Download Effect of antagonist weakening on developed tension in cat

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8. Elliott PJ, Mackic JB, Graney WF, Zlokovic BV. Intraveby SV-40 T antigen gene. Curr Eye Res. 1994; 13:109nous RMP-7 elevates ocular gancidovir levels. Wash118.
ington, DC: 2ndNatl ConfHuman Retroviruses & Related 10. De Schaepdrijver L, Simoens P, Lauwers H, De Geest
Infections Book of Abstracts. 1995; 106.
JP. Retinal vascular patterns in domestic animals. Res
Vet Sci. 1989;47:34-42.
9. Williams EF, Ezeonu I, Dutt K. Nucleoside transport
11. Davey PG. New drugs: New antiviral and antifungal
sites in a cultured human retinal cell line established
drugs. BrMedJ. 1990;300:793-798.
Effect of Antagonist Weakening on
Developed Tension in Cat
Extraocular Muscle
eral rectus muscle in the cat. Invest Ophthalmol Vis Sci.
1995; 36:2547-2550.
X atients with strabismus have congenital or acquired
misalignment of the ocular axes. If the alignment is
stable, we can assume that the elastic forces across
Purpose. In a previous study, the authors found that the involved extraocular muscles are at equilibrium.
These elastic forces consist of the elasticity of orbital
recession of an extraocular muscle resulted in atrophy
tissue other than muscle, the elasticity of the extraocuof both the recessed muscle and its antagonist. To deterlar muscles to passive stretch, and the elasticity associmine if atrophy, caused by weakening of an extraocular
muscle, results in changes in developed tension in the
ated with muscle contraction. Strabismus surgery alantagonist, the authors studied force development of
ters this equilibrium by changing the rotational posithe cat lateral rectus muscle after adductor weakening.
tion of the globe and by changing the resting tension
Methods. Tenotomy of the left inferior, medial, and su- of the operated muscles. Recession of a horizontal
rectus muscle, for example, results in a profound drop
perior rectus muscles was performed in 18 cats. At 3,
in the resting tension of that muscle at the new inser6, and 12 weeks after surgery, the right (control) and
left lateral rectus muscles were exposed through a lattion site.1
eral orbitotomy and were attached to isometric force
Studies in limb muscle have shown that long-term
transducers. Length-tension curves were obtained by
changes in resting tension result in changes in muscle
direct muscle stimulation using bipolar contact elecfiber morphometry. Decreased tension causes muscle
trodes at 0.1 Hz and 50% suprathreshold stimulus infiber atrophy2; increased tension results in compensatensity. In addition, peak tetanic tension was measured
tory hypertrophy.3 Our previous studies in extraocular
at the optimal resting tension using a 5-second stimulus
muscle indicated that a similar phenomenon occurs
train at 200 Hz. Pooled data from the operative and
after strabismus surgery. Recession procedures cause
control muscles at each postoperative interval were
atrophy of both the recessed muscle and its antagocompared.
nist,4 whereas resection causes hypertrophy of the agoResults. Three weeks after adductor weakening, a 28%
nist-antagonist pair.' These findings suggest that the
decrease in maximal single-twitch tension was seen in
change
in resting tension caused by the procedure
the left lateral rectus muscle when compared with conaffects both the operated muscle and its antagonist(s).
trols. This difference disappeared at 6 weeks. No statistiChanges in extraocular muscle morphometry are trancally significant changes in peak tetanic tension ocsient. Fiber diameters returned to normal within 2 to
curred at any time interval after surgery.
1
Conclusions. Adductor weakening results in a transient 3 months in recession and resection preparations.' '
The purpose of the current study was to determine
decrease in single-twitch tension in the antagonist latwhether the atrophy observed after recession of extraocular muscles results in any changes in developed
From the * Department of Ophthalmology, Jones Eye Institute, and the. f Departments tension in the antagonist, using the cat as a model.
Stephen P. Christiansen* MichaelE. Soulsby,^ and
Ernst E. Seifen%
of Physiology and % Pharmacology and Toxicology, University of Arkansas for
Medical Sciences, Little. Rock.
Presented at the annual meeting of the Association for Research in Vision and
Ophthalmology, Sarasota, Florida, May 1994.
Supported in part l/y Research to Prevent Blindness.
Submitted for publication January 26, 1995; revised June 23, 1995; accepted July
21, 1995.
Proprietary interest category: N.
Rejmnt requests: Stephen P. Christiansen, Department of Ophthalmology, University
of Arkansas for Medical Sciences, Arkansas Children's Hospital, 800 Marshall
Street, Little'Rock, AR 72202-3591.
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METHODS. Eighteen cats were premedicated
with intramuscular atropine, 0.05 mg/kg, and a mixture of ketamine, 20 mg/kg, and xylazine, 1 mg/kg.
After endotracheal intubation, anesthesia was continued with isoflurane. The animals were ventilated continuously, and core body temperature was monitored
2548
Investigative Ophthalmology & Visual Science, November 1995, Vol. 36, No. 12
and maintained within the normal range with a heating pad. Tenotomy of the left inferior, medial, and
superior rectus muscles was performed through a conjunctival peritomy. We elected to weaken all the adductors in this fashion because doing so results in a
small exotropic shift of the operated eye immediately
after surgery. Tenotomy of the medial rectus alone
did not result in any appreciable change in eye alignment. The cat with the largest exotropic shift was photographed 1 week after surgery. The angle of exotropia in this cat was estimated at 15° by comparing the
corneal light reflexes in the operated and unoperated
eyes. A combination ointment containing 0.3% tobramycin and 0.1% dexamethasone was placed in the
operated eye. Buprenorphine (0.05 mg/kg) was administered as needed for analgesia. No evidence of
anterior segment ischemia was noted in any of the
operated eyes.
The animals were maintained in animal care facilities accredited by the American Association of Laboratory Sciences. The project followed established rules
of safe use of laboratory animals, and it was approved
by the local Institutional Animal Care and Use Committee. The investigational protocol was in accord with
the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
At 3-, 6-, and 12-week intervals after surgery, six
cats each were reanesthetized and monitored as described above. The cat's head was mounted in a stereotactic head holder and secured to prevent any head
movement. The lateral rectus muscles of both orbits
were exposed through a lateral orbitotomy, and the
insertional tendons were transected from the globe.
The tendons were attached to isometric force transducers (Grass FT-03; Astro-Med, West Warwick, RI)
with 3-0 silk. The force transducers were mounted on
isometric tension clamps (Harvard Apparatus, South
Natick, MA), allowing adjustments in the resting
length of the muscles. Tension output was monitored
on a direct writing polygraph (Gould WindowGraf;
Gould, Valley View, OH). This approach was chosen
to study the muscles in situ in the live, anesthetized
animal, thus maintaining normal temperature and adequate perfusion of the muscles.
The muscles were stimulated direcdy by bipolar
platinum contact electrodes at 0.1 Hz, 50% above
threshold voltage (minimum, 5 V), and 0.4-msec impulse duration. Electrodes were positioned on the distal third of the muscle, near the insertional tendon,
to avoid indirect stimulation of the muscle by terminal
nerves or the endplate region. Isometric length-tension curves were established for each muscle by varying the preload (resting tension) over a range from
0.2 to 60 g. Preload was increased stepwise by adjusting
the resting muscle length after developed tension
reached a plateau for 10 consecutive single twitches.
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In addition, tetanic tension development was tested
at the resting tension that produced optimal force
output (preload of 15 to 20 g) by applying a 5-second,
200-Hz impulse train (Fig. 1). It should be noted that
the lack of fade of tetanic tension development and
the absence of posttetanic potentiation indicate that
indirect (nerve or endplate) stimulation did not occur
under the described experimental procedure.
Data from the operative and control muscles for
each postoperative interval were pooled. Statistical
analysis of individual groups was done by analysis of
variance and the Student's t-test when appropriate. P
< 0.05 was considered significant.
RESULTS. At 3 weeks after surgery, a 28% decrease in maximal single-twitch tension was seen in the
left lateral rectus muscle compared to the unoperated
controls (P < 0.01) (Fig. 2). This difference disappeared at 6 weeks after surgery. By 12 weeks, there
was a trend toward greater developed twitch tension
in the operated orbit than in the controls. It is unclear
from the current data whether this represents a true
change because these values showed no statistically
significant difference from those obtained in the corresponding control muscles.
The data suggest that maximal single-twitch tension may occur at a lower preload at 6 and 12 weeks
(15 g) than at 3 weeks (20 g) in the operated orbit
(Fig. 3). However, these differences are not statistically
significant. Maximal single-twitch tension developed
at a preload of 20 g in the control muscles. No statistically significant changes occurred in tetanic tension
development at any interval after surgery (Fig. 4).
DISCUSSION. Adductor weakening in the cat
resulted in a transient decrease in peak twitch tension
of the antagonist lateral rectus muscle. This pattern
of decreasing developed single-twitch tension followed
by recovery resembles the pattern of atrophy seen in
extraocular muscle after horizontal rectus recession.'1
In a previous study in rabbits, we found that a large
recession of extraocular muscle resulted in a 15% to
2 sec
l. Tetanic tension development in the left lateral
rectus muscle 3 weeks after surgery, stimulated for 5 seconds
at 200 Hz, preload 15 g.
FIGURE
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2549
15 -i
100
3
C
o
'to
10
80
I
T3
Q>
Q.
5 - Control (OD,N=16)
3 weeks post-op. (OS, N=5)
o
a>
o
3
o
"55
60
<D
40
6 weeks post-op. (OS, N=6)
O
12 weeks post-op. (OS, N=5)
0 \
10
' I
20
'
f
30
'
I
40
'
I
50
Pre-Load (g)
2. Developed tension-preload relationship for left
lateral rectus muscles 3, 6, and 12 weeks after left inferior,
medial, and superior rectus muscle tenotomy (± SEM). OS
= operated left orbit; OD = unoperated right orbit (control).
FIGURE
'E
3o
20
0
6
12
Weeks post op.
FIGURE 4. Peak tetanic tension (+ SEM) at 3, 6, and 12
weeks after surgery. OS = operated left orbit; OD = unoperated right orbit (control).
weakening, results in muscle fiber atrophy and a reduction in generated tension early, followed by gradual recovery. Recovery of peak twitch tension is complete by 6 weeks after surgery. Recovery from the atrophy, however, appears to take more than 16 weeks.'1
The decrease in peak twitch tension, demonstrated in this study, may not necessarily be correlated
with muscle fiber atrophy. In those muscles that
X
showed reduced single-twitch tension 3 weeks after
ns
surgery, the maximal tetanic force development was
J
100
equal to that of the controls. One might expect to see
E
a decrease in tetanic tension if muscle fiber atrophy
were present. In this model, the mechanism for preservation of peak tetanic tension is unknown. Possible
o 75 reasons for this include changes in transmembrane
calcium
movement and calcium release and changes
0
50 in excitation-contraction coupling mechanisms. The
current data, however, do not allow an analysis of the
"O
0)
cause.
Q. 25 The basis for recovery of generated tension and
JO
3 weeks post-op.
O
normal morphometry after a weakening procedure is
6 weeks post-op.
0 also uncertain. Studies of limb muscle immobilized in
a shortened position have demonstrated sarcomere
I
' I ' ! ' I ' I ' I
loss, presumably to reoptimize actin-myosin overlap.'1
10 20 30 40 50 60 A recent study by Scott7 demonstrated that sarcomere
regulation also occurs in extraocular muscle after a
Pre-Load (g)
sustained change in the rotational position of the
globe.
When the resting tension on a muscle is deFIGURE 3. A comparison of developed twitch tension in the
creased,
sarcomere overlap is excessive. Loss of sarleft lateral rectus muscle at 3 weeks (Jilted circles) and 6 weeks
comeres from the ends of the muscle readjusts the
(open circles) after surgery (± SEM).
20% decrease in mean cross-sectional fiber diameter
in both the recessed muscle and its antagonist. Maximum muscle fiber atrophy was seen 4 weeks after muscle recession.'1 These findings, together with those of
the current study, indicate that decreased extraocular
muscle resting tension, brought about by antagonist
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2550
Investigative Ophthalmology & Visual Science, November 1995, Vol. 36, No. 12
muscle length for optimum myofilament overlap, and
generated tension and fiber diameters normalize.
Conditions that would be expected to decrease
the resting tension of an extraocular muscle include
cranial nerve palsies, botulinum toxin injection, and
surgical or traumatic recession of a muscle. Our results
suggest that a transient decrease in peak single-twitch
tension might occur in the antagonist of the affected
muscle under any of these conditions.
The clinical effects of this phenomenon are unknown. For example, recession of an extraocular muscle should decrease the resting tension across agonist
and antagonist muscles so that any change in developed tension in one muscle is mirrored in the other.
In the case of extraocular muscle palsy, any transient
weakness of the antagonist probably would be overshadowed by the palsy of the agonist. Although the
clinical effects may be negligible, these changes in
developed tension represent an example of extraocular muscle plasticity and should be considered in ocular motility modeling.
Key Words
cat, extraocular muscle, eye muscle surgery, length-tension,
muscle plasticity
Inhibition of Lens Opacification
During the Early Stages of Cataract
Formation
Toshihiko Hiraoka*\ and John I. Clark* X
Purpose. To characterize the time period during cataract formation in which administration of pantethine
inhibits lens cell opacification in the selenite model for
cataract.
Methods. Pantethine was administered to neonatal rat
pups at selected time points from —0.5 to 17 hours with
respect to injection of selenite at time = 0. The injection dose of pantethine was 820 mg/kg (1.5 mmol/
kg) diluted in water at 410 mg/ml concentration. The
From the Departments oj*Biological Stniclure and^Ophlhalmology, University of
Washington School of Medicine, Seattle, and tlie\ Department of Ophthalmology at
Dokkyo University School of Medicine, Tochigi, Japan.
Supported in part liy grants EY04542 and EYOil30from the National Eye
Institute (National Institutes of Health, Bethesda, Maryland) and by grants from
Research to Prevent Blindness, Inc. (New York, Nexu York) and the Oculon
Corporation (Cambridge, Massachusetts).
Submitted for publication March 16, 1995; revised July 28, 1995; accepted August
I, 1995.
/Proprietary interest category: C2, C3.
Reprint requests:John I. Clark, Box 357420, Biological Structure, School of
Medicine, University of Washington, Seattle, WA 98195-1420.
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References
1. Rosenbaum AL, Egbert JE, Keogan T, Wheeler N,
Wang C, Buzard K. Length-tension properties of extraocular muscles in patients with esotropia and intermittent exotropia. Am J Ophthalmol. 1994; 117:791799.
2. Riley DA, Slocum GR, Bain JLW, Sedlak FR, Sowa
TE, Mellender JW. Rat hindlimb unloading: Soleus
histochemistry, ultrastructure, and electromyography.
J Appl Physiol. 1990; 69:58-66.
3. Schiaffino S, Hanzlikova V. On the mechanism of
compensatory hypertrophy in skeletal muscles. Experientia. 1970; 26:152,153.
4. Christiansen SP, Madhat M, Flynn JT. Extraocular
muscle fiber atrophy following medial rectus recession
in rabbits. ARVO Abstracts. Invest Ophthalmol Vis Sci.
1992; 33:1099.
5. Christiansen S, Madhat M, Baker L, Baker R. Fiber
hypertrophy in rat extraocular muscle following lateral rectus resection. J Pediatr Ophthalmol Strabismus.
1988;25:167-171.
6. Williams PE, Goldspink G. The effect of immobilization on the longitudinal growth of striated muscle
fibers. JAnat. 1973; 116:45-55.
7. Scott AB. Change of eye muscle sarcomeres according
to eye position. J Pediatr Ophthalmol Strabismus.
1994;31:85-88.
injection dose of selenite was 3.28 mg/kg (19 /Ltmol/
kg) diluted in saline at 1.8 mg/ml concentration. Opacification was observed using a slit lamp microscope at
selected time points over a 14-day period. Cataracts
were staged using a classification of opacity from 0 (normal) to 6 (mature).
Results. The effect of pantethine was characterized by
three different time periods: administration —0.5 to 6
hours with respect to selenite injection provided highly
significant protection, P < 0.001; administration 8
hours after selenite provided significant protection, P
< 0.005; administration 10 to 17 hours after selenite
was not protective.
Conclusions. The metabolite pantethine inhibited lens
opacification during cataract formation in the selenite
model. Even when pantethine was injected several
hours after the administration of selenite, opacification
was inhibited. Advanced stages of opacification were
unresponsive to the administration of pantethine. The
inhibitory effect of pantethine was statistically significant when administered during the earliest stage of
opacification in the selenite model for cataract. Invest
Ophthalmol Vis Sci. 1995; 36:2550-2555.
.Lens cell transparency is the result of short-range
order in the organization of cytoplasmic proteins.1