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FULL PAPER Internal Medicine
The Effects of the Loop Diuretics Furosemide and Torasemide on Diuresis in Dogs
and Cats
Masami UECHI1), Mika MATSUOKA 1), Emi KUWAJIMA1), Tomonari KANEKO1), Kazushi YAMASHITA1),
Ushio FUKUSHIMA1) and Yumi ISHIKAWA1)
1)
Veterinary Teaching Hospital, Kitasato University 23–35–1 Higashi, Towada, Aomori 034–8628, Japan
(Received 29 January 2003/Accepted 16 June 2003)
ABSTRACT.
Torasemide is a new loop diuretic that combines the effects of furosemide and spironolactone. There are no reports on the
effects of torasemide in cats and dogs. This study compared the diuretic effects of furosemide and torasemide in cats and dogs. Cats
with pressure overload cardiac hypertrophy were given oral placebo, torasemide 0.3 mg/kg, or furosemide 1 mg/kg or 3 mg/kg. Con trol
and mitral regurgitation dogs were given oral placebo, torasemide 0.2 mg/kg, and furosemide 2 mg/kg for 7 days. Urine samples were
obtained at baseline and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hr after each drug dose. Urine volume and urine Na+ and K+ were measured.
Both furosemide and torasemide increased urine volume 1 hr after administration. Furosemide caused a dose-dependent increase in urine
volume that peaked at 2–3 hr in cats and dogs. The diuretic effect of furosemide disappeared 6 hr after administration, while that of
torasemide peaked 2–4 hr after administration and persisted for 12 hr in cats and dogs. In MR dogs, torasemide for 7 days signi ficantly
decreased urine potassium excretion. Plasma aldosterone increased with torasemide, whereas there was no change with furosemide. In
conclusion, about 1/10 concentration of torasemide was as potent as furosemide and had a longer diuretic effect in cats and dogs . These
data suggest that torasemide is useful for treating congestive heart failure or edema in cats and dogs.
KEY WORDS: diuretic agent, feline, heart failure, renal function, urine.
J. Vet. Med. Sci. 65(10): 1057–1061, 2003
Torasemide is a pyridyl sulfonylurea with a chemical
structure between those of loop diuretics and Cl- channel
blockers [5, 13, 20]. The main tubular site of action of
torasemide is the ascending limb of the loop of Henle, where
it interacts with the Na+, 2Cl–, K+ cotransporter localized in
the luminal surface [19, 20]. Torasemide and furosemide
cause a significant, dose-dependant increase in urine flow
and the urinary excretion of sodium and potassium [14].
Torasemide has more potent, longer-acting diuretic activity
than furosemide [3]. Congestive heart failure, which is
characteristically associated with fluid retention and shortness of breath, is a leading cause of morbidity and mortality.
Therefore, animals with congestive heart failure require
management with diuretics, such as thiazide, bumetanide,
and furosemide. Furosemide is the diuretic most frequently
given for edema. Although torasemide has beneficial
effects in chronic congestive heart failure in humans [8],
there are fewer clinical reports than on furosemide. In veterinary medicine, there are no reports on the dose or diuretic
effects of torasemide for dogs and cats. Therefore, this
study compared the diuretic effects of torasemide and furosemide in dogs and cats.
MATERIALS AND METHODS
This study followed the Guidelines for Institutional Laboratory Animal Care and Use of the School of Veterinary
Medicine and Animal Science at Kitasato University.
Cat study: This study used 8 clinically healthy domestic
short hair cats (4 males, 4 females, 3–5 years old), weighing
3.0–4.0 kg, in which routine laboratory tests, including
blood tests and urinalysis, were normal. The cats were
housed in cages and fed commercial feed twice daily (Hill's,
Colgate, Japan). Water was given ad libitum.
Iatrogenic pressure overload left ventricular cardiac
hypertrophy (LVH): Before surgery to induce experimental
LVH, all cats were tranquilized with butorphanol (0.1–0.2
mg/kg) and diazepam (5 mg/kg), anesthetized with ketamine (5–10 mg/kg) and isoflurane, and intubated. During
surgery, the cats were anesthetized with isoflurane (1.5–
2.0%) with 100% O2. Body temperature was measured with
an anal probe and maintained at 37–38°C with a heating
pad. The heart rate was also monitored.
The chest was opened at the fourth intercostal space
under sterile conditions. The pericardium was opened, and
the ascending aorta dissected. An aortic band was made
with 1 nylon suture, so that it produced a thrill at the
descending aorta. The chest was closed in layers and evacuated using standard procedures. The cats were placed on
an antibiotic regimen (ampicillin sodium) for 5 days postoperatively. Follow-up care included daily monitoring of the
heart rate, respiratory rate, and temperature. The heart and
lungs were auscultated daily. Serial chest X-rays were taken
in each cat to identify the onset of pulmonary venous congestion. One month after surgery, echocardiography was
performed to confirm LVH. The experiments were performed 6–9 months after inducing LVH.
LVH cats were given oral placebo, torasemide 0.3 mg/kg,
or furosemide 1 mg/kg or 3 mg/kg. The dosage of
torasemide was decided by preliminary study. Each drug
was given at randomly, and each administration interval was
for 2 weeks. Urine samples were obtained with a bladder
M. UECHI ET AL.
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Fig. 1. The diuretic effects of furosemide 1 mg/kg ( ), 3 mg/kg ( ), torasemide ( ), and placebo ( ) in cats (A).
The diuretic effects of furosemide 2 mg/kg ( ) and torasemide ( ), and placebo ( ) in dogs (B). * is p<0.05 comparing with placebo.
catheter (3 or 4 Fr), and water intake was measured at baseline and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hr after each drug dose.
The urine was centrifuged (1,500 g × 10 min), and the supernatant was used to measure Na+ and K+.
Dog study: This study used 10 clinically healthy mongrel
dogs of either sex, 1–2 years old, weighing 7–11 kg, in
which routine laboratory tests, including blood tests and urinalysis, were normal. The dogs were housed in cages and
fed commercial feed twice daily (Hill's, Colgate, Japan).
Water was given ad libitum.
Iatrogenic mitral regurgitation: Five dogs served as controls and five dogs underwent surgery to induce mitral
regurgitation (MR). The surgical procedure was as
described previously [15]. The dogs were placed on an antibiotic regimen (ampicillin sodium) for 5 days postoperatively. Follow-up care was as described in the cat study.
Control and MR dogs were given oral placebo, furosemide 2 mg/kg, or torasemide 0.2 mg/kg for 7 days. The
dosage of torasemide was decided by preliminary study.
Each drug was given at randomly, and each administration
interval was for two weeks. Urine samples were obtained
with a bladder catheter (4–8 Fr), and water intake was measured at baseline and 1, 2, 4, 6, 8, 12, and 24 hr after each
drug dose on 1 and 7 day administration. The urine was centrifuged (1,500 g × 10 min), and the supernatant was used to
measure Na+ and K+. Blood samples in EDTA were taken
from the saphenous vein before drug administration.
Plasma was analyzed for renin activity, angiotensin II, and
aldosterone by radioimmunoassay (RIA).
All the data are expressed as the mean ± SD. Analysis of
variance (ANOVA) was used to compare results, followed
by Tukey’s test. A value of p<0.05 was considered statistically significant.
RESULTS
Cat study: The echocardiography, X-ray, and clinical sign
were not changed during study. Both furosemide and
torasemide increased urine volume 1 hr after administration.
Furosemide caused a dose-dependent increase in urine volume, which peaked at 2 (1 mg/kg) or 3 (3 mg/kg) hr. The
diuretic effect of furosemide disappeared 6 hr after administration. The diuretic effect of torasemide peaked 4 hr after
administration and persisted for 12 hr (Fig. 1A). The 24-hr
urine volume with furosemide 3 mg/kg or torasemide 0.3
mg/kg was significantly greater than with placebo or furosemide 1 mg/kg (Fig. 2A). The 24-hr urinary sodium excretion with furosemide 3 mg/kg or torasemide 0.3 mg/kg was
significantly greater than with placebo or furosemide 1 mg/
kg (Fig. 3A). The 24-hr urinary potassium excretion with
torasemide 0.3 mg/kg was significantly greater than with
placebo, or furosemide 1 mg/kg or 3 mg/kg (Fig. 4A).
Dog study: The echocardiography, X-ray, and clinical
sign were not changed during study. Both furosemide and
torasemide increased urine volume 1 hr after administration.
The significant diuretic effect of furosemide disappeared 6
hr after administration. The diuretic effect of torasemide
peaked 2 hr after administration and lasted for 12 hr (Fig.
1B). The 24-hr urine volume with furosemide or torasemide
was significantly increased compared with placebo in control and MR dogs (Fig. 2B). The 24-hr urinary sodium
excretion did not differ for placebo and furosemide, in control, while it was increased with torasemide (Fig. 3B). The
24-hr urine sodium excretion with furosemide or torasemide
was significantly increased compared with placebo in MR
dogs. The 24-hr urinary potassium excretion with
torasemide in 7 day administration was significantly
decreased compared with 1 day administration in control
and MR dogs (Fig. 4B). The plasma renin activity in control
and MR dogs did not differ with placebo (1.9 ± 0.2 and 1.9
± 0.2 ng/ml·hr, respectively), furosemide (1.9 ± 0.3 and 1.8
± 0.2 ng/ml·hr), and torasemide (1.4 ± 0.3 and 1.7 ± 0.3 ng/
ml·hr). The plasma angiotensin II concentration in the control and MR dogs with torasemide (220 ± 172, p<0.05 and
268 ± 113 pg/ml, p<0.05, respectively) and furosemide (266
± 135 pg/ml, p<0.05) in MR dogs were significantly
EFFECTS OF FUROSEMIDE AND TORASEMIDE IN DOGS AND CATS
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Fig. 2. The diuretic effects of furosemide and torasemide for 24
hr in cats (A) and dogs (B). * is p<0.05. ** is p<0.01.
Fig. 3. Urine sodium (Na) excretion by furosemide and
torasemide for 24 hr in cats (A) and dogs (B). * is p<0.05. ** is
p<0.01.
increased compared with placebo (35 ± 32 and 41 ± 27 pg/
ml, both p<0.05) and furosemide in the controls (51 ± 53 pg/
ml). The plasma aldosterone concentration in control and
MR dogs with torasemide (95.9 ± 5.1 and 87.0 ± 6.1 pg/ml,
respectively) was significantly increased compared with
placebo (75.7 ± 4.8 and 74.9 ± 7.8 pg/ml) and furosemide
(78.5 ± 5.0 and 76.3 ± 6.6 pg/ml) (Fig. 5).
ability (>80%) and a rapid rate of absorption in patients with
chronic renal failure or cirrhosis [7, 9, 11], whereas that of
furosemide is diminished in both cirrhosis [4] and congestive heart failure [1, 16, 17]. Since torasemide revealed long
diuretic action comparing furosemide in cats and dogs,
torasemide is able to decrease administration time and
increasing quality of life in treating severe congestive heart
failure in cats and dogs.
The urinary excretion rate of furosemide is very high
after intravenous administration and decreases rapidly in
dogs [12]. In contrast, the urinary excretion rate of
torasemide is much lower, and decreases gradually [12].
The plasma concentration of torasemide also decreases
more slowly. The slower transfer rate from plasma to the
nephron leads to the longer-lasting diuretic action of
torasemide compared with furosemide [12]. In both cats
and dogs, a diuretic effect was observed 12 hr after the
administration of torasemide, whereas the effect of furosemide diminished at 5~6 hr. These pharmacological properties of torasemide may be beneficial, not only in
congestive heart failure, but also in other forms of edema in
cats and dogs.
Torasemide has a diuretic profile similar to the combina-
DISCUSSION
In this study, although cardiac hypertrophy and left atrial
and ventricular enlargement were confirmed by echocardiography in all the cats and dogs, none of the animals showed
clinical signs. Since the animals were category II in the
New York Heart Association (NYHA) classification [2], it
may not have been appropriate to give diuretic agents at this
stage. Nevertheless, this is the first report comparing the
diuretic effects of furosemide and torasemide in cats and
dogs, and our data indicate that torasemide has a diuretic
effect equivalent to 1/10 of the dose of furosemide. This is
important for the clinical use of torasemide in cats and dogs.
Torasemide is effective in patients with edema caused by
congestive heart failure [8]. Torasemide has high bioavail-
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M. UECHI ET AL.
Fig. 5. Plasma renin activity (upper), plasma angiotensin II concentration (middle), Plasma aldosterone concentration (bottom)
in control and MR dogs. * is p<0.05.
Fig. 4. Urine potassium (K) excretion by furosemide and
torasemide for 24 hr in cats (A) and dogs (B). * is p<0.05. ** is
p<0.01.
tion of a diuretic and a potassium-sparing drug [13]. In
combination therapy, spironolactone depresses the
enhanced potassium excretion caused by furosemide or
trichlormethiazide in a dose-dependent manner [13]. The
potassium loss with torasemide is lower than with furosemide, despite similar aquaresis and natriuresis [5, 14].
Torasemide causes significant, dose-dependent inhibition of
the amount of receptor-bound aldosterone, whereas furosemide has no effect on aldosterone receptors [14]. This
may explain the decreased urinary potassium with
torasemide. In addition, torasemide inhibits aldosterone
secretion from adrenal cells in vitro [6]. In the cat study,
aquaresis, natriuresis, and kaliuresis were similar with
torasemide and furosemide, while in the control dogs, less
kaliuresis was observed compared with placebo. A decrease
in urinary potassium with torasemide may require administration for several days, because kaliuresis with a single
torasemide dose did not differ from placebo in cats or dogs,
whereas kaliuresis was not observed after administration for
7 days in control and MR dogs.
Furosemide increased plasma angiotensin II in MR dogs,
but there was no change in control dogs. Since no edema
was seen in the MR dogs, the diuresis caused by furosemide
may reduce the circulatory blood volume and renal blood
flow, stimulating the renin-angiotensin system [15]. This
suggests that the use of diuretics should depend on the
degree of edema and they should be used in combination
with angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Torasemide increased both plasma
angiotensin II and aldosterone. The increase in angiotensin
II is due to decreased circulatory blood volume, as with
furosemide, while the increased in aldosterone might occur
because torasemide prevents circulatory aldosterone from
binding to its receptor, just as receptor blockers and enzyme
inhibitors increase the receptor agonist or substrate [10, 18].
In conclusion, the diuretic effects of torasemide were
about 10 times greater at same dose and longer lasting than
those of furosemide in cats and dogs. Torasemide administration for several days makes the decrease of urine potassium. These results suggest that torasemide is useful for
treating congestive heart failure and edema in cats and dogs.
ACKNOWLEDGMENT. This study was supported in part
by a Grant-in-Aid for General Scientific Research (C12833009) from the Japanese Ministry of Education, Science and Culture.
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