Jacob Bell
New Member
Interaction of adrenergic antagonists with
prostaglandin E2 and tetrahydrocannabinol
in the eye
Keith Green and Keun Kim
Both a- and /3-adrenergic antagonists have been utilized in an attempt to discern the site
of action of prostaglandin (PG) and tetrahydrocannabinol (THC) in the eye. Both a- and
(1-adrenergic antagonists (a-antagonists, phentolamine and phenoxybenzamine; P-antagonists,
propranolol and sotalol) caused a dose-dependent reduction in intraocular pressure and blood
pressure and increased total outflow facility. The results are consistent with the concept that
both a- and fi-adrenergic receptors are present in the anterior uvea and that vasomotor tone
is essential to the maintenance of normal intraocidar pressure. No antagonist reduced the
PG-induced elevation of intraocular pressure unless the blood pressure was severely lowered.
All antagonists inhibit the normal PG-induced increase in total outflow facility, indicating that
these agents protect the blood-aqueous barrier from breakdown without altering the vasodilatory
response to PG. All antagonists reduced the fall in intraocular pressure produced by THC
by approximately 50 per cent, except for sotalol which completely abolished the intraocular
pressure fall. Only the a-adrenergic antagonists prevented the THC-induced increase in total
outflow facility. The results indicate that true outflow facility may well be regulated exclusively
by a-receptors. The data are consistent with the effect of THC being primarily a vasodilation
of the efferent blood vessels of the anterior uvea. The partial inhibition by a-adrenergic
antagonists may also suggest a lesser role of THC on the afferent vessels.
Key words: rabbit, intraocular pressure, total outflow facility, blood pressure, adrenergic
antagonists, propranolol, phenoxybenzamine, phentolamine, sotalol, prostaglandin Es,
tetrahydrocannabinol.
From the Departments of Ophthalmology and
Physiology, Medical College of Georgia,
Augusta, Ga.
Supported in part by Public Health Service Research
Grants EY 00863 and EY 01413 from
the National Eye Institute.
Submitted for publication April 17, 1975.
Reprint requests: Dr. Keith Green, 3 D 11, R & E
Building, Medical College of Georgia, Augusta,
Ga. 30902.
Intravenous a- and ^-adrenergic blocking
agents have been used extensively in
studies on aqueous humor dynamics1"4 to
determine the relative roles of a- and /3-
receptors in the control of aqueous humor
production and outflow from the eye, however,
there is a paucity of reports on the
interactions of these drugs with either
prostaglandins or tetrahydrocannabinol.
The present study was performed to examine
the possibility that either prostaglandin
EL. or tetrahydrocannabinol may
exert their ocular effects via the adrenergic
innervation system of the eye.
Prostaglandin (PG) effects in the rabbit
eye are well known.5' ° It has been shown
that neither intracameral phenoxybenzamine
(PBA)7 nor intracameral propranolol
(PR)S have any effect on the elevation of
intraocular pressure caused by the intracameral
administration of PG. The intravenous
administration of PBA (4.5 mg. per
kilogram) produced severe depression of
systemic blood pressure7 which masked any
intracameral PG effect. Neither PR nor
PBA blocked the in vitro PGE, activation
of ciliary process adenyl cyclase.0 PG's
have a profound effect on circulation
through the anterior uvea1012 and it would
be unlikely that the concentration of antagonist
in the circulation when administered
via the intracameral route would
reach that achieved with intravenous administration.
The interrelationship between
PG's and adrenergic antagonists has,
therefore, been studied with all agents
given intravenously.
The active ingredient of marihuana,
delta-1-tetrahydrocannabinol (THC), also
produces changes in anterior uveal blood
flow.11' u The present study employs
adrenergic antagonists to further examine
this effect in detail in an attempt to determine
the mode of action of THC in the
eye.
Two a- and two /?-adrenergic antagonists
were utilized since it is accepted that although
having primarily a similar effect
different antagonists either have different
actions, binding capacities, or varying
specificity of binding. It was thought,
therefore, that the use of two antagonists
for each primary receptor site would be
advantageous in revealing more exactly
the effects of drugs on the eye.
Materials and methods
Experimental procedure. Adult albino rabbits,
2 to 3 kilograms, of either sex were anesthetized
with 25 per cent urethane in 0.9 per cent NaCl
solution and the head held securely in a metal
stereotaxic holder. A new 22-gauge needle was
inserted into each eye once a suitable depth of
anesthesia was obtained: one needle was connected
via a 3-way stopcock to a transducer and
a capillary as described previously,12- 13 while
the other needle was connected directly to a
transducer. Intraocular pressure (IOP) was recorded
continuously and, in order to be accepted,
had to remain stable for at least 5 minutes before
intravenous injection of drugs. Total outflow
facility (Ctot) was measured as described previously,
12' r ! using the constant pressure perfusion
method of Barany15 with a pressure difference of
5 mm. Hg. Stable pre- and postfacility IOP had
to be within ± 2 mm. Hg. otherwise the eye was
discarded. IOP was, therefore, determined for
both eyes and Ct<,t for one eye of each pair; the
nonfacility eye acted as a control against the
possible efFects of the facility determinations per
se causing a change in the behavior of IOP. A
femoral artery was cannulated to measure systemic
blood pressure and the cannula was filled with
heparinized saline (100 units per milliliter), which
was replenished periodically via a 3-way stopcock.
In view of a discrepancy between the effects
of propranolol on IOP of the urethane-anesthetized
rabbit and results reported on conscious animals,
1- '-' 4 some experiments were performed to
determine the effect of the drug in conscious
animals. Adult albino rabbits were restrained in
canvas bags tied loosely at the neck and the IOP
measured using an air applanation tonometer10
suitably calibrated for the rabbit eye. The cornea
was anesthetized with one drop of 0.5 per cent
tetracaine hydrochloride (Alcon Laboratories, Inc.,
Fort Worth, Texas) which was irrigated after 10
seconds with 0.9 per cent NaCl solution prior to
the determination of IOP. Propranolol was given
at a rate of 1 mg. per minute in a marginal ear
vein to a final dose level of 5 mg. per kilogram.
IOP was measured every 30 minutes for 6 hours.
Drugs used. Prostaglandin (PGE2) was prepared
as before12' 14 and injected intravenously
at a rate of 0.79 fig per 7.9 fi\ per minute for a
period of 10 minutes; this rate of injection of
PGEj has been shown previously to cause a 10 to
15 mm. Hg. elevation of IOP.1- Tetrahydrocannabinol
(THC) was given intravenously at a
concentration of 0.005 mg. per 100 ml. of plasma
volume; this concentration is sufficient to cause a
10 to 20 per cent fall in IOP.13- " The adrenergic
antagonists used were as follows: a-blockers,
phentolamine HC1 (PH) (Regitine; Ciba Pharmaceutical
Company, N. J.), and phenoxybenzamine
HC1 (PBA) (Dibenzyline; Smith, Kline and
French Laboratories, Pa.); (3-blockers, propranolol
(PR) (Inderal; Ayerst Laboratories, N. Y., Lot
#IKSY), and sotalol HC1 (SO) (Regis Chemical
Company, 111.). When used in combination with
both PGE- and THC, the four blocking agents
were used at only the lowest two dose levels
which produced the minimal effects on IOP and
systemic blood pressure. All dose levels are given
as the salt and drugs were injected via a marginal
ear vein.
Results
a-Adrenergic antagonists. Phentolamine
(PH). PH caused a dose-dependent fall in
intraocular pressure (IOP), blood pressure
(BP) (Fig. 1), and a dose-related increase
in total outflow facility (Ctot) (Table I).
BP fell rapidly within five minutes after
injection thereafter being stable, whereas
the IOP, although it fell at a rapid initial
rate at high doses, continued a slower constant
rate of fall during the experimental
time period. PH did not reduce the peak
IOP elevation caused by PGE2, except
when the BP was severely depressed (0.5
mg. per kilogram PH). The normal increase
in C^t 30 minutes after PGE,(i-12-14
was not found after PH (Table I). The
dose of THC used normally produces a
3 to 5 mm. Hg fall in IOP at 60 minutes in
either anesthetized or conscious14 normal
rabbits: similar experiments here caused
a 2.4 and 4.5 mm. Hg (n=6) fall in IOP
at 30 and 60 minutes after THC, with corresponding
increases in Ctot from a control
value of 0.175 ± 0.009 to 0.186 ± 0.005 and
0.233 ± 0.021 (33 per cent increase from
control) /x\ per millimeter of mercury per
minute, respectively. PH significantly in
hibited the IOP reduction normally caused
by THC (Table II). THC prevented the
increase in Ctot normally seen with PH
(Table I), since the values for Ctot at 90
minutes after PH were less after THC than
with PH alone.
Phenoxybenzamine (PBA). PBA caused
a dose-dependent fall in IOP and BP
similar to that found with PH (Fig. 1),
although the increase in Ctot did not demonstrate
such an exact relationship to dose
(Table I). The IOP and BP fell over the
first 30 minutes, at a slower rate than with
PH (cf. Fig. 1) before assuming a steady
value. The effect of PG on IOP was relatively
unaffected by PBA, since an 8 mm.
Hg rise in IOP was found relative to the
normal of 10 to 12 mm. Hg as described
previously.5-c- "-14 With PBA the increase
in Ctot 30 minutes following PG was only
to the value that was normally found with
PBA alone (Table I), thus PBA prevented
the expected rise in Ctot which is normally
evoked by PG. Pretreatment of the animals
with PBA significantly inhibited the IOP
reducing effect of THC (Fig. 2 and Table
II). Ctot increased after THC (Table I)
but this change was no greater than that
induced by PBA alone at the same time
relative to the injection of the antagonist.
(3-Adrenergic antagonists. Propranolol
(PR). All concentrations of PR used here
in the urethane-anesthetized rabbit caused
a fall in IOP and BP in a dose-dependent
manner (Fig. 3). The increase in Ctot was
not clearly dose-dependent (Table III).
When PR was given at the rate of 1 mg.
per minute to a final dose of 5 mg. per
kilogram to three awake rabbits, little or
no change was seen in IOP over six hours.
No effect was seen of PR on the PGE2-
induced IOP increase although the increase
in Ctot normally seen 30 minutes after
PGE2 was not clearly evident (Table III).
PR appeared to have an influence on the
THC-induced IOP fall since the IOP decrease
caused by THC was about half of
that found in the absence of PR (Table II).
The THC effect on Ctot was uninfluenced
by PR (Table III), since Ctot increased
more than caused by PR alone, when the
two drugs were given together.
Sotalol (SO). All three dose levels of SO
caused a fall in IOP with only a minor
change in BP (cf. Fig. 3). The decrease in
IOP and BP at all dose levels were quan
titatively very similar (Fig. 4, 0 to 30
minutes) with no apparent dose-response
relationship. Ctot was found to increase
significantly after SO treatment alone
(Table III). The PG-induced IOP elevation
appeared to be unchanged by SO,
but the THC-induced IOP effect was completely
inhibited, even reversed by SO
(Fig. 4 and Table II). Ctot, after PG, was
also unchanged from the value found with
SO alone, thus SO appeared to inhibit
the induction of an increase in Ctot which
is normally generated by PG (Table III).
THC caused an increase in Ctot over and
above that induced by SO alone (Table
III).
Discussion
To place the following discussion in
perspective it is advantageous to outline,
albeit briefly, the current concepts of the
influence of adrenergic innervation on
aqueous humor dynamics. With specific
reference to the rabbit, the presence of
a-receptors in the regulation of total outflow
facility has been unequivocally demonstrated,
as well as a smaller /?-effect.ir
More detailed studies have indeed shown
that true outflow facility is exclusively controlled
by a-adrenergic innervation system,
18 thus the /3-adrenergic component
would be an effect on pseudofacility. With
regard to aqueous humor formation, the aand
/?-adrenergic receptors appear to play
significant roles, the former (a) producing
a minor increase and the latter (/?) producing
a major fall in aqueous formation.19
Their control may well be exerted in
blood flow regulation through the ciliary
body thereby influencing aqueous humor
formation.17*20> 21
Adrenergic antagonist effects alone. To
the best of our knowledge a systematic
dose-response study of the effect of the
most widely used adrenergic antagonists
simultaneously on IOP and BP has not
been reported previously. Phentolamine
(PH), phenoxybenzamine (PBA), and
propranolol (PR) all caused significant
dose-related decreases in IOP and BP
within a few minutes after intravenous
administration. Sotalol (SO) produced
only a minor reduction in BP although the
IOP fell significantly. All antagonists produced
a dose-related reduction in IOP
when the 90 minute and 30 minute IOP
were compared (Figs. 1 and 3 for examples
of a- and /^-antagonists). Presumably
some of this fall is related to the interference
of these agents with the maintenance
of normal vasomotor tone of the
ocular blood vessels. The a-antagonists
produced a dose-related increase in Ctot,
whereas the /^-antagonists, although increasing
Ctot, showed no dose relationship.
PH, PBA, and PR have been the most
widely used antagonists in studies on
aqueous dynamics1"4- 7-8-22 and while intravenous
PBA2' 7 and PH2 have been reported
to lower both IOP and BP, only
one report exists that intravenous PR reduces
IOP in the rabbit.3 PBA was reported
not to reduce IOP in conscious
rabbits, but later reports confirmed that
PBA did reduce IOP.2 Previous authors
have reported that PR has no effect on
IOP in either anesthetized2-22 or conscious1'
4 rabbits. In the urethane-anesthetized
rabbit, Takats, Szilvassy, and
Kerek3 reported that the IOP fell from
20.8 to 18.8 mm. Hg at a dose of 0.3 mg.
per kilogram PR, a concentration lower
than that often utilized, viz. 5 mg. per
kilogram. The experiments reported here
indicate that PR caused a fall in IOP at
concentrations from 5 to 0.05 mg. per kilogram
in the anesthetized rabbit, although
the latter dose had little effect on BP. In
the conscious rabbit little or no effect of
PR was seen on IOP, confirming previous
observations.1-4- 23 There was a difference
in the behavior, therefore, of the PR response
in the awake and anesthetized rabbit,
although the response of both the
awake and anesthetized rabbit to the same
dose of PH and PBA were almost identical.
(IOP reduction 60 minutes after PH in
awake2 and anesthetized [Fig. 1] rabbits
was 5.5 and 7.5 mm. Hg, respectively, and
for PBA in awake2 and anesthetized rabbits
the reductions were 6 and 6.5 mm. Hg,
respectively.) The difference in response
to PR may relate to the fact that PR is
known to have central effects as well as
act as a local anesthetic; both could possibly
be revealed in the anesthetized and
not in the conscious animal. In addition,
it is obviously important to relate reports
of either an effect on IOP or lack of an
effect to the time after administration of
the drug.
In the rabbit there is a- and /3-adrenergic
control of fluid outflow from the
eye.17 Ctot has two components, Ctr or
trabecular outflow and Cps or pseudofacility.
24 It is not possible in this study
to distinguish the relative effects of the
antagonists on these two components. In
the present experiments, Ctot is increased
with either a- or ^-antagonists (Tables I
and III), but the effect is greater with
the a- than with the ^-antagonists. The
formation of aqueous humor has been reported1
to be under ^-adrenergic control,
but both a- and /3-antagonists decrease
IOP.19 The ^-antagonists PR and SO, however,
appear to be more active on a weightfor-
weight basis than the a-antagonists
(Table II). From the present data, it is
not possible to assess the relative role of
the a- and /?-adrenergic system on the
various components which affect aqueous
humor dynamics since the appropriate
direct agonists were not employed. It is
possible that both a- and /?-adrenergic receptors
are located in the outflow pathways
because of the action of the drugs
on Ct,,t, although an effect on the formation
of aqueous humor by altering ultrafiltration
(C,,s), secretion, or blood flow
through the anterior uvea cannot be excluded.
In view of the effect on Ctot by
all the antagonists in the presence of PG
(see below), however, the major effector
site of the antagonists is strongly suggested
to be at the outflow channels regulating
Ctr.
Adrenergic antagonist interaction with
PGES. Both a-antagonists, even at low
concentrations, decreased BP by about 20
to 25 per cent and, as described previously,
following intracameral PG7 the depression
in BP markedly reduced the ocular PGE2
effect in a dose-dependent manner. Neither
a-antagonist had any effect on the characteristic
PG-induced lowering of systemic blood pressure. The PG-induced increase
in Ctot, seen about 30 minutes after
PG administration in normal animals,0-12
is also inhibited by the antagonists. The
early effect of PG is known to be on the
blood vessels of the anterior uvea,10'12
followed, as the local PG concentration
rises, by breakdown of the blood-aqueous
barrier.25 It appears, therefore, that the
a-antagonists protect the blood-aqueous
barrier from the breakdown without altering
the vasodilatory effect of PG, since
the PG-induced increase in Ctot is thought
to be due to an increase in Cps.G> 12 It is
interesting, in this regard, to note that
Hendley and Crombie22 also found that
PBA (a) and PR (p) prevented the leakage
of protein into the aqueous humor,
which is usually observed at the height of
the ganglionectomy effect, despite the
presence of hyperemic blood vessels in
the iris. Takase20 also found that /3-receptor
blockade caused a fall in aqueous
humor protein concentration. These findings
are most strongly suggestive of an
effect either on the ciliary epithelium
permeability or the capillary vessels. Since
the latter are very leaky to proteins even
under normal conditions the most likely
site of action would be the ciliary epithelium.
The /^-antagonists, PR and SO, had
similar effects on the ocular PGE2 response.
Neither PR nor SO influenced the PG effect
on IOP, and SO had very little effect
on BP. The characteristic fall in BP caused
by PG was also unaffected by PR or SO.
PG's are powerful vasodilators in the
eye10"12 and a /^-antagonist would be expected
to block the PG effect if PG stimulated
the /8-adrenergic system. Both PR
and SO prevent the characteristic rise in
C^t which is seen in normal eyes after
PG,Gi 12 indicating that these agents also
protect the blood-aqueous barrier from
breakdown normally caused by PG, although
the antagonists either themselves
increase Ctr (see above) or, by allowing
dominance of the nonantagonized adrenergic
system, cause the effect of this system
system
to be revealed more completely especially
when interactions where other
drugs are considered. The present data,
therefore, offer support for the mechanism
of action of PG being a vasodilation of the
afferent vessels to the anterior uvea. There
is some mediation of at least part of the
outflow system (C,)S) by adrenergic receptor
mechanisms through the protection
of the blood-aqueous barrier from the action
of PG provided by ^-adrenergic antagonists.
Adrenergic antagonist interaction with
THC. Both «- and /3-antagonists inhibit
THC-induced IOP reduction whereas only
the a-adrenergic antagonists strongly inhibit
THC-induced increase in Ctot- If the
control of Ctr is completely a-receptor
dominated in the rabbit1 s then these results
certainly support this concept. THC
is known to increase Ctot,13'14 and it has
been suggested that this, in part, is due
to an increase in Ctr." The a-antagonist
inhibition of this increase indicates that
THC acts by increasing Cfr per se; conversely,
the lack of effect of ^-antagonists
on the THC-induced increase in Ctot suggests
that ^-receptors play no role in
regulating the THC-induced increase of
Ctr- THC also causes an increase in the
permeability of the ciliary epithelium13
and, thereby increases C,)S in vivo.27 The
a-adrenergic antagonists may inhibit a
THC-induced effect on vasoconstriction of
afferent episcleral plexus vessels of the
rabbit, which are involved in aqueous
humor drainage and regulate Ctr.2S
THC has been proposed to act either
by vasodilating the efferent vessels or vasoconstricting
the afferent vessels supplying
the anterior uvea.13' 2!) It is apparent from
Table II that the percentage reduction in
IOP caused by THC is approximately
halved by the a-adrenergic antagonists and
the /^-antagonist PR, whereas the /3-adrenergic
antagonist SO inhibits the THCinduced
IOP fall completely. Such findings
may be related to those seen with
other drugs by Macri and Cevario20' 21 who
found that different drugs produce dif
ferential actions on both afferent and efferent
vessels of the arterially perfused cat
eye. Indeed, pilocarpine has been shown
to have stimulatory but contrary effects
on the arteriolar and venous sites controlling
blood flow through the anterior
uvea.21 The results indicate that THC acts
in the normal eye primarily by vasodilating
the efferent blood vessels of the eye thereby
reducing the capillary pressure within
the ciliary body thereby causing an
IOP fall (since SO completely blocks
the characteristic response). Such an action
is also consistent with the known
vasodilatory action on the conjunctival
blood vessels.30 The effect of other antagonists
on the THC-induced reduction in
IOP may also relate to the differential action
of THC on the blood supply to the
ciliary body. It is possible that THC also
causes some vaso constriction of the afferent
vessels since the a-antagonists reduce
the THC-induced IOP reduction by
half, while there is no further change in
CtOf PR appears to be in a unique position
since the IOP falls by half the normal
THC-induced amount and Ctot also increases.
Thus it would appear to be acting
less specifically or less powerfully than
SO to counteract the THC effect. The
present data leave undetermined the question
of the direct or indirect action of
THC on the blood vessels of the eye, although
mediation via the adrenergic system
appears likely.
We thank Ms. Deborah Hancock for her secretarial
assistance, Mrs. Karen Bowman for performing
the intraocular pressure measurements on
conscious rabbits, Drs. J. F. Bigger and J. L.
Matheny for their valuable comments on this
paper, and Dr. J. E. Pike, The Upjohn Company,
Kalamazoo, Mich, and Dr. Monique Braude,
National Institute on Drug Abuse, respectively,
for generously making the prostaglandin and
tetrahydrocannabinol available for this study.
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Source: Interaction of adrenergic antagonists with prostaglandin E2 and tetrahydrocannabinol in the eye.
prostaglandin E2 and tetrahydrocannabinol
in the eye
Keith Green and Keun Kim
Both a- and /3-adrenergic antagonists have been utilized in an attempt to discern the site
of action of prostaglandin (PG) and tetrahydrocannabinol (THC) in the eye. Both a- and
(1-adrenergic antagonists (a-antagonists, phentolamine and phenoxybenzamine; P-antagonists,
propranolol and sotalol) caused a dose-dependent reduction in intraocular pressure and blood
pressure and increased total outflow facility. The results are consistent with the concept that
both a- and fi-adrenergic receptors are present in the anterior uvea and that vasomotor tone
is essential to the maintenance of normal intraocidar pressure. No antagonist reduced the
PG-induced elevation of intraocular pressure unless the blood pressure was severely lowered.
All antagonists inhibit the normal PG-induced increase in total outflow facility, indicating that
these agents protect the blood-aqueous barrier from breakdown without altering the vasodilatory
response to PG. All antagonists reduced the fall in intraocular pressure produced by THC
by approximately 50 per cent, except for sotalol which completely abolished the intraocular
pressure fall. Only the a-adrenergic antagonists prevented the THC-induced increase in total
outflow facility. The results indicate that true outflow facility may well be regulated exclusively
by a-receptors. The data are consistent with the effect of THC being primarily a vasodilation
of the efferent blood vessels of the anterior uvea. The partial inhibition by a-adrenergic
antagonists may also suggest a lesser role of THC on the afferent vessels.
Key words: rabbit, intraocular pressure, total outflow facility, blood pressure, adrenergic
antagonists, propranolol, phenoxybenzamine, phentolamine, sotalol, prostaglandin Es,
tetrahydrocannabinol.
From the Departments of Ophthalmology and
Physiology, Medical College of Georgia,
Augusta, Ga.
Supported in part by Public Health Service Research
Grants EY 00863 and EY 01413 from
the National Eye Institute.
Submitted for publication April 17, 1975.
Reprint requests: Dr. Keith Green, 3 D 11, R & E
Building, Medical College of Georgia, Augusta,
Ga. 30902.
Intravenous a- and ^-adrenergic blocking
agents have been used extensively in
studies on aqueous humor dynamics1"4 to
determine the relative roles of a- and /3-
receptors in the control of aqueous humor
production and outflow from the eye, however,
there is a paucity of reports on the
interactions of these drugs with either
prostaglandins or tetrahydrocannabinol.
The present study was performed to examine
the possibility that either prostaglandin
EL. or tetrahydrocannabinol may
exert their ocular effects via the adrenergic
innervation system of the eye.
Prostaglandin (PG) effects in the rabbit
eye are well known.5' ° It has been shown
that neither intracameral phenoxybenzamine
(PBA)7 nor intracameral propranolol
(PR)S have any effect on the elevation of
intraocular pressure caused by the intracameral
administration of PG. The intravenous
administration of PBA (4.5 mg. per
kilogram) produced severe depression of
systemic blood pressure7 which masked any
intracameral PG effect. Neither PR nor
PBA blocked the in vitro PGE, activation
of ciliary process adenyl cyclase.0 PG's
have a profound effect on circulation
through the anterior uvea1012 and it would
be unlikely that the concentration of antagonist
in the circulation when administered
via the intracameral route would
reach that achieved with intravenous administration.
The interrelationship between
PG's and adrenergic antagonists has,
therefore, been studied with all agents
given intravenously.
The active ingredient of marihuana,
delta-1-tetrahydrocannabinol (THC), also
produces changes in anterior uveal blood
flow.11' u The present study employs
adrenergic antagonists to further examine
this effect in detail in an attempt to determine
the mode of action of THC in the
eye.
Two a- and two /?-adrenergic antagonists
were utilized since it is accepted that although
having primarily a similar effect
different antagonists either have different
actions, binding capacities, or varying
specificity of binding. It was thought,
therefore, that the use of two antagonists
for each primary receptor site would be
advantageous in revealing more exactly
the effects of drugs on the eye.
Materials and methods
Experimental procedure. Adult albino rabbits,
2 to 3 kilograms, of either sex were anesthetized
with 25 per cent urethane in 0.9 per cent NaCl
solution and the head held securely in a metal
stereotaxic holder. A new 22-gauge needle was
inserted into each eye once a suitable depth of
anesthesia was obtained: one needle was connected
via a 3-way stopcock to a transducer and
a capillary as described previously,12- 13 while
the other needle was connected directly to a
transducer. Intraocular pressure (IOP) was recorded
continuously and, in order to be accepted,
had to remain stable for at least 5 minutes before
intravenous injection of drugs. Total outflow
facility (Ctot) was measured as described previously,
12' r ! using the constant pressure perfusion
method of Barany15 with a pressure difference of
5 mm. Hg. Stable pre- and postfacility IOP had
to be within ± 2 mm. Hg. otherwise the eye was
discarded. IOP was, therefore, determined for
both eyes and Ct<,t for one eye of each pair; the
nonfacility eye acted as a control against the
possible efFects of the facility determinations per
se causing a change in the behavior of IOP. A
femoral artery was cannulated to measure systemic
blood pressure and the cannula was filled with
heparinized saline (100 units per milliliter), which
was replenished periodically via a 3-way stopcock.
In view of a discrepancy between the effects
of propranolol on IOP of the urethane-anesthetized
rabbit and results reported on conscious animals,
1- '-' 4 some experiments were performed to
determine the effect of the drug in conscious
animals. Adult albino rabbits were restrained in
canvas bags tied loosely at the neck and the IOP
measured using an air applanation tonometer10
suitably calibrated for the rabbit eye. The cornea
was anesthetized with one drop of 0.5 per cent
tetracaine hydrochloride (Alcon Laboratories, Inc.,
Fort Worth, Texas) which was irrigated after 10
seconds with 0.9 per cent NaCl solution prior to
the determination of IOP. Propranolol was given
at a rate of 1 mg. per minute in a marginal ear
vein to a final dose level of 5 mg. per kilogram.
IOP was measured every 30 minutes for 6 hours.
Drugs used. Prostaglandin (PGE2) was prepared
as before12' 14 and injected intravenously
at a rate of 0.79 fig per 7.9 fi\ per minute for a
period of 10 minutes; this rate of injection of
PGEj has been shown previously to cause a 10 to
15 mm. Hg. elevation of IOP.1- Tetrahydrocannabinol
(THC) was given intravenously at a
concentration of 0.005 mg. per 100 ml. of plasma
volume; this concentration is sufficient to cause a
10 to 20 per cent fall in IOP.13- " The adrenergic
antagonists used were as follows: a-blockers,
phentolamine HC1 (PH) (Regitine; Ciba Pharmaceutical
Company, N. J.), and phenoxybenzamine
HC1 (PBA) (Dibenzyline; Smith, Kline and
French Laboratories, Pa.); (3-blockers, propranolol
(PR) (Inderal; Ayerst Laboratories, N. Y., Lot
#IKSY), and sotalol HC1 (SO) (Regis Chemical
Company, 111.). When used in combination with
both PGE- and THC, the four blocking agents
were used at only the lowest two dose levels
which produced the minimal effects on IOP and
systemic blood pressure. All dose levels are given
as the salt and drugs were injected via a marginal
ear vein.
Results
a-Adrenergic antagonists. Phentolamine
(PH). PH caused a dose-dependent fall in
intraocular pressure (IOP), blood pressure
(BP) (Fig. 1), and a dose-related increase
in total outflow facility (Ctot) (Table I).
BP fell rapidly within five minutes after
injection thereafter being stable, whereas
the IOP, although it fell at a rapid initial
rate at high doses, continued a slower constant
rate of fall during the experimental
time period. PH did not reduce the peak
IOP elevation caused by PGE2, except
when the BP was severely depressed (0.5
mg. per kilogram PH). The normal increase
in C^t 30 minutes after PGE,(i-12-14
was not found after PH (Table I). The
dose of THC used normally produces a
3 to 5 mm. Hg fall in IOP at 60 minutes in
either anesthetized or conscious14 normal
rabbits: similar experiments here caused
a 2.4 and 4.5 mm. Hg (n=6) fall in IOP
at 30 and 60 minutes after THC, with corresponding
increases in Ctot from a control
value of 0.175 ± 0.009 to 0.186 ± 0.005 and
0.233 ± 0.021 (33 per cent increase from
control) /x\ per millimeter of mercury per
minute, respectively. PH significantly in
hibited the IOP reduction normally caused
by THC (Table II). THC prevented the
increase in Ctot normally seen with PH
(Table I), since the values for Ctot at 90
minutes after PH were less after THC than
with PH alone.
Phenoxybenzamine (PBA). PBA caused
a dose-dependent fall in IOP and BP
similar to that found with PH (Fig. 1),
although the increase in Ctot did not demonstrate
such an exact relationship to dose
(Table I). The IOP and BP fell over the
first 30 minutes, at a slower rate than with
PH (cf. Fig. 1) before assuming a steady
value. The effect of PG on IOP was relatively
unaffected by PBA, since an 8 mm.
Hg rise in IOP was found relative to the
normal of 10 to 12 mm. Hg as described
previously.5-c- "-14 With PBA the increase
in Ctot 30 minutes following PG was only
to the value that was normally found with
PBA alone (Table I), thus PBA prevented
the expected rise in Ctot which is normally
evoked by PG. Pretreatment of the animals
with PBA significantly inhibited the IOP
reducing effect of THC (Fig. 2 and Table
II). Ctot increased after THC (Table I)
but this change was no greater than that
induced by PBA alone at the same time
relative to the injection of the antagonist.
(3-Adrenergic antagonists. Propranolol
(PR). All concentrations of PR used here
in the urethane-anesthetized rabbit caused
a fall in IOP and BP in a dose-dependent
manner (Fig. 3). The increase in Ctot was
not clearly dose-dependent (Table III).
When PR was given at the rate of 1 mg.
per minute to a final dose of 5 mg. per
kilogram to three awake rabbits, little or
no change was seen in IOP over six hours.
No effect was seen of PR on the PGE2-
induced IOP increase although the increase
in Ctot normally seen 30 minutes after
PGE2 was not clearly evident (Table III).
PR appeared to have an influence on the
THC-induced IOP fall since the IOP decrease
caused by THC was about half of
that found in the absence of PR (Table II).
The THC effect on Ctot was uninfluenced
by PR (Table III), since Ctot increased
more than caused by PR alone, when the
two drugs were given together.
Sotalol (SO). All three dose levels of SO
caused a fall in IOP with only a minor
change in BP (cf. Fig. 3). The decrease in
IOP and BP at all dose levels were quan
titatively very similar (Fig. 4, 0 to 30
minutes) with no apparent dose-response
relationship. Ctot was found to increase
significantly after SO treatment alone
(Table III). The PG-induced IOP elevation
appeared to be unchanged by SO,
but the THC-induced IOP effect was completely
inhibited, even reversed by SO
(Fig. 4 and Table II). Ctot, after PG, was
also unchanged from the value found with
SO alone, thus SO appeared to inhibit
the induction of an increase in Ctot which
is normally generated by PG (Table III).
THC caused an increase in Ctot over and
above that induced by SO alone (Table
III).
Discussion
To place the following discussion in
perspective it is advantageous to outline,
albeit briefly, the current concepts of the
influence of adrenergic innervation on
aqueous humor dynamics. With specific
reference to the rabbit, the presence of
a-receptors in the regulation of total outflow
facility has been unequivocally demonstrated,
as well as a smaller /?-effect.ir
More detailed studies have indeed shown
that true outflow facility is exclusively controlled
by a-adrenergic innervation system,
18 thus the /3-adrenergic component
would be an effect on pseudofacility. With
regard to aqueous humor formation, the aand
/?-adrenergic receptors appear to play
significant roles, the former (a) producing
a minor increase and the latter (/?) producing
a major fall in aqueous formation.19
Their control may well be exerted in
blood flow regulation through the ciliary
body thereby influencing aqueous humor
formation.17*20> 21
Adrenergic antagonist effects alone. To
the best of our knowledge a systematic
dose-response study of the effect of the
most widely used adrenergic antagonists
simultaneously on IOP and BP has not
been reported previously. Phentolamine
(PH), phenoxybenzamine (PBA), and
propranolol (PR) all caused significant
dose-related decreases in IOP and BP
within a few minutes after intravenous
administration. Sotalol (SO) produced
only a minor reduction in BP although the
IOP fell significantly. All antagonists produced
a dose-related reduction in IOP
when the 90 minute and 30 minute IOP
were compared (Figs. 1 and 3 for examples
of a- and /^-antagonists). Presumably
some of this fall is related to the interference
of these agents with the maintenance
of normal vasomotor tone of the
ocular blood vessels. The a-antagonists
produced a dose-related increase in Ctot,
whereas the /^-antagonists, although increasing
Ctot, showed no dose relationship.
PH, PBA, and PR have been the most
widely used antagonists in studies on
aqueous dynamics1"4- 7-8-22 and while intravenous
PBA2' 7 and PH2 have been reported
to lower both IOP and BP, only
one report exists that intravenous PR reduces
IOP in the rabbit.3 PBA was reported
not to reduce IOP in conscious
rabbits, but later reports confirmed that
PBA did reduce IOP.2 Previous authors
have reported that PR has no effect on
IOP in either anesthetized2-22 or conscious1'
4 rabbits. In the urethane-anesthetized
rabbit, Takats, Szilvassy, and
Kerek3 reported that the IOP fell from
20.8 to 18.8 mm. Hg at a dose of 0.3 mg.
per kilogram PR, a concentration lower
than that often utilized, viz. 5 mg. per
kilogram. The experiments reported here
indicate that PR caused a fall in IOP at
concentrations from 5 to 0.05 mg. per kilogram
in the anesthetized rabbit, although
the latter dose had little effect on BP. In
the conscious rabbit little or no effect of
PR was seen on IOP, confirming previous
observations.1-4- 23 There was a difference
in the behavior, therefore, of the PR response
in the awake and anesthetized rabbit,
although the response of both the
awake and anesthetized rabbit to the same
dose of PH and PBA were almost identical.
(IOP reduction 60 minutes after PH in
awake2 and anesthetized [Fig. 1] rabbits
was 5.5 and 7.5 mm. Hg, respectively, and
for PBA in awake2 and anesthetized rabbits
the reductions were 6 and 6.5 mm. Hg,
respectively.) The difference in response
to PR may relate to the fact that PR is
known to have central effects as well as
act as a local anesthetic; both could possibly
be revealed in the anesthetized and
not in the conscious animal. In addition,
it is obviously important to relate reports
of either an effect on IOP or lack of an
effect to the time after administration of
the drug.
In the rabbit there is a- and /3-adrenergic
control of fluid outflow from the
eye.17 Ctot has two components, Ctr or
trabecular outflow and Cps or pseudofacility.
24 It is not possible in this study
to distinguish the relative effects of the
antagonists on these two components. In
the present experiments, Ctot is increased
with either a- or ^-antagonists (Tables I
and III), but the effect is greater with
the a- than with the ^-antagonists. The
formation of aqueous humor has been reported1
to be under ^-adrenergic control,
but both a- and /3-antagonists decrease
IOP.19 The ^-antagonists PR and SO, however,
appear to be more active on a weightfor-
weight basis than the a-antagonists
(Table II). From the present data, it is
not possible to assess the relative role of
the a- and /?-adrenergic system on the
various components which affect aqueous
humor dynamics since the appropriate
direct agonists were not employed. It is
possible that both a- and /?-adrenergic receptors
are located in the outflow pathways
because of the action of the drugs
on Ct,,t, although an effect on the formation
of aqueous humor by altering ultrafiltration
(C,,s), secretion, or blood flow
through the anterior uvea cannot be excluded.
In view of the effect on Ctot by
all the antagonists in the presence of PG
(see below), however, the major effector
site of the antagonists is strongly suggested
to be at the outflow channels regulating
Ctr.
Adrenergic antagonist interaction with
PGES. Both a-antagonists, even at low
concentrations, decreased BP by about 20
to 25 per cent and, as described previously,
following intracameral PG7 the depression
in BP markedly reduced the ocular PGE2
effect in a dose-dependent manner. Neither
a-antagonist had any effect on the characteristic
PG-induced lowering of systemic blood pressure. The PG-induced increase
in Ctot, seen about 30 minutes after
PG administration in normal animals,0-12
is also inhibited by the antagonists. The
early effect of PG is known to be on the
blood vessels of the anterior uvea,10'12
followed, as the local PG concentration
rises, by breakdown of the blood-aqueous
barrier.25 It appears, therefore, that the
a-antagonists protect the blood-aqueous
barrier from the breakdown without altering
the vasodilatory effect of PG, since
the PG-induced increase in Ctot is thought
to be due to an increase in Cps.G> 12 It is
interesting, in this regard, to note that
Hendley and Crombie22 also found that
PBA (a) and PR (p) prevented the leakage
of protein into the aqueous humor,
which is usually observed at the height of
the ganglionectomy effect, despite the
presence of hyperemic blood vessels in
the iris. Takase20 also found that /3-receptor
blockade caused a fall in aqueous
humor protein concentration. These findings
are most strongly suggestive of an
effect either on the ciliary epithelium
permeability or the capillary vessels. Since
the latter are very leaky to proteins even
under normal conditions the most likely
site of action would be the ciliary epithelium.
The /^-antagonists, PR and SO, had
similar effects on the ocular PGE2 response.
Neither PR nor SO influenced the PG effect
on IOP, and SO had very little effect
on BP. The characteristic fall in BP caused
by PG was also unaffected by PR or SO.
PG's are powerful vasodilators in the
eye10"12 and a /^-antagonist would be expected
to block the PG effect if PG stimulated
the /8-adrenergic system. Both PR
and SO prevent the characteristic rise in
C^t which is seen in normal eyes after
PG,Gi 12 indicating that these agents also
protect the blood-aqueous barrier from
breakdown normally caused by PG, although
the antagonists either themselves
increase Ctr (see above) or, by allowing
dominance of the nonantagonized adrenergic
system, cause the effect of this system
system
to be revealed more completely especially
when interactions where other
drugs are considered. The present data,
therefore, offer support for the mechanism
of action of PG being a vasodilation of the
afferent vessels to the anterior uvea. There
is some mediation of at least part of the
outflow system (C,)S) by adrenergic receptor
mechanisms through the protection
of the blood-aqueous barrier from the action
of PG provided by ^-adrenergic antagonists.
Adrenergic antagonist interaction with
THC. Both «- and /3-antagonists inhibit
THC-induced IOP reduction whereas only
the a-adrenergic antagonists strongly inhibit
THC-induced increase in Ctot- If the
control of Ctr is completely a-receptor
dominated in the rabbit1 s then these results
certainly support this concept. THC
is known to increase Ctot,13'14 and it has
been suggested that this, in part, is due
to an increase in Ctr." The a-antagonist
inhibition of this increase indicates that
THC acts by increasing Cfr per se; conversely,
the lack of effect of ^-antagonists
on the THC-induced increase in Ctot suggests
that ^-receptors play no role in
regulating the THC-induced increase of
Ctr- THC also causes an increase in the
permeability of the ciliary epithelium13
and, thereby increases C,)S in vivo.27 The
a-adrenergic antagonists may inhibit a
THC-induced effect on vasoconstriction of
afferent episcleral plexus vessels of the
rabbit, which are involved in aqueous
humor drainage and regulate Ctr.2S
THC has been proposed to act either
by vasodilating the efferent vessels or vasoconstricting
the afferent vessels supplying
the anterior uvea.13' 2!) It is apparent from
Table II that the percentage reduction in
IOP caused by THC is approximately
halved by the a-adrenergic antagonists and
the /^-antagonist PR, whereas the /3-adrenergic
antagonist SO inhibits the THCinduced
IOP fall completely. Such findings
may be related to those seen with
other drugs by Macri and Cevario20' 21 who
found that different drugs produce dif
ferential actions on both afferent and efferent
vessels of the arterially perfused cat
eye. Indeed, pilocarpine has been shown
to have stimulatory but contrary effects
on the arteriolar and venous sites controlling
blood flow through the anterior
uvea.21 The results indicate that THC acts
in the normal eye primarily by vasodilating
the efferent blood vessels of the eye thereby
reducing the capillary pressure within
the ciliary body thereby causing an
IOP fall (since SO completely blocks
the characteristic response). Such an action
is also consistent with the known
vasodilatory action on the conjunctival
blood vessels.30 The effect of other antagonists
on the THC-induced reduction in
IOP may also relate to the differential action
of THC on the blood supply to the
ciliary body. It is possible that THC also
causes some vaso constriction of the afferent
vessels since the a-antagonists reduce
the THC-induced IOP reduction by
half, while there is no further change in
CtOf PR appears to be in a unique position
since the IOP falls by half the normal
THC-induced amount and Ctot also increases.
Thus it would appear to be acting
less specifically or less powerfully than
SO to counteract the THC effect. The
present data leave undetermined the question
of the direct or indirect action of
THC on the blood vessels of the eye, although
mediation via the adrenergic system
appears likely.
We thank Ms. Deborah Hancock for her secretarial
assistance, Mrs. Karen Bowman for performing
the intraocular pressure measurements on
conscious rabbits, Drs. J. F. Bigger and J. L.
Matheny for their valuable comments on this
paper, and Dr. J. E. Pike, The Upjohn Company,
Kalamazoo, Mich, and Dr. Monique Braude,
National Institute on Drug Abuse, respectively,
for generously making the prostaglandin and
tetrahydrocannabinol available for this study.
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