Investigative Urology

EFFECTS OF A PDE4 INHIBITOR ON DETRUSOR OVERACTIVITY IN FEMALE RATS WITH BOOKAIHO

et al.

The effects of a type 4 phosphodiesterase inhibitor

and the muscarinic cholinergic antagonist tolterodine
tartrate on detrusor overactivity in female rats with
bladder outlet obstruction
Yasuhiro Kaiho*†, Jun Nishiguchi*, Dong Duek Kwon*, Michael B. Chancellor*,
Yoichi Arai†, Peter B. Snyder‡ and Naoki Yoshimura*
*Departments of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA, †Tohoku
University School of Medicine, Sendai, Japan, and ‡ICOS Corporation, Seattle WA, USA
Accepted for publication 17 August 2007

conscious rats were assessed by cystometry
Study Type – Aetiology (case control)
with the urethral ligature intact. The effects of
Level of Evidence 3b
IC485 (5, 10 and 50 mg/kg intravenous, i.v.)
were examined and compared with those of
OBJECTIVE tolterodine (0.01, 0.1 and 1 mg/kg i.v.).
To investigate the effects of the selective
phosphodiesterase (PDE) type 4 inhibitor RESULTS
IC485 and the widely used antimuscarinic
drug tolterodine tartrate on bladder activity in IC485 (5–50 mg/kg i.v.) decreased the number
rats with bladder outlet obstruction (BOO), as and amplitude of non-voiding contractions
inhibition of PDE4 leads to elevation of during the storage phase by 63–88% and
intracellular cAMP levels and relaxation of 49–83%, respectively; IC485 also increased
smooth muscle. bladder capacity by 28–37%. There was no
change in blood pressure after applying
MATERIALS AND METHODS IC485. Tolterodine tartrate (0.1 and 1.0 mg/kg)
significantly decreased the number and
BOO was induced in female Sprague-Dawley amplitude of non-voiding contractions by
rats by tying a silk ligature around the 38–74% and 29–44%, respectively, and
urethra. Six weeks after inducing BOO, increased bladder capacity by 19–51%.
Whereas voiding efficiency and maximum
voiding pressure were not altered by IC485 at
any dose, tolterodine significantly reduced
both, by 35–67% and 19–34%, respectively.
CONCLUSION
Both IC485 and tolterodine tartrate reduced
detrusor overactivity in rats with BOO. In
addition, doses of IC485 that suppressed non-
voiding contractions had no effect on voiding
function. Therefore, selective PDE4 inhibitors
deserve further study as potential agents for
treating detrusor overactivity in patients with
BOO.
KEYWORDS
bladder outlet obstruction, detrusor
overactivity, rat, type 4 phosphodiesterase

INTRODUCTION resulting in incomplete or poor therapeutic high-affinity, cAMP-specific type 4 PDE (PDE4)
responses. by studies showing relaxant effects of PDE4
Urinary frequency, urgency and urgency inhibitors on isolated bladder strips from
incontinence are common bothersome Cyclic nucleotides (cAMP and cGMP) are several species, including humans [7–10].
storage symptoms in men with BOO due to important secondary messengers that
BPH [1]. Detrusor overactivity (DOA), modulate the contractility of smooth muscle. We previously reported an inhibitory effect of
defined as involuntary bladder contractions Cyclic nucleotide phosphodiesterases (PDEs), a PDE4 inhibitor (IC486051) on DOA in rats
during filling cystometry, is thought to be a which hydrolyse cyclic nucleotides, are with BOO induced by partial urethral ligation,
major cause of LUTS in patients with BPH important in regulating the level and duration although there was also a transient
[1]. Antimuscarinic drugs are often of action of cyclic nucleotides inside cells. PDE stimulatory effect of this compound on the
prescribed for the treatment of LUTS/BPH. inhibitors elevate intracellular levels of cyclic micturition reflex [11]. In the present study we
While they can increase postvoid residual nucleotides and thereby relax many types of report results with a second selective PDE4
volume, it appears that antimuscarinics smooth muscle, including corpus cavernosal inhibitor, IC485, to further elucidate the
can be used in men with BOO with no [3], vascular [4] and tracheal [5] smooth effects of PDE4 inhibition on bladder function
significant risk of acute urinary retention muscle. Previous studies showed that in vivo. Furthermore, the effects of IC485 were
[2]. However, they also produce bothersome relaxation of bladder smooth muscle is mainly compared with those of tolterodine tartrate,
side-effects, including dry mouth, mediated by agents that elevate cAMP [6–8]. an antimuscarinic agent widely used for
constipation and cognitive impairment, Interest has been focused on the role of the treating overactive bladder.

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K A I H O ET AL.

MATERIALS AND METHODS
Sixty-three adult female Sprague-Dawley
rats (weighing 251–369 g) were used.
Experimental protocols were approved by the
local Institutional Animal Care and Use
gravity. The bladder capacity (BC) was
calculated as VV + RV. Voiding efficiency (VE)
was calculated as (VV/BC) × 100. The number
and amplitude of non-voiding contractions
(NVC) were measured during the period
4-2 min before each voiding contraction
FIG. 1. Representative cystometric recording
obtained from an obstructed rat, showing the MVP,
PT, BPV; amplitude and number of NVC were
evaluated at 4-2 min before each voiding
contraction (shaded area).

Intravesical Pressure, cmH2O

Committee. Under halothane anaesthesia, the
bladder and proximal urethra were exposed
via a lower abdominal midline incision. A 3-0
silk ligature was placed around the urethra
and tied in the presence of a PE-90
polyethylene catheter (outside diameter
1.27 mm, Clay Adams, Parsippany, NJ, USA)
inserted with a 20 G steel needle and placed
alongside the urethra [11,12]. After removing
the needle and catheter, the abdominal
wound was closed. Six weeks after inducing
BOO the rats were prepared for cystometry.
Under halothane anaesthesia, the right
jugular vein was exposed and a polyethylene
catheter (PE-10, Clay Adams) was inserted.
The catheter was exteriorized through a s.c.
tunnel in the retroscapular area. A PE-90
catheter with a cuff was inserted into the
bladder through the bladder dome. The
urethral ligature was not removed before or
during cystometry. After the surgery, rats
were placed in restraining cages and allowed
to recover from halothane anaesthesia for
1–2 h before starting cystometry. The
intravesical catheter was connected via a
three-way stopcock to a pressure transducer
(Transbridge 4M, World Precision Instruments,
Sarasota, FL, USA) for recording intravesical
bladder pressure, and a syringe pump for
infusing saline. Because variability in bladder
capacity among rats is typical of this model,
saline was initially infused at 10 mL/h;
subsequently, the infusion rate was adjusted
to 2–20 mL/h to obtain an intercontraction
interval of ≈15 min. Intravesical pressure
changes were measured using data
acquisition software (AD Instruments, Castle
Hill, NSW, Australia) at a sampling rate of
100 Hz using a PowerLab system (AD
Instruments).
Saline infusion was continued until stable
voiding cycles were established. The
following cystometric variables were
determined from cystometrograms:
maximum voiding pressure (MVP), pressure
threshold for voiding (PT) and baseline
pressure after voiding (BPV) (Fig. 1). Voided
volume (VV) was determined by collecting
voided saline. After the VV was determined,
saline infusion was stopped and the residual
volume (RV) was measured by withdrawing
intravesical fluid through the catheter by
(shaded area in Fig. 1). NVC were defined as 125
MVP
bladder contractions of >4 cmH2O from 100
baseline pressure not associated with release
75
of fluid from the urethra [12]. Values for
50 No. of NVC
individual rats represent the mean of two or Amplitude
three voiding cycles. After measuring of NVC
25
baseline cystometric variables each rat PT
0 BPV
received an i.v. administration of IC485 or
2 min
tolterodine at the indicated dose, in a volume
of 1 mL/kg. Cystometry was repeated and the
variables after drug administration were FIG. 2. Typical cystometric recording obtained from a
measured and compared with those before rat with BOO before (top panel) and after (bottom
treatment. Control rats were injected with panel) administering IC485 50 mg/kg i.v. Note that
vehicle (30% cremophor/PBS for experiments IC485 significantly reduced NVC during bladder
with IC485; saline for experiments with filling.
tolterodine tartrate; five for each vehicle).
cmH2O pre-treatment
75
In three rats with BOO, the effects of IC485
50 mg/kg i.v. on blood pressure were 50
examined during cystometry. Under
halothane anaesthesia, the right jugular 25
artery was exposed and a polyethylene
catheter (PE50, Clay Adams) was inserted and 0
0 5 10 min
exteriorized through a s.c. tunnel in the
retroscapular area. The catheter was cmH2O Post-treatment,
connected to a pressure transducer 75 IC485 50 mg/kg
(Transbridge 4M) for recording blood pressure.
50
IC485 and tolterodine tartrate were provided
by ICOS Corporation (Bothell, WA, USA); IC485 25
is a potent and selective PDE4 inhibitor (50%
0
inhibitory concentration against recombinant 0 5 10 min
human PDE4 of 10 nM; selectivity vs other
PDE families, 1000-fold). It was administered
to rats with BOO at doses of 5 (11 rats), 10 (11) all tests P < 0.05 was considered to indicate
and 50 mg/kg (seven). Tolterodine tartrate significance.
was administered at doses of 0.01, 0.1 and
1.0 mg/kg (eight rats each). Each dose of
IC485 or tolterodine was tested in a separate RESULTS
group of rats; IC485 was dissolved in 30%
cremophor/PBS; tolterodine was dissolved in IC485 significantly decreased the number and
saline. amplitude of NVC (Fig. 2). After administering
IC485, the number of NVC was decreased
All values are expressed as the mean (SEM) for by 63%, 65% and 88% from pretreatment
5–11 rats per treatment group. Variables values at doses of 5, 10 and 50 mg/kg i.v.,
before and after drug administration were respectively (Fig. 3A, Table 1). At all doses, the
compared using Student’s t-test for effect of IC485 was statistically significant
correlated samples, except for the number of (P < 0.05) vs values before treatment and vs
NVC, which was assessed using the Wilcoxon the vehicle-treated group. The amplitude of
matched-pair signed-rank test. One-way NVC was decreased by 49%, 67% and 83%
ANOVA, followed by Dunnett’s multiple from the pretreatment values at doses of 5, 10
comparison test, was used to compare effects and 50 mg/kg, respectively (Fig. 3B, Table 1).
between vehicle- and drug-treated groups; in The effect of IC485 on the amplitude of NVC

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 EFFECTS OF A PDE4 INHIBITOR ON DETRUSOR OVERACTIVITY IN FEMALE RATS WITH BOO

FIG. 3. The effects of IC485 and tolterodine on the number (A) and amplitude (B) of NVC, VE (C) and MVP (D) by 19% and 34%, at doses of 0.1 and 1 mg/kg,
in rats with BOO. IC5, IC10 and IC50 signify IC485 at doses of 5, 10 and 50 mg/kg i.v., respectively; Tol0.01, respectively (Fig. 3C,D, Table 1). The changes
Tol0.1 and Tol1 signify tolterodine tartrate at doses of 0.01, 0.1 and 1.0 mg/kg i.v., respectively. †P < 0.05 vs were also significant vs the vehicle-treated
vehicle control group (one-way ANOVA with Dunnett’s multiple comparison post-test). group at both doses. PT and BPV were
increased significantly vs before treatment at
A Number of NVC B Amplitude of NVC 1.0 mg/kg (Table 1). Tolterodine at 0.01 mg/kg
150 150 had no effect on the cystometric variables.
125 125
% of pre-treatment

% of pre-treatment
100 100
Arterial blood pressure was measured in rats
that were given IC485 at 50 mg/kg i.v.; there
75 75 were no changes in blood pressure (data not
† † †
50 50 shown).
† †
25 25
0 0
DISCUSSION
e
5
10
50

To le
To 1
.1
l1

le
5
10
50

To cle
To 1
.1
l1
l

.0

.0
hic

hic

hic
l0

l0
IC

IC
To

To
hi
l0

l0
IC

IC
IC

IC
Ve

Ve

Ve

Ve
PDE4, the cAMP-specific, rolipram-sensitive
C VE D MVP PDE, has been implicated in the control of
150 150 bladder smooth muscle tone in vitro. PDE4
inhibitors reduce the contractile response of
125 125
% of pre-treatment

guinea pig [8], rat [9], non-human primate [9]

% of pre-treatment

100 100 † and human [10] bladder strips, and suppress

† †
75 75 rhythmic bladder contractions of the isolated
† guinea pig bladder [13]. We showed
50 50
previously that another PDE4 inhibitor
25 25 (IC486051) suppresses DOA in rats with BOO
0 0 [11]. The results reported here extend these
le
5
10
50

To cle
To 1
.1
l1

le
5
10
50

To cle
To 1
.1
l1

observations to a second PDE4 inhibitor,

.0

.0
hic

hic
l0

l0
IC

IC
To

To
hi

hi
l0

l0
IC

IC
IC

IC

IC485, and compare the effects of IC485 with

Ve

Ve

Ve

Ve

† p < 0.05 Dunnett's multiple comparison test those of the antimuscarinic agent tolterodine
tartrate.

was significant vs baseline values at all doses increased by 34%, 28% and 37% from
tested, but was significant vs the vehicle- pretreatment values at doses of 5, 10 and
treated group only at 50 mg/kg. 50 mg/kg, respectively (Table 1); PT was also
increased by 21%, 18% and 23% from
Tolterodine tartrate also decreased the pretreatment values at the same respective
number and amplitude of NVC, although the doses (Table 1). Changes in BC and PT were
effects were not as large as those with IC485. significant vs pretreatment values at all doses
Tolterodine at 0.01 mg/kg had no effect on tested, but not vs the vehicle-treated group.
NVC, but at 0.1 and 1 mg/kg the number of
NVC was decreased by 38% and 64% from Tolterodine increased the BC by 19% and 51%
baseline values, respectively (Fig. 3A, Table 1). at doses of 0.1 and 1 mg/kg, respectively
The effect of tolterodine was significant vs (Table 1). These changes were statistically
baseline values at both doses, but was significant vs pretreatment levels at both
significant vs the vehicle-treated group only doses and vs the vehicle-treated group at
at 1 mg/kg. The amplitude of NVC was 1 mg/kg. However, tolterodine tended to
decreased by 29% and 44% from baseline decrease the VV at 0.1 mg/kg and significantly
values at 0.1 and 1 mg/kg, respectively decreased VV by 37% from pretreatment
(Fig. 3B, Table 1). The effect at both doses was values at 1.0 mg/kg (Table 1). This difference
significant vs baseline levels, but not vs the was also significant vs the vehicle-treated
vehicle-treated group. group. Tolterodine also increased RV by 52%
and 136% at doses of 0.1 and 1 mg/kg,
While both IC485 and tolterodine tartrate respectively (Table 1). These changes were
suppressed NVC in rats with BOO, they statistically significant vs values before
differed in their effects on voiding bladder treatment at both doses, and vs the vehicle-
contractions. IC485 did not affect VV, RV, VE, treated group at 1 mg/kg. In addition,
MVP or BVP (Fig. 3C,D and Table 1). However, tolterodine significantly reduced VE by 35%
after administration of IC485, BC was and 67% from pretreatment values, and MVP
IC485 (5–50 mg/kg, i.v.) significantly
decreased the number and amplitude of NVC
and increased BC, without significantly
changing either VE or MVP. Thus, IC485
suppressed DOA during bladder filling without
compromising voiding function. In
comparison, tolterodine tartrate (0.1 and
1.0 mg/kg) decreased the number and
amplitude of NVC and increased BC, while
decreasing VE and MVP.
In pharmacokinetic studies, rats dosed with
IC485 at 10 mg/kg i.v. had a mean peak
plasma concentration (Cmax) of 26 (4.6) μM
(unpublished observations). Assuming linear
dose proportionality, the Cmax values of IC485
at 5 and 50 mg/kg are expected to be ≈13 and
130 μM, respectively. IC485 has a 50%
inhibitory concentration (IC50) against
recombinant human PDE4 of 0.01 μM, but its
half-maximum effective concentration in
cell-based assays is 0.74 μM in the presence
of serum. It is at least 1000-fold selective for
PDE4 over other PDE families. Hence, no
significant inhibition of other PDE families
would be expected in vivo at concentrations
of <740 μM. Thus, it can be inferred that the

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K A I H O ET AL.

TABLE 1 The number and amplitude of NVC, and the cystometric variables before and after treatment

IC485, mg/kg Tolterodine, mg/kg

Treatment Vehicle 5 10 50 Vehicle 0.01 0.1 1.0
Number of rats 5 11 11 7 5 8 8 8
NVC
Before 3.93 (1.33) 6.00 (1.61) 3.73 (0.69) 4.02 (1.31) 3.77 (0.78) 5.06 (1.12) 6.63 (1.14) 4.67 (0.86)
After 3.60 (0.51) 2.36 (0.81)*† 1.00 (0.45)*† 0.86 (0.59)*† 3.60 (0.51) 4.50 (1.96) 4.13 (1.09)* 1.75 (0.56)*†
Amplitude of NVC, cmH2O
Before 8.08 (1.09) 7.80 (0.72) 6.57 (0.47) 6.89 (1.12) 7.78 (1.54) 7.28 (0.52) 8.65 (0.95) 7.53 (0.59)
After 7.36 (1.28) 4.27 (1.44)* 2.84 (1.05)* 1.67 (1.09)*† 7.93 (1.23) 6.71 (1.39) 6.49 (1.28)* 4.45 (1.50)*
BC, mL
Before 2.61 (1.10) 2.26 (0.83) 2.08 (0.39) 2.08 (0.82) 2.71 (0.89) 2.22 (0.76) 2.51 (0.90) 2.22 (0.59)
After 2.85 (1.26) 3.07 (1.11)* 2.91 (0.64)* 2.64 (0.99)* 2.83 (0.89) 2.13 (0.80) 2.94 (1.09)* 3.39 (1.00)*†
VV, mL
Before 1.35 (0.42) 1.15 (0.41) 0.81 (0.18) 0.75 (0.35) 1.29 (0.48) 1.02 (0.52) 0.99 (0.31) 0.92 (0.27)
After 1.47 (0.53) 1.37 (0.49) 1.02 (0.34) 0.68 (0.18) 1.52 (0.61) 1.14 (0.62) 0.63 (0.13) 0.34 (0.15)*†
RV, mL
Before 1.26 (0.68) 1.11 (0.50) 1.28 (0.29) 1.33 (0.66) 1.42 (0.46) 1.20 (0.34) 1.52 (0.69) 1.29 (0.40)
After 1.38 (0.74) 1.70 (0.85) 1.90 (0.52) 1.96 (0.92) 1.31 (0.37) 0.99 (0.23) 2.31 (1.03)* 3.05 (0.94)*†
VE, %
Before 0.59 (0.07) 62.3 (6.6) 43.4 (6.2) 41.1 (9.2) 0.42 (0.10) 42.7 (10.5) 54.2 (9.3) 46.2 (8.7)
After 0.57 (0.08) 65.3 (8.1) 40.9 (7.0) 37.1 (9.4) 0.46 (0.11) 45.0 (9.5) 40.2 (10.7)*† 11.8 (4.2)*†
MVP, cmH2O
Before 89.3 (15.51) 69.9 (10.82) 83.6 (10.50) 102.3 (11.29) 95.4 (11.85) 65.0 (8.46) 80.76 (11.14) 67.7 (9.63)
After 89.4 (15.84) 66.7 (9.73) 81.6 (9.90) 95.9 (12.03) 100.4 (11.52) 56.1 (6.70) 65.2 (10.12)*† 41.8 (4.15)*†
BPV, cmH2O
Before 8.90 (1.75) 6.87 (0.95) 5.97 (0.62) 7.58 (0.95) 6.78 (0.85) 7.61 (0.93) 8.71 (1.52) 5.73 (0.75)
After 9.38 (1.74) 6.99 (1.11) 6.51 (0.75) 8.77 (0.85) 6.73 (0.85) 6.74 (1.09) 10.92 (2.48) 8.15 (0.67)*†
PT, cmH2O
Before 12.74 (2.48) 10.79 (1.40) 8.60 (0.72) 10.85 (1.32) 9.71 (1.20) 9.76 (0.99) 13.19 (1.92) 8.96 (0.94)
After 14.15 (3.41) 13.13 (1.93)* 10.08 (0.95)* 12.91 (1.16)* 10.33 (1.53) 9.45 (1.56) 16.14 (3.88) 11.51 (1.39)*

*P < 0.05 vs value before treatment (number of NVC by Wilcoxon matched-pair signed-rank test; amplitude of NVC, Student’s t-test for correlated samples); or
†P < 0.05 vs vehicle-treated rats (one-way ANOVA with Dunnett’s multiple comparison post-test).

effects of IC485 at the doses used in the
present study are due to inhibition of PDE4.
After 0.5 mg/kg i.v., the Cmax of tolterodine
tartrate in the rat is expected to be ≈100 nM
[14]. Assuming linear dose-proportionality,
Cmax values for doses of 0.01, 0.1 and 1 mg/kg
would be ≈2, 20 and 200 nM, respectively. In
patients who have taken a 4-mg dose of
extended-release tolterodine tartrate, the
median peak plasma level is ≈7 nM (package
insert). Hence, exposures achieved in the two
lower-dose groups in the present study
should be in the range of a clinically effective
dose. These results suggest that a
therapeutically relevant dose of tolterodine
can suppress DOA induced by BOO. However,
the effect on DOA produced at this exposure
(38% reduction in the number of NVC at
0.1 mg/kg) was less than that with the lowest
dose of IC485 (49% reduction at 5 mg/kg).
Tolterodine also reduced the MVP and VE at
this dose, which was not so with IC485 at any
dose. Hence, IC485 appears to be more
selective than tolterodine for suppressing
NVC vs voiding bladder contractions.
However, because, in men with BOO,
tolterodine (2 mg twice daily) had only a
minimal effect on detrusor pressure at
maximum urine flow [2], our results showing
the inhibitory effects of tolterodine on
voiding bladder contraction in female rats
might not directly be applicable to humans.
DOA in rats with BOO is not affected by
desensitization of bladder sensory afferent C-
fibres with the neurotoxin resiniferatoxin [12],
suggesting that the emergence of DOA in this
model is primarily due to changes in bladder
smooth muscle. Therefore, it is likely that the
effect of IC485 and tolterodine tartrate on
NVC is mediated by a direct action on bladder
smooth muscle cells. During bladder filling,
elevation of intracellular cAMP to produce
bladder smooth muscle relaxation could be
mediated by activation of adenylyl cyclase
following stimulation of β-adrenoceptors by
noradrenaline released from sympathetic
bladder efferent nerves [15], or after
stimulation of vasoactive intestinal peptide
(VIP) receptors (VPAC) by VIP or pituitary
adenylate cyclase-activating polypeptide
released from peptidergic neurones [16]. Both
PDE4 inhibitors and antimuscarinic drugs
have the potential to modulate cAMP-
dependent relaxation of bladder smooth
muscle (Fig. 4). PDE4 inhibitors increase
intracellular cAMP levels by directly
suppressing cAMP hydrolysis [8]; muscarinic
M2 receptors negatively couple to adenylyl
cyclase through Gi/o. Hence, tolterodine
tartrate might increase intracellular cAMP by
antagonizing M2 receptors [17] in addition to

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 EFFECTS OF A PDE4 INHIBITOR ON DETRUSOR OVERACTIVITY IN FEMALE RATS WITH BOO
FIG. 4.
Possible sites of action of IC485
and tolterodine tartrate for
suppressing DOA. IC485 inhibits
hydrolysis of cAMP by PDE4. Beta-
adrenergic
Tolterodine tartrate antagonizes
receptor
M2 muscarinic receptors, which
are negatively coupled to adenylyl
(+)
cyclase. Both agents could
increase cAMP levels in bladder
smooth muscle cells, leading to
relaxation. Tolterodine tartrate
also inhibits M3 receptors, which
directly induce detrusor
ATP
contraction.
antagonism of M3 receptors on bladder
smooth muscle [18] (Fig. 4).
The lack of effect of IC485 on voiding bladder
contractions is consistent with the hypothesis
that IC485 potentiates inhibitory inputs to the
bladder during bladder filling. As these
inhibitory signals are centrally suppressed
during micturition, it is not expected that a
PDE4 inhibitor would have effects on voiding
contractions. Clinically, the preservation of
effective voiding might mean less propensity
for causing increased postvoid residual
volume, which sometimes occurs when
antimuscarinic drugs are prescribed to
patients with BOO [2].
In our previous study, IC486051, another
PDE4 inhibitor, had a transient stimulatory
effect on the micturition reflex immediately
after drug administration. We hypothesized
that this is due to activation of bladder
afferent neurones, leading to a vesico-
vascular reflex [11]. This response was not
observed in the present study using IC485,
suggesting that IC485 primarily acts on
bladder smooth muscles at the doses given.
The difference in the response to the two
PDE4 inhibitors for this transient stimulatory
effect might be due either to differences in
potency or in partitioning between different
tissues.
If the effects of PDE4 inhibition shown in the
present study also occur in humans, PDE4
inhibitors might be an attractive therapy for
treating LUTS in patients with BOO. However,
in clinical studies, emesis has been found to
be a dose-limiting side-effect of PDE4
inhibitors [19]. In addition, administration of
PDE4 inhibitors to rats is associated with
vascular mesenteritis [20,21]. Furthermore,
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Inhibitory effect of
tolterodine
M2
receptor M3
receptor
(−)
Detrusor contraction
Adenylyl
cyclase Inhibitory effect of
IC 485
PDE
(+)
cAMP
hydrolysis
recent studies indicated that PDE4D
‘knockout’ mice are susceptible to
cardiomyopathy and arrhythmia as they age
[22]. Therefore, it remains to be determined
whether or not PDE4 inhibitors will have
therapeutic effects on DOA in patients at
doses that are safe and well-tolerated.
In conclusion, both IC485 and tolterodine
tartrate reduced DOA in rats with BOO. In
addition, effective doses of IC485 had no
effect on voiding function. Thus selective
PDE4 inhibitors deserve further study for
treating DOA in patients with BOO.
ACKNOWLEDGEMENTS
This work was supported by a grant from ICOS
Corporation.
CONFLICT OF INTEREST
Peter B. Snyder was an employee of ICOS and
Naoki Yoshimura is a Study Investigator
funded by ICOS.
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2 Abrams P, Kaplan S, De Koning Gans
HJ, Millard R. Safety and tolerability
of tolterodine for the treatment of
overactive bladder in men with bladder
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1004
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Correspondence: Naoki Yoshimura,
Department of Urology, University of
Pittsburgh School of Medicine, Suite 700,
Kaufmann Medical Bldg., 3471 Fifth Avenue,
Pittsburgh, PA 15213, USA.
e-mail: nyos@pitt.edu
Abbreviations: DOA, detrusor overactivity;
PDE, phosphodiesterase; MVP, maximum
voiding pressure; PT, pressure threshold for
voiding; BPV, baseline pressure after voiding;
NVC, non-voiding contractions; VV, volume
voided; RV, residual volume; VE, voiding
efficiency; Cmax, peak plasma concentration;
IC50, 50% inhibitory concentration; VIP
(VPAC), vasoactive intestinal peptide
(receptor).
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