The Veterinary Journal 202 (2014) 573–577

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The Veterinary Journal

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t v j l

The influence of enalapril and spironolactone on electrolyte

concentrations in Doberman pinschers with dilated cardiomyopathy
J.D. Thomason a,*, G. Rapoport b, T. Fallaw b, C.A. Calvert b
a Department of Veterinary Clinical Sciences, Veterinary Health Center, Kansas State University, 1800 Dension Ave., Manhattan, KS 66506, USA
b Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, 501 DW Brooks Dr., Athens, GA 30602, USA

A R T I C L E I N F O A B S T R A C T

Article history: The combination of an angiotensin-converting enzyme inhibitor (ACEI) with an aldosterone receptor an-
Accepted 5 September 2014 tagonist can increase serum potassium and magnesium and lower serum sodium concentrations. The
objective of this study was to retrospectively determine whether an ACEI and spironolactone can be co-
Keywords: administered to Doberman pinschers with occult dilated cardiomyopathy without serious adverse influences
Enalapril on serum electrolyte concentrations. Between 2001 and 2007, 26 client-owned Doberman pinschers were
Magnesium
given enalapril, spironolactone, and carvedilol and followed for at least 6 months. Most dogs had been
Potassium
prescribed mexiletine for ventricular tachyarrhythmia suppression. Dogs were treated with pimobendan
Cardiomyopathy
Spironolactone when congestive heart failure was imminent. Baseline and follow-up (3–10 visits) color-flow Doppler
Dog echocardiograms, serum urea nitrogen (SUN), creatinine, sodium, potassium, and magnesium concen-
tration data were tabulated.
Compared to baseline data, there were no significant changes in serum sodium or serum creatinine
concentrations. Serum magnesium (P = 0.003), serum potassium (P = 0.0001), and SUN (P = 0.0001) con-
centrations increased significantly with time. Although the combination of ACEI and spironolactone was
associated with significant increases in magnesium, potassium, and SUN concentrations, these changes
were of no apparent clinical relevance. At the dosages used in this study, this combination of drugs
appears safe.
© 2014 Elsevier Ltd. All rights reserved.

Introduction patients with CHF. The influence of beta-blockers or spironolac-

Dilated cardiomyopathy is a common problem in Doberman pin-
schers (Calvert et al., 1982, 1997a, 1997b, 2000a, 2000b; Calvert and
Brown, 1986; Smucker et al., 1990). In Doberman pinschers, there
is a long subclinical or preclinical phase, the so-called occult phase,
of disease progression which can be terminated by either sudden
arrhythmic death (SAD) or congestive heart failure (CHF) (Calvert
et al., 1982, 1997a, 1997b, 2000a, 2000b; Calvert and Brown, 1986;
Smucker et al., 1990).
Drugs that have been demonstrated to exert a favorable influ-
ence on disease progression in humans with dilated cardiomyopathy
include angiotensin converting enzyme inhibitors (ACEIs), spirono-
lactone, and beta-adrenergic receptor blocking drugs (CONSENSUS
Trial Study Group, 1987; SOLVD Investigators, 1992; Dahlström and
Karlsson, 1993; RALES Investigators, 1996). In dogs, ACEIs have been
shown to improve hemodynamic and quality of life indices (COVE
Study Group, 1995; IMPROVE Study Group, 1995; Kitagawa et al.,
1997; Ettinger et al., 1998). These studies mostly pertained to
* Corresponding author. Tel.: +1 785 5325690.
E-mail address: jthomason11@vet.k-state.edu (J.D. Thomason).
tone on progression of CHF caused by dilated cardiomyopathy in
dogs has not been reported. Recently, a retrospective study dem-
onstrated that ACEIs may exert a positive influence on disease
progression in Doberman pinschers with occult dilated cardiomy-
opathy (O’Grady et al., 2009).
There have been reports in humans of hyperkalemia, some-
times severe, associated with the co-administration of an ACEI and
spironolactone (Barr et al., 1995; Berry and McMurray, 2001;
Schepkens et al., 2001). For this reason, it has been recommended
that these classes of drugs are not combined or only with caution
and at low dosages (Greenblatt and Koch-Weser, 1973; Papich, 1995;
Berry and McMurray, 2001; Schepkens et al., 2001). Although the
safe administration of an ACEI and spironolactone has been re-
ported in small dogs with myxomatous valvular disease without CHF,
dogs with dilated cardiomyopathy are a unique cohort because of
the greater potential of impaired kidney function through renal ar-
terial underfilling and reduced renal blood flow secondary to low
cardiac output via systolic dysfunction and/or arrhythmia (Desai et al.,
2007; Thomason et al., 2007; Konstam et al., 2009). In humans, block-
ade of the renin–angiotensin–aldosterone system may induce
worsening of renal function and more likely result in hyperkale-
mia in patients with reduced ejection fraction (Desai et al., 2007;
Konstam et al., 2009).

http://dx.doi.org/10.1016/j.tvjl.2014.09.004
1090-0233/© 2014 Elsevier Ltd. All rights reserved.
574 J.D. Thomason et al./The Veterinary Journal 202 (2014) 573–577

The purpose of this retrospective paper was to report the influ-

ence of the combination of enalapril and spironolactone on serum
electrolyte concentrations administered to Doberman pinschers with
occult dilated cardiomyopathy. Our hypothesis was that an ACEI and
spironolactone can be co-administered to Doberman pinschers with
occult dilated cardiomyopathy without serious adverse influences
on serum electrolyte concentrations.

Materials and methods

Animals
The study population was comprised of 26 client-owned, previously untreated
Doberman pinschers in which we diagnosed occult dilated cardiomyopathy by
echocardiography and 24 h Holter recording between June of 2001 and December
of 2007. The study dogs were presented for cardiomyopathy diagnostic screening
tests. To that end, a color-flow Doppler echocardiogram and a 24 h Holter record-
ing were performed on each dog at the first examination.
To be included in the study, each dog must have had an abnormal echocardiogram
consistent with dilated cardiomyopathy (Calvert et al., 2000a, 2000b), >300 ven-
tricular premature contractions (VPC) on 24 h Holter recording, and at least three
follow-up examinations encompassing at least 6 months. Baseline and multiple follow-
up samples were collected from each dog and tabulated. These samples included
measurements of serum urea nitrogen (SUN), creatinine, potassium, magnesium, and
sodium concentrations (Hitachi Serum Chemistry Analyzer; Roche Diagnostics).
Follow-up visit samples were collected at approximately 1–5 month intervals.
Each dog was administered (1) spironolactone (Aldactone, GD Searle) at a dosage
of 50 mg orally (PO) twice daily, (2) enalapril (Vasotec, Merck) at a dosage of 10 mg
PO twice daily for 1 week and then a maintenance dosage of 20 mg PO twice daily,
and (3) carvedilol (Coreg, SmithKline Beecham) at a dosage of 12.5 mg PO twice daily
for 1 week and then increased to 25 mg PO twice daily. After 1 or 2 additional weeks,
the dosage of carvedilol was increased to 37.5 mg PO twice daily for dogs weigh-
ing >35 kg. The dosages chosen were a product of dog and tablet sizes.
At the time of the study initiation, eight dogs were also administered mexiletine
(Mexiletine, Boehringer Manheim Therapeutics) and mexiletine was later added to
the treatment of 14 dogs. Mexiletine was administered when either rapid (>200 beats/
min; bpm) ventricular tachycardia was detected or when >6000 ventricular premature
complexes (VPC) per 24 h with couplets or triplets of VPC were detected by Holter
recording. Mexiletine was given at either 150 mg (n = 5) or 200 mg (n = 17) PO three
times daily.
At the time of initiation of the study, no dog was administered pimobendan
(Vetmedin, Boehringer Manheim Therapeutics) but this was added later in some dogs
where CHF was considered imminent i.e. when a gallop heart sound was auscul-
tated, if nocturnal dyspnea was reported by the owner, and/or when echocardiographic
data consistent with severe myocardial failure were present. Such echocardiographic
data included left ventricular end-diastolic dimension >55 mm, fractional shorten-
ing <18% and E-point septal separation (EPSS) >15 mm. No further data were collected
once furosemide was added to the treatment regimen.
Statistical methods
A repeated measures model that recognized multiple observations as belong-
ing to the same dog was used to analyze SUN, serum creatinine, and serum electrolyte
concentrations for changes over the follow-up period. Follow-up time (in weeks)
and weight were included in the model as continuous variables. An unstructured
covariance structure was used. All hypothesis tests were two-sided and the signif-
icance level was P = 0.05. The analysis was performed using PROC MIXED in SAS v.9.1.
Fig. 1. Box and whiskers plot of the serum sodium concentrations in dogs at base-
line (time 0 week; 26 dogs) and at follow-up (26 dogs) after the administration of
an angiotensin-converting enzyme inhibitor (ACEI) and spironolactone. The bold line
indicates the median. The boxes contain the 25–75th percentiles. The whiskers rep-
resent the 5th and 95th percentiles with lines below and above representing the
0–5th and 95–100th percentiles, respectively. There was no significant (P < 0.05) dif-
ference between baseline and follow-up serum sodium concentrations. Mean follow-
up visit interval (±SD, range), 12 weeks (3.2, 8–20); mean follow-up visit number,
4.5 (1.8, 3–10).
magnesium 1.6–2.4 mg/dL, and sodium 146–154 mmol/L. Base-
line renal and electrolytes were as follows: (1) median (range) SUN
14 mg/dL (9–32); (2) mean serum creatinine 0.8 mg/dL (0.6–1.3);
(3) median serum potassium concentration 5.1 mmol/L (4.4–6.2);
(4) median serum magnesium concentration 2.1 mg/dL (1.9–2.6);
and (5) median serum sodium concentration 148 mmol/L
(138–152).
Follow-up visit samples were obtained at a mean (±SD, range)
of 12 week intervals (3.2, 8–20). The mean number of follow-up visits
was 4.5 (1.8, 3–10).
There were no significant changes found in serum sodium
(P = 0.91) or serum creatinine (P = 0.68) concentrations (Figs. 1 and
2). Serum magnesium (P = 0.003), serum potassium (P = 0.0001), and
SUN (P = 0.0001) concentrations increased significantly with time
(Figs. 3, 4, and 5). On at least one occasion, post-treatment SUN, po-
tassium, and magnesium concentrations were above the reference
ranges in 3 (12%), 13 (50%), and 4 (15%) dogs, respectively.
Discussion
The combination of enalapril and spironolactone at the dosages
administered in Doberman pinschers with normal or nearly normal
baseline serum creatinine and SUN was associated with signifi-
cant increases in serum magnesium, serum potassium and SUN over
time. This is not surprising considering that these drugs can
individually alter serum electrolyte concentrations in this manner.

Results

At the time of entry into the study, the mean (±SD, range) age
of the dogs was 7.5 years (2.3, 5–12). There were 17 males and 9
females. The mean weight of the dogs was 36 kg (7.3, 28–45).
At the time of entry into the study, the mean (±SD, range) left
ventricular end-diastolic dimension was 52 mm (2.8, 50–58), the
mean left ventricular end-systolic dimension was 42 mm (2.5,
40–49), the mean left ventricular fractional shortening was 22% (2.2,
Fig. 2. Box and whiskers plot of the creatinine concentrations in dogs at baseline
19–25), and the mean EPSS was 11.8 mm (1.7, 10–14). (time 0 week; 26 dogs) and at follow-up (26 dogs) after the administration of an
The mean (±SD, range) dosages were for spironolactone 1.4 mg/ angiotensin-converting enzyme inhibitor (ACEI) and spironolactone. The bold line
kg twice daily (0.2, 1.1–1.6); for enalapril 0.56 mg/kg twice daily (0.1, indicates the median. The boxes contain the 25–75th percentiles. The whiskers rep-
0.49–0.65); for carvedilol 0.89 mg/kg twice daily (0.1, 0.76–1.01); resent the 5th and 95th percentiles with lines below and above representing the
0–5th and 95–100th percentiles, respectively. There was no significant (P < 0.05) dif-
and for mexiletine 5.2 mg/kg three times daily (0.28, 4.3–6.1). ference between baseline and follow-up serum creatinine concentrations. Mean
The normal reference ranges for renal values and electrolytes were follow-up visit interval (±SD, range), 12 weeks (3.2, 8–20); mean follow-up visit
SUN <31 mg/dL, creatinine <1.7 mg/dL, potassium 3.9–5.0 mmol/L, number, 4.5 (1.8, 3–10).
 J.D. Thomason et al./The Veterinary Journal 202 (2014) 573–577
Fig. 3. Box and whiskers plot of the serum potassium concentrations in dogs at base-
line (time 0 week; 26 dogs) and at follow-up (26 dogs) after the administration of
an angiotensin-converting enzyme inhibitor (ACEI) and spironolactone. The bold line
indicates the median. The boxes contain the 25–75th percentiles. The whiskers rep-
resent the 5th and 95th percentiles with lines below and above representing the
0–5th and 95–100th percentiles, respectively. *, significant difference (P < 0.05) from
baseline. Mean follow-up visit interval (±SD, range), 12 weeks (3.2, 8–20); mean follow-
up visit number, 4.5 (1.8, 3–10).
However, the degree of changes was usually small and was most
likely clinically insignificant.
In humans, there has been a tremendous increase in the inci-
dence of kidney dysfunction associated with treatment with ACEIs,
beta-blockers, and diuretics to reverse congestion in patients with
fluid overload, the so-called cardiorenal syndrome (Nohria et al.,
2003). The cardiorenal syndrome is defined as ‘a pathophysiologi-
cal disorder of the heart and kidney in which acute or chronic
dysfunction in one organ may induce acute or chronic dysfunction of
Fig. 4. Box and whiskers plot of the serum magnesium concentrations in dogs at
baseline (time 0 week; 26 dogs) and at follow-up (26 dogs) after the administra-
tion of an angiotensin-converting enzyme inhibitor (ACEI) and spironolactone. The
bold line indicates the median. The boxes contain the 25–75th percentiles. The whis-
kers represent the 5th and 95th percentiles with lines below and above representing
the 0–5th and 95–100th percentiles, respectively. *, significant difference (P < 0.05)
from baseline. Mean follow-up visit interval (±SD, range), 12 weeks (3.2, 8–20); mean
follow-up visit number, 4.5 (1.8, 3–10).
Fig. 5. Box and whiskers plot of the serum urea nitrogen concentrations in dogs at
baseline (time 0 week; 26 dogs) and at follow-up (26 dogs) after the administra-
tion of an angiotensin-converting enzyme inhibitor (ACEI) and spironolactone. The
bold line indicates the median. The boxes contain the 25–75th percentiles. The whis-
kers represent the 5th and 95th percentiles with lines below and above representing
the 0–5th and 95–100th percentiles, respectively. *, significant difference (P < 0.05)
from baseline. Mean follow-up visit interval (±SD, range), 12 weeks (3.2, 8–20); mean
follow-up visit number, 4.5 (1.8, 3–10).
575
the other organ’ (Ronco et al., 2008). The pathophysiology of car-
diorenal syndrome is not completely understood. Decline in cardiac
function causing a decrease in renal perfusion likely contributes to
some aspects of the cardiorenal syndrome (Nohria et al., 2003). In
humans, blockade of the renin–angiotensin–aldosterone system may
induce worsening of renal function and is more likely to cause hy-
perkalemia in patients with reduced ejection fraction (Desai et al.,
2007; Konstam et al., 2009).
Although the safe administration of ACEIs and spironolactone
has been reported in small dogs with myxomatous valvular disease
without CHF, dogs with dilated cardiomyopathy are a unique cohort
because of the greater potential of impaired kidney function through
renal arterial underfilling and reduced renal blood flow secondary
to low cardiac output via systolic dysfunction and/or arrhythmia
(Desai et al., 2007; Thomason et al., 2007; Konstam et al., 2009).
The cause of the significant increase in SUN over the study period
was not determined for the dogs in this report. Azotemia was mild
and may have been the result of a number of factors (including
enalapril and spironolactone administration); an adverse influ-
ence on renal function caused by progressive myocardial failure and/
or worsening arrhythmia may also have contributed. Furthermore,
we cannot rule out mild dehydration in some dogs as contribut-
ing to the azotemia.
The combined administration of an ACEI and spironolactone has
been shown to exert a favorable influence on survival in humans
with dilated cardiomyopathy and CHF (Zannad, 1993; RALES
Investigators, 1996; Pitt et al., 1999; Weber, 1999; Farquharson and
Struthers, 2000). Spironolactone’s influence in this regard may be
exerted by favorable effects on vascular remodeling, endothelial func-
tion, ventricular hypertrophy and fibrosis (RALES Investigators, 1996;
Lijnen and Petrov, 2000). ACEI may exert a favorable influence on
the survival of Doberman pinschers with occult dilated cardiomy-
opathy (O’Grady et al., 2009). The influence of spironolactone on
survival in the present cohort was not evaluated.
The administration of a beta-adrenoreceptor blocking drug, such
as carvedilol, has been shown to exert a favorable influence on
disease progression in humans with dilated cardiomyopathy and
CHF (Packer et al., 1996, 2001; Poole-Wilson et al., 2003). We chose
to administer carvedilol to Doberman pinschers with occult dilated
cardiomyopathy based on these studies. The influence, if any, of
carvedilol on disease progression in Doberman pinschers with occult
cardiomyopathy has not been reported. Beta-adrenoreceptor block-
ers, via β-2 receptor blockade, have also been advocated in the
treatment hypokalemia associated with thyrotoxic periodic paral-
ysis in humans to counteract the adrenergic stimulation of the Na–K
ATPase pump (Barnabé, 2005). In addition, carvedilol has been dem-
onstrated to suppress aldosterone production in heart failure patients
receiving ACEI therapy. Therefore, in theory, nonselective beta-
adrenergic blockers could result in hyperkalemia especially with
exercise and when combined with an ACEI and spironolactone
(Aggarwal et al., 2006; Saito et al., 2006).
Mexiletine was administered to those Doberman pinschers that
had severe ventricular tachyarrhythmias. There were no laborato-
ry interactions identified in the literature associated with mexiletine
administration.
Pimobendan is recommended for use in dogs with preclinical
dilated cardiomyopathy and in dogs with dilated cardiomyopathy
and overt CHF (Luis Fuentes et al., 2002; O’Grady et al., 2008;
PROTECT STUDY, 2012). Pimobendan was administered to dogs in
this study only when it appeared that overt CHF was imminent. A
previous study noted small, but significant reductions in baseline
and follow-up creatinine and potassium concentrations in dogs that
had been given pimobendan (Fusellier et al., 2008). Although the
follow-up creatinine and potassium concentrations were within
the reference range, Fusellier et al. (2008) concluded that the
changes were normal variation. The effect of pimobendan on the
576 J.D. Thomason et al./The Veterinary Journal 202 (2014) 573–577
creatinine and potassium concentrations of the patients in our study
is unknown.
Our study is limited by the small number of dogs, the fact that
a single breed of dog was studied, the different medication dosages
used in this study compared to others (Bernay et al., 2010; Guyonnet
et al., 2010; Gordon et al., 2012), and its retrospective nature. Given
that we investigated a small number of Doberman pinschers, ex-
trapolation of our results to other breeds with dilated cardio-
myopathy should be exercised with caution. In addition, given that
no additional data were collected for patients once furosemide was
added to the treatment regimen, we may have selected for a more
stable group of patients. The potential for more serious electro-
lyte imbalances could occur in more severe disease. However, once
furosemide was added to the treatment regimen, the risk of hy-
perkalemia would probably lessen due to the potassium wasting
properties of the loop diuretics. Because this was a retrospective
study, possible adverse effects may not have been recorded ade-
quately; also evaluation of dehydration was not possible due to the
lack of packed cell volumes and total solids data for all dogs, treat-
ment modalities were not standardized for all dogs, and there were
variable time periods between visits.
Conclusions
The combination of enalapril and spironolactone administered
to Doberman pinschers with occult dilated cardiomyopathy and
normal or nearly normal SUN and creatinine concentrations may
have influenced SUN, potassium and magnesium concentrations.
However, the changes over the time of the study were considered
to be of limited clinical relevance. Nonetheless, renal function and
electrolyte concentrations should be measured periodically, pref-
erably with intervals of less than 3 months.
Conflict of interest statement
None of the authors of this paper has a financial or personal re-
lationship with other people or organizations that could
inappropriately influence or bias the content of the paper.
Acknowledgements
These data were in part presented as an abstract at the 2011
ACVIM Forum in Denver, Colorado.
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