URODYNAMICS

EFFECTOFBACLOFENANDDANTROLENE

ON BLADDER STIMULATOR-INDUCED

DETRUSOR-SPHINCTER DYSSYNERGIA IN DOGS*

CHARLES T. TEAGUE, M.D.

DANIEL C. MERRILL, M.D.

From the Department of Urology, Veterans Administration

Hospital, Martinez, and University of California, Davis, California

ABSTRACT - The effect of baclofen (Lioresal) and dantrolene (Dantrium) on bladder stimulation-
induced detrusor-sphincter dyssynergia was studied in normal and chronic T-10 paraplegic dogs.
Dantrolene, which depresses skeletal muscle contractility, had little effect on electrically evoked
contractions of the urethral sphincter in dogs. Baclofen, which acts centrally by potentiating pre-
synaptic inhibition, depressed the pudendal to pudendal nerve reflex and decreased urethral resist-
ance during bladder stimulation.

Prior to the development of the Mentor bladder electrical detrusor-sphincter dyssynergia in hu-
stimulator, electrically induced detrusor- mans.6 Thus, for practical purposes today, the
sphincter dyssynergia resulted from a combina- use of electrical vesical stimulation has been
tion of direct (current spread)lp’ and indirect limited to patients with either lower motor
(reflex)3,4 activation of the pelvic floor skeletal neuron lesions or vesical hypotonia of unknown
muscles. Although the Mentor stimulator elimi- etiology. 723
nated current spread it did not decrease the ef- This report describes a pharmacologic study
fect of reflex-induced sphincter dyssynergia in of electrically induced detrusor-sphincter dys-
patients with upper motor neuron lesions4 synergia in dogs. The recent development of
The problem of reflexogenic detrusor- two pharmacologic agents baclofen (amino-
sphincter dyssynergia, which has severely lim- methyl-p-chlorohydrocinnamic acid) (Lioresal)f
ited the clinical application of bladder stimula- and dantrolene (Dantrium)$ prompted the
tion, has been attacked in several ways. study. Since baclofen acts centrally by poten-
Sphincterotomy has failed to control electrically tiating presynaptic inhibitiongs” and dantro-
induced sphincter dyssynergia because the en- lene acts peripherally by reducing striated
tire pelvic lloor is activated by this reflex and muscle contractile force, 12,i3 we postulated that
not just the external sphincter.4 The increase in the two drugs might be used synergistically to
urethral resistance caused by bladder stimula- decrease urethral resistance during bladder
tion has been decreased by chemical stimulation.
rhizotomy;4 however, this procedure most often
is not acceptable to patient or physician because Material and Methods
of its inherent side effect, impotence. Finally, Six mongrel female dogs were prepared four
intermittent stimulation, although potentially to twelve weeks before experimentation by
useful in dogs, 5 has not solved the problem of

WIBA-Giegy Corporation, Summit, New Jersey.

*Study supported by Veterans Administration Project #Eaton Laboratories, Division of Norwich Products,
MRIS 5764-01 and The Mentor Corporation. Inc., Norwich, New York.

UROLOGY / MAY 1978 / VOLUME XI, NUMBER 5 531

 bladder rtimuloting
elrctreder
FIGURE 1. The experimental model.
transecting the spinal cord at the tenth thoracic
vertebra. Urine was expressed from their blad-
der by Credk pressure twice daily after spinal
cord section. Studies also were performed on six
dogs with normal spinal cords.
Prior to testing the animals were anesthetized
with sodium thiamylol (Surital) 25 mg./Kg., in-
travenously and decerebrated by suction.
Thereafter, anesthesia was discontinued. The
bladder and urethra were exposed by an abdom-
inal midline incision, and the urethra was sev-
ered at the urethrovesical junction (Fig. 1). A
polyethylene tube was passed into the bladder
through the severed bladder neck and intravesi-
cal pressure was measured with a Hewlett-
Packard pressure transducer (128OC). To record
urethral pressure a polyethylene tubing was
passed into the proximal urethra and tied into
place with a periurethral ligature. The tubing
was connected to a Cole-Parmer Masterflex tub-
ing pump and fluid was forced through the ure-
532
thra at a rate of 10 ml. per minute while simul-
taneously recording pressure with a second
Hewlett-Packard pressure transducer. The
bladder was stimulated with two Mentor blad-
der stimulator electrodes which were imbri-
cated into the detrusor muscle so that they
crossed the neurovascular pedicles on either
side of the bladder. The electrical stimulus was
generated by a Triad isolation transformer (HS-
470), Hewlett-Packard amplifier (6823A), and a
Mentor pulse generator (401).
The pudendal’ nerves were approached in the
ischiorectal fossa through bilateral incisions at
the base of the tail. To stimulate and record
from the pudendal nerves the bared tips of bipo-
tar silver wire electrodes were wrapped around
each nerve and isolated from surrounding tissue
with paraffin wax. Neural activity was monitored
with Tektronix differential amplifiers (AM502).
Electrical pudendal nerve stimulation was ac-
complished with the amplifier, pulse generator
(Tektronix, PG 5Ol), and isolation transformer.
Bladder pressure, urethral pressure, and
femoral blood pressure were recorded using a
4-channel chart recorder (Hewlett-Packard,
7414). All pressures and neural activity also
were recorded on magnetic tape (CPR-4010).
One mg. per ml. baclofen solutions were pre-
pared by dissolving the powdered drug in Ring-
er’s lactate solution. One mg. per ml. dantrolene
solutions were prepared by dissolving the drug
in a 1.25 mM. sodium hydroxide solution. All
drugs were injected through a femoral vein
catheter.
Results
Effect of dantrolene
The effect of dantrolene was tested by meas-
uring the drug-induced change in peak urethral
pressure during bilateral pudendal nerve
stimulation. The pudendal nerves were stimu-
tated with 1 ms., 20 Hz., 4 V. pulses applied at
five-minute intervals. The maximum reduction
(15 to 20 per cent) in urethral resistance was
achieved with cumulative doses of dantrolene
between 2 and 3 mg./Kg.; additional injections
of dantrolene, up to cumulative doses of 14
mg./Kg., had no further effect on peak urethral
pressure (Fig. 2).
Effect of baclofen
The effect of baclofen on the pudendal to pu-
dendal nerve reflex was tested by stimulating
the proximal cut end of one pudendal nerve
UROLOGY ! MAY 1978 / VOLUME XI, NUMBER 5
 Dontrium, me/kg 0.0
,+J~~mJ~J~~~~~
urethral prassura
Pudendal nrrvr I I
stimulation, 20 HZ
FIGURE 2. Effect of dantrolene on urethral pressure during bilateral pudendal nerve stimulation.
with 0.1 ms., 4 V., 0.2 Hz. pulses and recording
the evoked response in the contralateral puden-
dal nerve. The evoked pudendal nerve response
was progressively reduced in amplitude by in-
cremental doses of baclofen; the maximal ef-
fect (80 to 90 per cent) was achieved with
cumulative doses of 4 to 6 mg./Kg. (Fig. 3).
Doses of baclofen as large as 10 mg./Kg. pro-
duced no further reduction in neural activity.
The evoked nerve response remained depressed
during concurrent detrusor stimulation (Fig. 3).
The effect of baclofen also was studied by
measuring changes in urethral resistance during
bladder stimulation in 3 dogs with chronic spi-
nal cord disease. Electrical vesical stimulation in
these animals produced an increase of 40 to 150
cm. of water in urethral pressure rather than
the urethral pressure decrease observed in
normal decerebrate dogs (Fig. 4). In 2 of these
animals a striking post-stimulus urethral pres-
sure rebound also developed which was sub-
stantially greater than that observed in the
“normal” decerebrate dog (Fig. 4).
Lior~sol.mp/kp 0.0
CONCURRENT DETRUSOR STIMULATION
FIGURE 3. Effect of baclofen on evoked pudendal nerve response in chronic T-10 paraplegic dog.
UROLOGY I MAY1978 / VOLUMEXI,
1.0 2.5 4.5
- - I -
In 2 dogs low doses of baclofen (1 to 1.5
mg./Kg.) increased urethral resistance 25 and 60
per cent, respectively, during bladder stimula-
tion. In all 3 experiments larger doses of baclo-
fen (4 to 6 mg./Kg.) reduced the evoked ure-
thral response by 75 to 90 per cent (Fig. 5).
Higher doses of baclofen produced no further
decrease in urethral pressure response. Baclo-
fen depressed the post-stimulus urethral pres-
sure rebound by 50 per cent in 2 dogs, and in 1
experiment this response was entirely elimi-
nated. Four to 6 mg./Kg. doses of baclofen also
decreased the peak intravesical pressure 20 to
40 per cent during bladder stimulation; how-
ever, the drug-induced reduction in urethral
pressure was always greater than the reduction
in bladder pressure (Fig. 5).
Comment
Electrical vesical stimulation characteristically
induces voiding in upper motor neuron lesion
canine preparations. iv4,14 Unfortunately, the
2.0 5.6 a.4
20 Ha JIO InI
I I”
NUMBER5 533
 DECEREBRATE DOG CHRONIC T-IO SPINAL DOG

norm01 dyssynrrgic

100
cm
introvcsicol

pressure -

H20

I min

urethral

pressure

- detruror stimulation, 20 Hz -
FIGURE 4. Comparison of intravesical and urethral pressures during bladder stimulation in decerebrate dog
and chronic T-10 spinal cord dog.

success achieved in dogs has not been repro- high doses, has no substantial effect on nonelec-
duced in humans with similar spinal cord le- trical detrusor-sphincter dyssynergia even
sions.4’* This discrepancy results from the fact though the drug often has a, marked effect on
that electrical stimulation most often provides other forms of skeletal muscle spasticity in the
less sphincter and pelvic floor spasm in dogs same patients.
than it does in humans. Because of this species Baclofen depressed both the pudendal to pu-
difference, the dog does not provide an ideal dendal and the pelvic to pudendal nerve re-
model for the study of electrical vesical stimula- flexes in the animals we studied. However, the
tion. Nevertheless, we believe the canine effect of baclofen on the pelvic to pudendal
studies described are meaningful because the nerve reflex was dose-related. Low doses (1 to
abnormal pelvic to pudendal nerve reflex re- 1.5 mg./Kg.) of baclofen increased urethral re-
sponsible for electrically induced detrusor- sistance 25 to 60 per cent during bladder stimu-
sphincter dyssynergia in dogs is similar, if not lation in two of three experiments while larger,
identical, to the reflex responsible for sphincter but still clinically acceptable, doses (4 to 6
dyssynergia in man. The primary effects of dan- mg./Kg.) decreased electrically induced
trolene and baclofen on the muscles and reflexes detrusor-sphincter dyssynergia 75 to 90 per cent
responsible for dyssynergia also probably are in all animals studied. Preliminary clinical trials
similar in dogs and in man; however, the rela- suggest that baclofen has a similar effect on
tive effectiveness of these agents in reducing nonelectrical detrusor-sphincter dyssyner-
electrical sphincter dyssynergia may differ in gia. 15,16
the two species of animals. Baclofen in doses of 4 to 6 mg./Kg. also re-
We initially had hoped to demonstrate a duced intravesical pressure 20 to 40 per cent
synergistic effect between dantrolene and baclo- during bladder stimulation; whether the latter
fen. This aspect of the study was abandoned response was secondary to an as yet unrecog-
when it was shown that dantrolene had little ef- nized peripheral effect of the drug or to inhibi-
fect on the dog’s pelvic floor response to puden- tion of the pelvic to pelvic (detrusor) reflex was
dal nerve stimulation. This laboratory finding, not determined. However, in all three experi-
which may be due to the differential susceptibil- ments, baclofen decreased urethral resistance
ity of striated muscle to dantrolene,13 supports more than it did intravesical pressure during
our clinical observation that dantrolene, even at bladder stimulation. Therefore the over-all

534 UROLOGY / MAY 1978 / VOLUME XI, NUMBER 5

 3.5 4.2
mg/kg

I
100
cm Ii20

I min

urethral

pressure

- - - - -
detrusor
stimulation, 20 Hz

FIGURE 5. Effect of baclofen on intravesical and urethral pressures during bladder stimulation.

effect of baclofen should be beneficial during References

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6. Merrill DC: Unpublished data.
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7. IDEM: Clinical experience with the Mentor bladder
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8. Halverstadt DB, and Parry WL: Electronic stimulation of
sistance which occurred in normal animals was
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that intermittent stimulation has not been any action of /3(4-chlorphenyl)-GABA, Exp. Neural. 48: 343 (1975).
12. Ellis, KO, et al: Dantrolene, a direct-acting skeletal muscle
more successful than continuous stimulation in relaxant, J, Pharm. Sci. 62: 948 (1973).
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Veterans Administration Hospital Bladder training: its role in evaluating the effect of an antispastic-
Martinez, California 94553 ity drug on voiding in patients with neurogenic bladder, ibid. 56:
(DR. MERRILL) 463 (1975).

UROLOGY / MAY 1978 / VOLUME XI, NUMBER 5 535