Download pharmacological modulation of ureteral peristalsis in a

0022-5347/03/1701-0264/0
THE JOURNAL OF UROLOGY®
Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 170, 264 –267, July 2003
Printed in U.S.A.
DOI: 10.1097/01.ju.0000071964.04804.e4
PHARMACOLOGICAL MODULATION OF URETERAL PERISTALSIS IN A
CHRONICALLY INSTRUMENTED CONSCIOUS PIG MODEL. I: EFFECT
OF CHOLINERGIC STIMULATION AND INHIBITION
H. ROSHANI, N. F. DABHOIWALA, T. DIJKHUIS, M. PFAFFENDORF, T. A. BOON
AND W. H. LAMERS*
From the Department of Urology (HR, TAB), University Medical Center, Utrecht and Departments of Urology (NFD, TD), Anatomy and
Embryology (WHL), and Pharmacology (MP), Academic Medical Center, Amsterdam, The Netherlands
ABSTRACT
Purpose: We evaluated in vivo the role of muscarinic receptors on ureteral peristaltic frequency
and contraction force in a large animal model using pharmacological manipulation.
Materials and Methods: A total of 12 female pigs weighing a mean ⫾ SEM of 72 ⫾ 4 kg were
chronically instrumented using an electronic pressure monitoring catheter in the right ureter.
Furthermore, nephrostomy, arterial, venous and cystostomy catheters were placed. Ureteral
peristalsis was repeatedly recorded before and after the administration of atropine and carbachol.
Results: Systemic and local effects of the 2 agents were observed. Compared with controls we
recorded an increase in mean ureteral peristaltic frequency (2.0 ⫾ 0.3 versus 1.6 ⫾ 0.6 minutes⫺1, p ⬍0.05) and mean contraction force (50.1 ⫾ 1.4 versus 45.3 ⫾ 1.7 cm H2O, p ⬍0.05)
during renal pelvis perfusion with 0.25 ml per minute saline. Administration of atropine or
carbachol modulated neither the force of contraction nor the frequency of ureteral peristalsis in
vivo (p ⬎0.05).
Conclusions: Smooth muscle motor activity at the mid and distal ureter is not modulated by
muscarinic receptors. Peristaltic frequency is directly related to the pyelocaliceal load during a
rate of diuresis not exceeding animal normal diuresis plus 0.25 ml per minute. Ureteral contraction force increases only in the mid ureter with increased diuresis.
KEY WORDS: ureter; swine; peristalsis; diuresis; muscle, smooth
During the normal rate of diuresis the ureter transports
urine from kidney to bladder by peristalsis. Myogenic and
neurogenic theories have been propounded to explain ureteral peristalsis. However, denervation of the ureter, kidney
transplantation and even reversed ureteral autotransplantation do not abolish peristalsis.1, 2 Therefore, only the myogenic theory of ureteral peristalsis can explain why peristalsis is possible in an isolated ureteral segment in vitro and in
vivo.3, 4 The development of renal colic in patients with urolithiasis proves the existence of sensory innervation of the
ureter but much less is known about neurogenic modulation
of ureteral peristalsis. Nevertheless, it is well established
that the mammalian ureter is extensively innervated by unmyelinated axons from different levels of the spinal cord.5– 8
Using immunohistochemistry and radioimmunoassay considerable information has become available about the expression of receptors for neurotransmitters that presumably control neuromuscular physiology of the ureter.5, 7
We have previously reported the morphology and functional properties of the human and porcine ureter.9 –12 A
chronically instrumented animal model to investigate the
physiological relevance of histologically demonstrated receptors for neuromuscular transmission is missing in the literature. In this study we evaluated the effect of inhibition and
stimulation of muscarinic receptors on ureteral peristalsis in
a chronically instrumented, conscious pig model.
The density of cholinergic nerve fibers in the ureter in-
creases from renal pelvis to bladder with the ureterovesical
junction the most densely innervated region.13, 14 Acetylcholine increases tonic and phasic contractile activity of different
segments of the ureter in vitro14 –17 and also increases peristaltic frequency.18 After nerve stimulation acetylcholine is
released from isolated renal pelvis and ureter.19 Therefore,
our hypothesis was that stimulation and inhibition of muscarinic receptors in vivo would increase and decrease, respectively, the frequency and contraction force of ureteral peristalsis.
MATERIAL AND METHODS
Experimental animals and preoperative procedures. A total
of 12 female land pigs weighing a mean ⫾ SEM of 72 ⫾ 4 kg
were studied. Pigs were individually acclimatized and socialized during 2 weeks in the laboratory environment in a 2 ⫻
3 m pen next to the measuring station. All experiments were
monitored and documented via this station. This hall contained 20 pens and had a circadian day and night rhythm.
The pigs were fed a mineral poor laboratory pig diet. They
drank and could move freely in the pen during experiments.
As premedication 1 mg/kg ketamine and 3 mg/kg Stresnyl
(Janssen Farmaceutical, Tilburg, The Netherlands) were
used. The number of animals needed for the study was estimated using the Sigmastat (SPSS Science, Chicago, Illinois)
computer program based on a power of 90%. Sample size
estimation revealed that 9 pigs were the minimal requirement. All experiments were performed under protocols approved by the local committee on animal research.
Experimental operation. Intravenous anesthesia was induced using 5 mg/kg thiopental (Nesdonal Rhône Meurieux,
Lyon, France) and 0.1 mg/kg atropine. The pigs were intu-
Accepted for publication January 31, 2003.
Supported by a grant from the Netherlands Organization for
Health Research and Development, Project 920-03-054.
* Corresponding author: Department of Anatomy and Embryology
and AMC Liver Centre, Academic Medical Center, Meibergdreef
69-71, 1105 BK Amsterdam, The Netherlands.
264
PHARMACOLOGICAL MODULATION OF URETERAL PERISTALSIS
bated and ventilated. Booster doses of 0.04 mg/kg Sufentanyl
(Janssen Farmaceutical) 0.6 mg/kg midazolam and 0.1 mg/kg
pancuronium (Pavulon/Organon, Oss, The Netherlands)
were administered. Anesthesia was maintained using 0.1
ml/kg per hour Sufentanyl, 0.13 ml/kg per hour midazolam
and 0.06 ml/kg per hour pancuronium. The animals were
hydrated with 0.9% saline (approximately 10 ml/kg per
hour). Electrocardiogram monitoring was done. Perioperatively antibiotic coverage was administered using 0.067 mg
penicillin per kg body weight. An 8Fr ureteral balloon catheter was manipulated endoscopically into the distal right
ureter and the balloon was lightly inflated. Under fluoroscopic control iodine contrast medium was injected through
the core channel of this balloon catheter to visualize the
pyelocaliceal system. Under ultrasound guidance fine needle
puncture of the pyelocaliceal system was performed and a
guide wire was positioned under x-ray guidance. Subsequently the puncture traject was dilated telescopically. An
electronic 6Fr pressure monitoring catheter with twin measuring points19 was tunneled subcutaneously from the cervical
area and positioned antegrade under fluoroscopic guidance
into the right ureter. The distal and proximal measuring
points lay respectively in the perivesical portion of the ureter
and 6.5 cm more proximal in the mid ureter. A pigtail nephrostomy catheter was anchored in situ. A tunneled vesicostomy catheter to measure bladder pressure was also anchored in situ via minilaparotomy. Separate arterial and
venous catheters were tunneled and inserted into the carotid
artery and jugular vein. All tunneled catheters were protected with a Kevlar jacket (van Baal, Utrecht, The Netherlands, see figure). After the procedure the animals were
allowed to recover for 9 days. During this postoperative recovery period followup documentation of ureteral peristalsis
was performed daily to assess the recovery of ureteral peristalsis after surgery on the renal pelvis.
Pressure monitoring catheter and hardware. A special 6Fr
Gaeltec (Dunvegan, Isle of Skye, Scotland) with a twin pressure crystal transducer was used to record peristalsis.19 The
distance between the pressure measuring points was 6.5 cm.
Two electrodes were localized adjacent to each pressure
transducer to measure EMG and impedance, and serve as a
positive control for the peristaltic waves.11, 19 EMG was recorded using a bipolar setting and filter between 0 and 100
Hz. electrocardiogram was also recorded as a superimposed
signal on the EMG curves. Impedance was measured between the 2 intraluminally placed ureteral electrodes and an
electrode on shaved, defatted skin in the homolateral lumbar
region. A skin electrode was used to earth the animal. Im-
Schematic drawing of position of respective catheters and electrodes. Measuring cables from cervical area are connected to transducer 1 m above pig. Transducer is connected to computer in measuring station next to animal pen by glass fiber cable. PCN,
percutaneous nephrostomy. RR, Riva Rochi (blood pressure). R/,
recipe (medication). P, pressure.
265
pedance measurements were fed using an alternating current of 500 Hz and a 12 V transducer. Direct current resistance was less than 5 K⍀. The measurement box was about
1 m above the animal and connected to the computer using a
glass fiber cable. Data were recorded using LabVIEW (National Instruments Corp., Austin, Texas) software on a Windows NT4 (Microsoft, Redmond, Oregon) operating system.
The catheter was set to zero before introduction at operation
and again controlled at each data recording session. The
criteria to identify a peristaltic wave were those reported
earlier.19 Documentation of the curves was possible at all
sessions. In 2 pigs recording only 1 channel was possible due
to a broken wire in the other channel. Another pig destroyed
the measuring catheter, so that a second operation was necessary to replace the damaged catheter.
Monitoring of hemodynamic and urodynamic signals. A
multichannel HP-78342A (Hewlett-Packard, Andover, Massachusetts) pressure transducer was used to record blood
pressure via the arterial catheter. The jugular venous catheter was used for drug administration. To document hydrostatic pressure in the renal pelvis and bladder the nephrostomy and cystostomy catheters were used. The pressure
transduction chambers were flushed and set to zero regularly
at the level of the organ concerned.
Animal care and maintenance. Each animal was examined
daily. In all animals urinary leakage from the nephrostomy
tube ceased within 24 hours. Urinary sediment and culture
samples were collected and always negative. Daily physical
examination revealed no evidence of pyelonephritis. Ultrasound of the kidneys using a 3535 (B-K, 3535, B-K Medical,
Herlev, Denmark) device was done before each data recording session. Only 1 animal had dilatation of the pyelocaliceal
system and it was excluded from study. Nursing care of the
animals was also regularly done by the investigator to cultivate and develop a social bond as well as decrease animal
stress to a minimum during the study.
Drug administration and data documentation. At the start
of each session physical examination of the pig under study
as well as ultrasound of its upper urinary tract was performed. Furthermore, baseline urine production and blood
pressure as well as pressure in the renal pelvis and bladder
during approximately 30 minutes were assessed. In addition,
ureteral EMG, impedance and pressure changes due to peristalsis were recorded during a period of 1,000 seconds and
used as reference (REF-1). Diuresis during this REF-1 period
was measured by emptying the bladder via the vesicostomy.
The percutaneous nephrostomy catheter was then perfused
with 0.25 ml per minute saline at body temperature using a
pump (Becton-Dickinson, Oxford, United Kingdom) and recording was repeated as described as a second control
(REF-2) to ensure that a pyelocaliceal load was present (360
ml per 24 hours plus endogenous diuresis). This control study
was important because this baseline provided guidance when
blood pressure decreased and diuresis decreased due to drug
administration. Agonists and antagonists of muscarinic, ␤
and ␣-adrenergic, and nitrergic receptors were administered
intravenously, while perfusion of percutaneous nephrostomy
continued with 0.25 ml per minute saline. These drugs were
administered according to a preplanned rotating schedule at
3-day intervals to eliminate any drug interaction. Systemic
effects of medication were noted. In the current study 0.004
mg/kg carbachol and 0.5 mg/kg atropine were administered
as muscarinic agonist and antagonist, respectively. These
doses were chosen based on available human and veterinary
literature. Each experiment lasted 6 weeks.
Terminal assessment of ureteral function. The pigs were
sedated as described. X-ray imaging of the upper tract was
done after perfusion (0.25 ml per minute) of the nephrostomy
with dilute iodine contrast medium as described to confirm
the presence of normal peristalsis 6 weeks postoperatively.
Peristaltic activity was similar to that observed during the
266
PHARMACOLOGICAL MODULATION OF URETERAL PERISTALSIS
initial operation but the intraluminal catheter was seen to
have advanced approximately 2 cm proximal in all cases
compared with its position on the day of introduction (due to
animal growth and/or movement). The pigs were then sacrificed in accordance with laboratory guidelines (10 ml pentobarbital sodium 200 mg/ml intravenously). The urinary
tracts were immediately harvested for histological analysis.
Data analysis. The amplitude (Pmax) in cm H2O of each
pressure signal, its duration (in seconds and frequency in
minutes⫺1) of the peristaltic curves were manually analyzed
and recorded in a spreadsheet program. The duration of the
pressure signal was converted in pressure signal length in
mm by multiplying duration by propagation velocity.12 Frequency distribution analysis of our data revealed a natural
distribution that justified determination of the mean ⫾ SEM
and p value using the 2-tailed unpaired Student t test.
Quantitative description of documented peristalsis. Quantitative analysis of the acquired data from the REF-1, REF-2,
atropine and carbachol sessions was done using the Excel
2000 spreadsheet program.
RESULTS
Systemic effects. Atropine and carbachol caused a significant increase (180 ⫾ 6 minutes⫺1) and decrease (56 ⫾ 3
minutes⫺1), respectively, in heart rate (control 83 ⫾ 4 minutes⫺1, p ⬍0.05). Blood pressure was not affected. Average
diuresis of the pigs during atropine and carbachol was 64.6 ⫾
0.8 and 62.6 ⫾ 0.7 ml per hour, respectively, and it did not
differ significantly from the control condition (63.9 ⫾ 0.2 ml
per hour). Atropine caused a dry cough and mydriasis,
whereas carbachol initiated massive saliva production.
Urological effects. Postoperative measurement of ureteral
peristalsis within 4 hours after catheter implantation revealed ureteral peristalsis at a frequency of 1.4 ⫾ 0.7 minutes⫺1 and a Pmax of 39.2 ⫾ 1.6 cm H2O in the mid ureter.
Ureteral peristalsis vanished on days 1 and 2 after the operation. Urine production was similar during these 2 days
(62.8 ⫾ 0.8 ml per hour) compared with the other postoperative days (63.4 ⫾ 0.6 ml per hour). We did not perform
fluoroscopic imaging to avoid a second anesthesia but ultrasonography did not reveal detectable dilatation of the renal
pelvis. Ureteral activity reappeared gradually during the
subsequent days. Up to day 5 peristaltic activity in the mid
ureter was irregular in amplitude and occurred in clusters,
followed by a long inactive period. Single wave patterns ensued from day 7 and thereafter. Normal ureteral peristalsis
in the distal ureter was reestablished a day later than in the
mid ureter. Hydrostatic pressure in the renal pelvis became
measurable again on postoperative day 3. Its rhythmicity
reappeared on postoperative day 4 with peaks of 7 cm H2O
and dips of 1 cm H2O. The rhythmicity in hydrostatic pressure in the renal pelvis did not correlate with ureteral peristaltic frequency.
The table lists variations in maximal pressure during a
peristaltic wave or Pmax in the REF-1 and REF-2 periods as
well as the effects of atropine and carbachol. Average baseline pressure or REF-1 did not fluctuate significantly during
experiments in individual pigs but differences were seen
between pigs. Pmax, the length of the pressure wave and
peristaltic frequency were unaffected by atropine or carbachol. Perfusion of 0.25 ml saline through the nephrostomy
caused a significant increase of Pmax and peristaltic frequency but in the mid ureter only (p ⬍0.05). Hydrostatic
pressure in the renal pelvis showed a rhythmic variation
between 0 and 6.5 cm H2O that was nonsynchronous with
respiration and also unaffected by atropine or carbachol. The
2 drugs did not change intravesical pressure. This finding
does not support the hypothesis that anticholinergic drugs
decrease detrusor contractility. We cannot explain this observation completely. It may be due to species differences.
Another possible explanation may be relatively low bladder
filling (150 to 250 ml) during these experiments. Imaging
studies with x-rays revealed that peristalsis was still present
6 weeks postoperatively. The measuring catheter was displaced approximately 2 cm proximal compared with its level
on the day of introduction. Histological staining with hematoxylin and eosin of the harvested ureter revealed only a mild
inflammatory response.
DISCUSSION
Importance of chronically instrumented animal studies versus acute experiments. A considerable number of studies on
ureteral physiology that are based on in vitro or acute in vivo
experiments have been published.14 –17 The most important
criticism of these data is the influence of anesthesia and
trauma on normal physiology. Results of in vitro studies can
never fully explain the effects of a complex and dynamic
multivariate regulatory circuit, eg the effects of receptor
stimulation or inhibition on motor activity in the ureter. The
mammalian upper urinary tract (UUT) is also difficult to
reach since it is hidden safely in the retroperitoneal area.
Radioactive imaging techniques such as mercaptoacetyltriglycine renography, as used in clinical studies of UUT motility, are unsuitable for experimental study in a conscious,
chronically instrumented animal. Movement artifacts would
render the study impossible or useless. Our experimental
setup is similar to that used in humans for percutaneous
nephrolithotripsy with a double pigtail catheter left in situ.
Our detailed control studies revealed that the UUT in our
animals was not affected to any significant degree by inflammation or signs of obstructive uropathy.
Extensive searches in the Medline database failed to reveal
reports with an approach similar to that in our physiological
study of the UUT. There were several technical problems to
overcome. Successful puncture of a minimally dilated UUT of
the pig is more difficult than in humans because of the long
thoracic cage covering the kidney. Pigs are by nature intelligent but rooting, inquisitive and destructive animals. There-
REF-1 before and REF-2 after perfusion of upper urinary tract with 0.25 ml per minute saline and after administration of atropine or
carbachol
Experimental
Condition
Mean Pmax ⫾ SEM (cm H2O)
Proximal
Distal
Mean Signal Length ⫾ SEM (mm)
Proximal
Distal
Mean Frequency ⫾ SEM
(min⫺1)
Antagonist:
REF-1
45.3 ⫾ 1.7*
46.5 ⫾ 1.7
26.0 ⫾ 1.7
25.5 ⫾ 1.7
REF-2
50.1 ⫾ 1.4*
48.6 ⫾ 1.5
25.6 ⫾ 1.5
27.6 ⫾ 1.5
Atropine
51.4 ⫾ 1.4
50.3 ⫾ 1.5
28.3 ⫾ 1.5
26.3 ⫾ 1.5
Agonist:
REF-1
43.7 ⫾ 1.5*
53.4 ⫾ 2.0
29.3 ⫾ 1.8
27.1 ⫾ 2.0
REF-2
48.2 ⫾ 1.7*
55.2 ⫾ 2.1
29.4 ⫾ 2.2
27.4 ⫾ 2.1
Carbachol
49.4 ⫾ 1.9
50.7 ⫾ 2.0
30.1 ⫾ 2.1
27.6 ⫾ 1.9
Pmax and peristaltic frequency in mid ureter were significantly increased during perfusion of renal pelvis with 0.25 ml per minute
REF-1), and atropine and carbachol failed to affect ureteral peristalsis in any parameters compared with REF-2 results.
* p ⬍0.05.
1.6 ⫾ 0.6*
2.0 ⫾ 0.3*
2.0 ⫾ 0.8
1.3 ⫾ 0.5*
1.6 ⫾ 0.4*
1.6 ⫾ 1.1
saline (REF-2 versus
PHARMACOLOGICAL MODULATION OF URETERAL PERISTALSIS
fore, it was a great challenge to position and maintain all
tunneled measuring catheters in situ during the weeks of
experimentation. Despite our efforts we lost 1 catheter, as
mentioned. Animal movement negatively affects the documentation of slight signals. To this end the pig socialization
program with the investigator was of crucial importance to
decrease the number of artifacts to a minimum and ensure
the success of the experiments.
Discrepancy between in vivo and in vitro studies. Cholinergic nerve fibers are present in various densities in the
UUT.13, 14 They are reported to be of the muscarinic type in
most species, including pigs.17 In vitro acetylcholine is reported to have an inotropic and chronotropic effect on the
UUT.14 –18 Since the systemic effects of cholinergic stimulation and inhibition were observed in all animals in our study,
there can be no doubt that an effective biological dose of the
drug was administered. Furthermore, our experimental
setup was calibrated to register changes in the frequency and
contraction force of ureteral peristalsis when the renal pelvis
was perfused with 0.25 ml per minute saline. Therefore, our
results appear to negate any functional relevance of the
muscarinergic receptors in the UUT of the conscious pig. The
reason why cholinergic receptor manipulation failed to show
any functional response is puzzling but the possibilities are
that other regulatory circuits are superimposed on cholinergic receptor function or cholinergic receptors are involved
in sensory rather than motor pathways. Although the drugs
in the concentrations used were effective on the heart and
glands, their local concentration in the UUT may also have
be too low to influence effectively its function.
Presumed clinical relevance. Anticholinergic (antimuscarinic) drugs are used in clinical urology to treat bladder
motor hyperreflexia and renal or ureteral colic. The mechanistic hypothesis underlying this therapy is that an antimuscarinic drug would decrease hypercontractility and spasms of
the bladder and ureter. Based on our experiments this spasmolytic effect does not exist. In confirmation to our knowledge no clinical evidence has ever been reported that the
continuous use of anticholinergic medication for a long period
for bladder hyperreflexia resulted in UUT dilation. However,
the observed co-localization of muscarinic receptors with calcitonin gene-related peptide positive nerves may suggest a
sensory function for muscarinic receptors.20 Therefore, anticholinergic agents may provide relief from the pain of ureteral or renal colic via this pathway. Nevertheless, we are
aware that species differences may have an important role in
any experimental animal model.
CONCLUSIONS
Ureteral peristalsis persisted in the initial hours after the
operation on the pyelocaliceal system. Normal function was
reestablished a week after manipulation. Recovery followed a
gradual and hierarchic pattern from proximal to distal.
At low diuresis rates peristaltic frequency was directly
related to the pyelocaliceal urine load. Although ureteral
contraction force was increased in the mid ureter when the
diuresis rate was increased, Pmax failed to increase in the
distal perivesical ureter.
Ureteral smooth muscle motor activity at the mid and
distal ureteral level was not modulated by muscarinic receptors in our chronically instrumented animal model. Therefore, the presumed spasmolytic effect of anticholinergic therapy for renal colic is not supported by our findings.
Dr. GEPM van Venrooij, Department of Urology, University Hospital Utrecht provided criticisms and suggestions,
and Dr. KH Kurth provided encouragement. Hardware and
software were developed in collaboration with the Department of Biophysics, University of Amsterdam and BIOSEMI,
The Netherlands.
267
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