Sudden bladder distention in a female rat abdominal distention

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					                                                                                                              WHAT’S YOUR DIAGNOSIS
Thomas M. Donnelly, DVM, Column Editor

Sudden bladder distention in a female rat
Genaro A. Coria-Avila, DVM, MSc, Erica Barbosa-Vargas, BA & James G. Pfaus, PhD

We purchased a batch of 48 female Long-
Evans rats, weighing 200–250 g, from an
accredited animal supplier for studies on
sexual behavior. The animals lived in groups
of four in large wire-mesh cages in a colony
room maintained on a reversed 12:12 h light/
dark cycle at approximately 21º ± 2º C. The
rats had ad libitum access to commercial rat
feed and water.
   We anesthetized the females with a mix-
ture of ketamine (50 mg/ml) and xylazine (4
mg/ml), mixed at a ratio of 4:3 respectively,
and injected intraperitoneally in a volume
of 1 ml/kg of body weight. The anesthetized
                                                                                                               FIGURE 2 | Conical tube containing 17 ml of
females then underwent bilateral ovariec-
                                                       FIGURE 1 | Exposed abdominal cavity of a 200–           urine taken from the urinary bladder of the rat
tomy via a lumbar incision. We allowed the                                                                     in Figure 1. Notice the white sediment at the
                                                       250 g female Long-Evans rat with severe urinary
animals one week of post surgical recov-               bladder distention.                                     bottom of the tube. Its presence is abnormal.
ery before copulatory trials, after which we
induced sexual receptivity by subcutaneous
injections of estradiol benzoate (10 µg) 48            iner did not detect any abnormal vaginal                then returned the animal to its home cage.
hours and progesterone (500 µg) 4 hours                secretions, but he did notice a foul odor.              Two days later the same clinical signs were
before each test. All females underwent this           Once the plug was removed, the examiner                 present (i.e., extreme bladder distention and
hormonal treatment every four days during              voided the bladder very gently. He gave the             dehydration) but this time the examiner did
10 copulatory sessions.                                rat saline subcutaneously to hydrate it and             not find a vaginal plug
   Due to the hormonal injection schedule,                                                                       After a tentative diagnosis, we decided to
we handled and checked all animals every                                                                       euthanize the rat with an overdose of sodium
two days. After nine copulatory sessions,                                                                      pentobarbital. The gross necropsy revealed a
we noticed one rat with an enlarged abdo-
men, which we determined to be caused by
severe bladder distention. This condition
was not present two days before. On clini-
cal examination, the rat was dehydrated, but
we found no abnormalities in gait, postural
reactions, or spinal reflexes. External exami-
nation of the vagina did not reveal abnormal
secretions either. Very gently, the examiner
tried to void the bladder by compressing the
anterior border, but it was not successful.
Then, on closer examination of the vagina,
the examiner found a tightly fitted sperm                                                                      FIGURE 4 | Photomicrograph (40X) of unstained
plug. He used a rat restrainer to hold the rat         FIGURE 3 | Detail of the abdominal organs of            urine sediment from Figure 2. Notice the small
still and upside down and gently removed               the rat in Figure 1. Notice the distended ureter        rounded crystals with pointed protuberances. We
the plug with surgical tweezers. The exam-             pointed to by the tip of tweezers.                      considered the crystals to be ammonium urate.

Center for Studies in Behavioral Neurobiology, Psychology Department, Concordia University, Montreal, Quebec, Canada. Correspondence should be addressed to
G.A.C. (

LAB ANIMAL                                                                                                                Volume 34, No. 6 | JUNE 2005           1

clean vagina with no inflammatory signs.        urine (Fig. 3). We stored samples of urine and    ammonium urate. They appeared as round-
The uterus was not affected and no secre-       the vaginal plug in a 4˚C refrigerator. We used   ed crystals with pointed protuberances along
tions were detected. The remarkable sign        a pH meter strip to measure the acidity of the    the surface.
was a greatly distended bladder (Fig. 1) with   urine, which indicated an abnormal pH of 6.5        Based on the clinical signs and necropsy,
approximately 17 ml of clear urine that con-    (normal pH is 7.3–8.5). Microscopic exami-        what do you consider is the cause of the rat’s
tained abundant white sand-like sediments       nation of the vaginal plug was unremarkable,      condition? How frequent is this problem?
and small traces of blood (Fig. 2). Kidneys     but microscopic examination (40X) of the
were normal, but the ureters and renal pelvis   urine sediments (Fig. 4) indicated the pres-
of both kidneys were highly distended with      ence of crystals resembling mainly those of       What’s your diagnosis?

2   Volume 34, No. 6 | JUNE 2005                                                                                 
                                                                                                    WHAT’S YOUR DIAGNOSIS

Diagnosis | Urolithiasis
The rat had urolithiasis, or bladder stones,         The second possibility is that a urinary       crystal deposition. However, Matsushita20
that obstructed the urethra, preventing           tract infection contributed to urolithia-         found the administration of 1 mg estradiol
urination. Urolithiasis is a heterogeneous        sis formation. Urinary tract infection is         every other week for 12 weeks to female
disorder, with varying chemical composi-          a known risk factor in spontaneously              rats resulted in a 50% incidence of stru-
tion and pathophysiologic background1.            occurring urolithiasis in cats, dogs, rab-        vite bladder stones. Matsushita suggested
Multiple predisposing factors may also            bits, and guinea pigs, and in experimen-          there was a predisposition to urinary tract
initiate urolithiasis 1. In humans, calculi       tally induced urolithiasis in rats12–15. If the   infection due to metaplasia of the transi-
develop from a variety of metabolic or            female rat received a sperm plug that was         tional bladder epithelium by estrogen to
environmental disturbances, including             not properly dislodged from the vagina,           a stratified or pseudostratified columnar
varying forms of hypercalciuria, hypoci-          it could become a focus of infection and          epithelium20. Enterobacteria, staphylococ-
traturia, undue urinary acidity, hyper-           this may have contributed to formation            cus, and streptococcus were identified as
uricosuria, hyperoxaluria, infection with         of urolithiasis. During the procedure of          infecting organisms.
urease-producing organisms, and cystin-           vaginal plug removal, the rat was also held          Acute urolithiasis and urethral obstruc-
uria. While spontaneous urinary calculi           still with the pelvic area directed upwards,      tion in rats can be accompanied by difficul-
are common in dogs, cats, rabbits and             which we assumed helped remove the                ty in urinating or complete absence of uri-
guinea pigs, they are rare in rats. Diet and      bladder stones from the urethral sphincter        nation, with bladder distention, foul odor,
the predisposition of certain inbred strains      and facilitate manual voiding. Sediments          and some behavioral signs, like constant
(e.g., DA and ACI strains) are associated         may have blocked the exit immediately             licking of the anogenital area. Complete
with spontaneous urolithiasis in rats2–6.         after, since two days later the bladder was       bladder obstruction can cause uremia, lead-
Experimentally, unusual dietary supple-           distended again.                                  ing to depression, anorexia, dehydration,
ments, a large number of chemicals, and              Urolithiasis in rats has also been report-     and sometimes coma and death.
inherited metabolic defects in inbred             ed to be induced by autologous or homol-             The spontaneous formation of blad-
strains (e.g., genetic hypercalciuric stone-      ogous sperm experimentally deposited in           der stones in domestic animals appears to
forming (GHS) rat7) are associated with           the bladder neck of males6. We considered         be associated with hypercalciuria, urine
urolithiasis in rats8–10.                         that following several ejaculations, some         retention, and bladder infection. Calculi
   We considered two possible mechanisms          sperm might have reached the bladder, ini-        do not appear to form unless the concen-
to explain the unusual clinical presenta-         tiating the formation of stones.                  tration of urine components is sufficiently
tion in this rat. The first possibility is that      Researchers have observed a signifi-           high. Additionally, the transit of crystals
the bladder distention was caused by an           cant negative correlation between urinary         within the urinary tract has to be slowed
acute obstruction of the bladder exit, due        oxalate and plasma estradiol/testosterone         down and urine pH modified to facilitate
to a physical barrier made up of sand-like        ratio16–19. In one study, estradiol-implant-      stone formation1.
bladder stones that precipitated by gravity.      ed rats, whether male or female, intact
This event prevented micturition, which           or castrated, developed kidney crystal            1.   Kahn, C.M. & Line, S. in The Merck Veterinary
usually helps to rinse out the vagina after       deposits18. Yet in the same study, testos-             Manual (Online book). (2003). http://
copulation, including those remnants of           terone-implanted rats had a 43–88% rate      
copulatory plugs not dislodged by male            of kidney calcium oxalate crystal deposi-         2.   Klurfeld, D.M. Kidney and bladder stones in
intromissions11. This explanation suggests        tion. These results indicate that androgens            rodents fed purified diets. J. Nutr. 132(12),
that the copulatory plug found in the vagi-       increase and estrogens decrease urinary                3784 (2002).
                                                                                                    3.   Kuhlmann, E.T. & Longnecker, D.S. Urinary
na of the rat was secondary to obstructive        oxalate excretion, plasma oxalate con-                 calculi in Lewis and Wistar rats. Lab. Anim. Sci.
urolithiasis.                                     centration, and kidney calcium oxalate                 34(3), 299–302 (1984).
                                                                                                    4.   Kunstyr, I., Naumann, S. & Werner, S. Urinary
                                                                                                         bladder stones in some inbred and hybrid
  LAB ANIMAL welcomes reader contributions to “What’s Your Diagnosis” in case history/                   strains of “SPF” rats. Z. Versuchstierkd. 23(3),
                                                                                                         181 (1981).
  diagnosis format. Submissions should include two to five illustrations or photos. Please          5.   Kunstyr, I., Naumann, S. & Werner, J.
  email manuscripts to Selections are made on the basis of                        Urolithiasis in female inbred SPF rats. Possible
  relevance and interest to readers. Please refer to the Guide to Authors for information                predisposition of DA and ACI strains. Z.
  on submission of digital figures.                                                                      Versuchstierkd. 24(4), 214–218 (1982).
                                                                                                    6.   Paterson, M. Urolithiasis in the Sprague-
                                                                                                         Dawley rat. Lab. Anim. 13(1), 17–20 (1979).

LAB ANIMAL                                                                                                     Volume 34, No. 6 | JUNE 2005             3

7.    Bushinsky, D.A. Genetic hypercalciuric stone-
      forming rats. Curr. Opin. Nephrol. Hypertens.
      8(4), 479–488 (1999).
8.    Khan, S.R. & Hackett, R.L. Calcium oxalate
      urolithiasis in the rat: is it a model for human
      stone disease? A review of recent literature.
      Scan. Electron Microsc. Pt 2,: 759–774 (1985).
9.    Linnemann, U., Kuch, P. & Schwille, P.O.
      Ammonium urate urolithiasis in the rat with
      portocaval shunt--some aspects of mineral
      metabolism and urine composition. Urol. Res.
      14(6), 319–322 (1986).
10.   Khan, S.R. Animal models of kidney stone
      formation: an analysis. World J. Urol. 15(4),
      236–243 (1997).
11.   Wallach, S.J. & Hart, B.L. The role of the
      striated penile muscles of the male rat in
      seminal plug dislodgement and deposition.
      Physiol. Behav. 31(6), 815–821 (1983).
12.   Ruutu, M. & Lehtonen, T. Urinary tract
      complications in spinal cord injury patients.
      Ann. Chir. Gynaecol. 73(6), 325–330 (1984).
13.   Morrisey, J.K. Urinary tract disorders in rabbits
      and guinea pigs. Exotic Pet Pract. 2(1), 1–2
14.   Osborne, C.A. & Lulich, J.P. Risk and protective
      factors for urolithiasis. What do they mean?
      Vet. Clin. North Am. Small Anim. Pract. 29(1),
      39–43 (1999).
15.   Linsenmeyer, T.A. & Ottenweller, J. Bladder
      stones following SCI in the Sprague-Dawley
      rat. J. Spinal Cord Med. 26(1), 65–68 (2003).
16.   Lee, Y.H. et al. Determinant role of
      testosterone in the pathogenesis of urolithiasis
      in rats. J. Urol. 147(4), 1134–1138 (1992).
17.   Terada, S., Suzuki, N., Uchide, K., Akasofu,
      K. & Nishida, E. Effect of testosterone on the
      development of bladder tumors and calculi in
      female rats. Gyneco. Obstet. Invest. 34(2),
      105–110 (1992).
18.   Fan, J., Chandhoke, P.S. & Grampsas, S.A.
      Role of sex hormones in experimental calcium
      oxalate nephrolithiasis. J. Am. Soc. Nephrol.
      10 (Suppl 14), S376–S380 (1999).
19.   Iguchi, M., Takamura, C., Umekawa, T., Kurita,
      T. & Kohri, K. Inhibitory effects of female sex
      hormones on urinary stone formation in rats.
      Kidney Int. 56(2), 479–485 (1999).
20.   Matsushita, K. Effect of estrogen on the
      formation of struvite calculi in female rats.
      Urol. Int. 39(5), 303–307 (1984).

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