometric measurement of IOP and
thus were limited to short periods of time.
Recently, a technique has been described to perform prolonged stimulation of the cervical sympathetic nerve in unanesthetized animals using chronically implanted electrodes.9 We have applied this
method to examine the effects of sustained electrical
stimulation of the ocular sympathetic nerves during
extended periods of time on IOP and aqueous humor
flow. Also, the actions of a- and jft-adrenergic antagonists on the IOP responses to adrenergic nerve stimulation have been explored.
Adrenergic influences on aqueous humor dynamics and intraocular pressure (IOP) are documented1"3; however, the responsiveness of these parameters to adrenergic manipulations depends
greatly on the experimental conditions and on the
animal species employed. Noted differences in responsiveness may be due in part to the degree of
efferent sympathetic activity. For example, stress,
circadian rhythm or anesthesia alters release of endogenous transmitter and causes variation in background levels of activity upon which exogenous
adrenergic influences interact.
Electrical stimulation of the cervical sympathetic
nerves has been employed repeatedly to mimic the
effects of physiological excitation of the ocular
adrenergic fibers on aqueous humor dynamics and
From the Ophthalmic Pharmacology Unit, Eye Research Institute of Retina Foundation, Boston, Massachusetts, and the Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
* Visiting Professor from the Department of Physiology, University of Alicante Medical School, Alicante, Spain.
Supported by NEI grants EY-04914, EY-05671, and EY-06416,
and by the National Society to Prevent Blindness.
Submitted for publication: January 6, 1987.
Reprint requests: Stephen Bartels, PhD, Eye Research Institute,
20 Staniford Street, Boston, MA 02114.
Materials and Methods
Pigmented rabbits of both sexes weighing 2.5-3.5
kg were used. Experiments were performed according
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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / October 1987
Vol. 28
sponse again checked. Stimulations were maintained
for periods of 30-270 min depending on the experimental design. The animals were removed from the
restraint box when long stimulation periods were
used, but the stimulator remained connected to the
electrodes and secured in a jacket worn by the rabbit.
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Fig. 1. IOP during electrical stimulation (9 Hz) of the cervical
sympathetic nerves in conscious rabbits. All points are means
± SEM (n = 7).
to the ARVO Resolution on the Use of Animals in
Research.
Electrode Implantation
Animals were anesthetized with ketamine (66
mg/kg) and xylazine (7 mg/kg) injected intramuscularly, followed by pentobarbital (15 mg/kg) intravenously. The preganglionic sympathetic trunk was
carefully dissected and two stimulating electrodes
were implanted on the nerve, according to the technique described by Belmonte et al.9
The electrode terminals were exteriorized at the
back of the neck. Electrical stimulation was performed briefly at the end of surgery and the pupillary
response checked in order to ascertain the integrity of
the ocular sympathetic fibers. The animals were allowed to recover from surgery for 1 week. The pupillary response was provoked several days later, and
only those rabbits that exhibited a clear mydriasis in
response to electrical stimulation were used.
Electrical Stimulation
Postoperative rabbits were put into restraint boxes.
Stimulation of the cervical sympathetic nerve was
performed using a portable electrical stimulator that
could deliver continuous trains of 0.5 to 1 msec
pulses of 1 to 12 V at a frequency of 1 to 20 Hz.9 In
some experiments a stimulator coupled to a stimulus
isolation unit (Grass Instruments, Quincy, MA) was
also used. Prior to the experiment, the stimulating
voltage was adjusted to the value necessary to evoke a
maximal pupillary response at the desired frequency.
The stimulatory pulses were visualized on the screen
of an oscilloscope to adjust accurately the amplitude
and frequency of the stimulation.
After basal IOP readings were taken for at least 30
min, the stimulus was initiated and the pupillary re-
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IOP Measurements
IOP was measured with a pneumatonometer probe
(Digilab Inc., Cambridge, MA) attached to a pressure
transducer and a physiograph. The calibration of the
tonometer was performed in intact eyes of anesthetized rabbits by the closed stopcock manometric
method. Half percent proparacaine was used as local
anesthetic before tonometry. At least three successive
IOP readings were taken and the average was recorded for each measurement. Postoperative rabbits
were acclimated to pneumatonometry by making
several IOP measurements prior to beginning each
experiment.
Fluorophotometry
Corneas were stained with topical fluorescein on
the day prior to fluorophotometric studies. Concentrations of fluorescein in the cornea and anterior
chamber were measured at 30 min intervals with a
slit-lamp fluorophotometer.10 Anterior chamber
aqueous humorflowrate was calculated using a clearance method based on that described by Brubaker.''
Corneal volume was assumed to be 75 (i\ and anterior
chamber volume 250 n\.
Drugs
All concentrations refer to weight/volume of base.
Ketamine was from Parke-Davis (Morris Plains, NJ),
xylazine from Haver-Lockhart (Shawnee, KS), pentobarbital from Abbott Laboratories (North Chicago,
IL), phentolamine mesylate was the generous gift of
Ciba-Geigy Corp. (Summit, NJ) and timolol maleate
was the generous gift of Merck, Sharp and Dohme
(West Point, PA).
Results
Changes of IOP With Sympathetic Stimulation
Figure 1 shows the pattern of IOP variation resulting from the electrical stimulation of the cervical
sympathetic nerve for 3 hr. Data were pooled from
experiments in seven rabbits stimulated with continuous trains of 1 msec, 12 V pulses at 9 Hz on different
days with a minimum interval of 4 days between
trials. Initiation of the stimulus resulted in an immediate IOP drop of 4.4 mmHg concomitant with
marked mydriasis, followed by slow recovery of IOP
to control values, within 60 to 90 min after the onset
of stimulation. Cessation of nerve stimulation re-
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EFFECT OF SYMPATHETIC STIMULATION ON IOP AND AQUEOUS FLOW / Delmonre er d .
10
8
Fig. 2. (a) Initial IOP drop
and IOP rebound during
chronic electrical stimulation with different frequencies in conscious rabbits. All
data are means ± SEM (n
= 8-13). (b) The recovery of
IOP during electrical stimulation at different frequencies in conscious rabbits. D,
3 Hz; 0, 6 Hz; A, 9 Hz; and
V, 12 Hz. All points are
means ± SEM (n = 5-11).
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suited in an abrupt pressure rebound of 2.1 mmHg,
followed by a gradual IOP decay that reached prestimulation levels in approximately 30 min.
The magnitude of the initial IOP drop immediately
following initiation of the stimulus was proportional
to the stimulatory frequency, as illustrated in Figure
2a. Maximal effects were observed with 12 Hz, which
produced a mean ± SEM pressure decrease of 6.8
±1.5 mmHg (n = 10), compared with an IOP drop of
3.2 ± 0.8 mmHg (n = 10) when 3 Hz were applied.
The time course of the subsequent IOP recovery during maintained stimulation was related to the frequency of stimulation (Fig. 2b). At lower stimulatory
frequencies (3 and 6 Hz), mean control values recovered after 30 min, whereas, when higher frequencies
were used, IOP still remained 2-3 mmHg under prestimulation levels at this time period. At the higher
frequencies, IOP recovered to pre-stimulation values
within 60 min (Fig. 2b) and remained normotensive
for the next 2 hr. The magnitude of the IOP rebound
following cessation of stimulation was also directly
related to the stimulatory frequency (Fig. 2a) and was
proportionally smaller for a given frequency than the
corresponding initial IOP drop elicited by the onset of
the stimulus.
and the operated sides (3.18 ± 0.19
Thus, implantation of the electrodes did not alter the
basal aqueous humor flow rate.
Sympathetic stimulation for 3 hr at 8-10 Hz causes
a relatively small reduction (12-19%) in aqueous
humor flow rate of the stimulated side when compared with the contralateral, non-stimulated eye. The
time course of this reduction in flow is shown in Figure 3. Theflowrate was calculated at 30 min intervals
throughout a 4.5 hr stimulation period, starting immediately after the onset of the stimulus. The consistently, statistically significant reduction of aqueous
humor flow occurred as early as 120 min after beginning stimulation and persisted. Perhaps flow was decreased at earlier time points but the data does not
permit resolution of these points. Thus, aqueous
humor flow rate was reduced at a time during continuous stimulation when IOP had recovered to prestimulation values.
°2
Effects of Sympathetic Stimulation on Anterior
Chamber Aqueous Humor Flow
Aqueous humor flow rate was measured in both
eyes of rabbits at baseline, control conditions and
during a 4.5 hr unilateral stimulation of the cervical
sympathetic nerves. The basal rates in both eyes of
each animal (n = 13), when no stimulation was performed, were quite similar and no significant differences were found between the control (3.08 ±0.19
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HIM,IN
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Fig. 3. Effects on aqueous flow with chronic electrical stimulation of the cervical sympathetic nerves in conscious rabbits. Electrical stimulation was started at time = 0. 8-10 Hz were used. All
data are means ± SEM (n = 6-9). • = contralateral control, •
= electrically stimulated.
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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / October 1987
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Fig. 4. (a) IOP following treatment of conscious rabbits with 2%
phentolamine. Drug treated (•) and contralateral untreated (0)
eyes. All points are means ± SEM (n = 7). (b) IOP during chronic
electrical stimulation of the cervical sympathetic nerves in conscious rabbits pretreated with phentolamine (0, n = 5) compared to
IOP in phentolamine-treated eyes of control, non-operated rabbits
(•, n = 7). All points are means ± SEM.
The Influences of Adrenergic Antagonists on IOP
Responses to Sympathetic Stimulation
The effects of the a-adrenergic antagonist, phentolamine, and the /3-adrenergic antagonist, timolol, were
explored in separate series of experiments.
As depicted in Figure 4a, topical 2% phentolamine
applied twice to one eye of non-operated rabbits pro-
duced a gradual decrease of IOP in the treated eye
over a 2 hr period and also, to a lesser extent, in the
non-treated, contralateral eye. Two hours after the
administration of the drug, the IOP had fallen about
8 mmHg in the treated eye and about 4 mmHg in the
contralateral eye. At 4 hr, low IOP values were still
present in both eyes and at 7 hr, IOP had recovered
only partially.
Electrical stimulation of the cervical sympathetic
nerves was performed in rabbits pretreated unilaterally with 2% phentolamine in the stimulated eye 1 hr
before the onset of stimulation. The IOP of phentolamine-treated, stimulated eyes was compared to the
IOP of phentolamine-treated eyes of non-operated
rabbits (Fig. 4b). The curve for stimulated eyes is not
significantly different than that resulting from the
administration of phentolamine alone. Thus, when
phentolamine is present, the initial IOP drop and
subsequent IOP recovery does not occur in response
to electrical stimulation.
Timolol (1%) was administered bilaterally and followed 1 hr later by unilateral electrical stimulation of
the cervical sympathetic nerves for 3 hr. In the presence of timolol, electrical stimulation caused the initial IOP to drop about 3 mmHg in 1 min. However,
within 15-30 min, IOP recovered to pre-stimulation
levels. The IOP continued to rise during the following
hour of stimulation, attaining values that were higher
than the pre-stimulation values and that persisted
during the remaining stimulation time (Fig. 5). Interruption of the stimulus resulted in an acute IOP rebound and a gradual return to control values.
The hypertensive action of sympathetic stimulation in timolol-treated eyes is illustrated in Figure 5
by comparison to the effects of sympathetic stimulation on IOP in animals not treated with timolol. Figure 5 presents the IOP differences compared to prestimulation values of electrically stimulated eyes either in the absence or presence of timolol. In
timolol-treated animals, the amplitude to which IOP
recovers during electrical stimulation is significantly
higher from 60-180 min. Thus, in the presence of
timolol, eyes receiving continuous sympathetic stimulation become hypertensive.
Discussion
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Fig. 5. IOP changes during chronic electrical stimulation (8-9
Hz) of the cervical sympathetic nerves in conscious rabbits pretreated with timolol (•, n = 6) compared to IOP changes in electrically stimulated eyes of untreated rabbits (0, n = 9). All points
are means ± SEM.
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Chronic implantation of stimulating electrodes on
the cervical sympathetic nerves does not appear to
interrupt the spontaneous nervous traffic in the
adrenergic nerve fibers to the eye. No atypical IOP,
pupillary or vascular signs were observed on the
operated side in the days following surgery that would
have been suggestive of damage to the nerve. Thus,
we assume that electrical stimulation activates the
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EFFECT OF SYMPATHETIC STIMULATION ON IOP AND AQUEOUS FLOW / Delmonre er ol.
ocular sympathetic fibers, resetting the spontaneous
activity to the imposed stimulatory train frequency
and reproducing experimentally the effects of a
maintained sympathetic discharge on the eye.9
Sustained stimulation of the ocular sympathetic
fibers evoked in our experiments a consistent response of the IOP. The decrease in IOP that followed
onset of stimulation has been observed in anesthetized animals8 and has been attributed to reduction in
blood volume resulting from vasoconstriction of the
richly innervated uveal vascular bed.12 In monkeys,
Casey13 estimated that the decrease of ocular volume
that occurs when sympathetic nerves are stimulated
at 10 Hz is about 5 n\. Measurements of blood flow
changes with equivalent sympathetic stimulation in
the rabbit indicate that such a volume decrease is the
result of a 60-75% reduction in ocular blood flow.1214
The increasing magnitudes of the initial drops in IOP
with higher stimulatory frequencies reflect the wellknown relationship between frequency of sympathetic discharge and degree of vasconstriction.914 Apparently the opposite effect, a sharp increase in IOP,
occurs when the stimulus is interrupted, and the IOP
rebounds. The smaller amplitude of this pressure rise,
in comparison with the magnitude of the equivalent
IOP decrease at the onset of the stimulation, probably
reflects a degree of smooth muscle relaxation in the
ocular vessels which occurs even in the presence of
maintained adrenergic stimulation.
Continuous measurements of IOP during sympathetic stimulation in anesthetized animals performed
by previous investigators indicate that IOP did not
return to pre-stimulation levels after 30 min of sustained stimulation. Langham and Rosenthal8 reported that under these conditions, blood flow to the
ciliary processes and aqueous humor production
were steadily decreased while outflow resistance was
not altered. These authors concluded that adrenergic
stimulation produced a sustained lowering of ocular
equilibrium pressure as a consequence of reduction
in aqueous humor inflow.
Our data confirm the 30 min time point of the
above studies and provide evidence that when longer
stimulations are performed in unanesthetized animals, IOP returns to control values despite a sustained lowering of the aqueous humor flow rate. This
implies that a decrease in outflow occurs over time as
a result of the maintained adrenergic stimulation.
Decreased outflow can occur because of increased
outflow resistance or decreased outflow pressure. Paterson15 reported an increase in outflow facility (decreased outflow resistance) in the cocaine-pretreated
anesthetized rabbit approximately 30 min after electrical stimulation of the sympathetic nerves. Perhaps,
intrascleral vasoconstriction during sustained electri-
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cal stimulation decreases outflow by decreasing net
outflow pressure.
The topical, unilateral administration of the aadrenergic antagonist, phentolamine, lowered IOP
both in the treated and the contralateral eyes, confirming previous data on the action of a-adrenergic
antagonists on IOP.16"20 The drug also blocked the
IOP effects of electrical stimulation of the sympathetic nerves, confirming that the immediate IOP decrease 1 min after onset of stimulation is due to vasoconstriction via mostly a-adrenergic activity. However, the low IOP values produced by the drug may
obscure other, more subtle actions resulting from the
excitation of/3-adrenergic receptors by endogenously
released neurotransmitter. In the presence of phentolamine, IOP did not recover to control levels during
sustained stimulation. Perhaps phentolamine also
blocked an a-adrenergic-mediated decrease in outflow, ie, vasoconstriction.
The electrically stimulated, endogenously released
neurotransmitter, norepinephrine, clearly acts at /?adrenergic receptors. This is indicated by the results
of the timolol experiments. In these experiments, the
initial IOP drop is quickly followed by a rapid increase of IOP to values higher than pre-stimulation
levels. Thus, timolol potentiates and enhances the
recovery of IOP during continuous sympathetic stimulation, perhaps because timolol blocks /J-adrenergic-mediated decrease in inflow and therefore potentiates the a-adrenergic-mediated decrease in outflow.
We hypothesize that prolonged stimulation of /?adrenergic receptors in rabbits reduces IOP by decreasing aqueous humor formation. Ourfindingscan
therefore be interpreted as a decrease in the outflow
produced by a-adrenergic stimulation during prolonged sympathetic stimulation offset by decreased
aqueous humor formation produced by jS-adrenergic
receptor stimulation. Prolonged, high-frequency
nerve stimulation may give different results than
acute nerve stimulation or use of topical agonists.
However, in all these cases, the initial effect may be
increased aqueous human formation which becomes
decreased upon prolonged stimulation because of j8adrenergic receptor desensitization.21
The existence of a continuous adrenergic tone influencing IOP is controversial.3 Probably the amount
of sympathetic activity reaching the eye varies widely
and depends on environmental conditions, diurnal
rhythm and the level of stress involved in the experimental manipulations. This could explain in part the
variable effects produced by ocular drugs that influence the adrenergic system. In our experiments, electrical stimulation of sympathetic nerves excites simultaneously all adrenergic fibers directed to the eye
and corresponding receptor sites. Therefore, the elec-
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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / October 1987
trical stimulation of the ocular sympathetic nerve is a
useful method to minimize the variations in ocular
adrenergic tone, because it clamps spontaneous nervous activity at an established level. This technique
will be useful in evaluating the IOP responses to
adrenergic drugs.
Key words: intraocular pressure, aqueous humorflow,sympathetic nerves, a-adrenergic antagonist, j8-adrenergic antagonist, rabbit
Acknowledgment
The authors thank Isabel Ivorra for her excellent technical assistance throughout these studies.
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