Topics in Companion An Med 50 (2022) 100674

Research Article

Comparative Efficacy of Antihypertensive Drugs in Dogs: A Systematic Review

Hyeong-Il Choia,b, Joonyoung Kima,b, In-Sik Shinb, Ha-Jung Kima,b,*

Keywords: A B S T R A C T
angiotensin-converting enzyme inhibitor
angiotensin II receptor blocker Systemic arterial hypertension is a health condition causing target organ damage (TOD) in dogs. Early and
dog
effective treatment is essential to prevent hypertensive emergencies and to reduce the risk of TOD. This study
hypertension
investigated the diseases underlying hypertension and compared the short-term efficacy of antihypertensive
drugs in dogs. We evaluated the medical records of client-owned dogs treated with antihypertensive drugs
a
Department of Internal Medicine, College of between 2017 and 2018. The study included 75 dogs diagnosed with systemic arterial hypertension (systolic
Veterinary Medicine, Chonnam National
blood pressure
150 mmHg). The dogs were classified based on treatment with the following antihyperten-
University, Gwangju, Korea
sive drugs: calcium channel blocker amlodipine, angiotensin-converting enzyme inhibitor ramipril, and
b
BK21 Project Team, College of Veterinary angiotensin receptor blocker telmisartan, either as monotherapy or combination therapy (telmisar-
Medicine, Chonnam National University,
tan + amlodipine or ramipril + amlodipine). Systolic blood pressure was measured using an indirect Doppler
Gwangju, Korea
method over 4 weeks. Naturally acquired hyperadrenocorticism was the most common disorder to be diag-
nosed in conjunction with systemic hypertension. In the telmisartan group, the systolic blood pressure
decreased more rapidly for 3 weeks compared to ramipril. The combination of telmisartan and amlodipine
showed the greatest decrease in systolic blood pressure throughout the 4-week treatment period. This study
is meaningful as it suggests guidelines for the use of various antihypertensive drugs in dogs.
© 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction Successful treatment of hypertension with reduced side effects is

feasible with combination therapy.16 Previously, the efficacy of a sin-
Systemic arterial hypertension is a concern because chronic gle drug, mainly a CCB, was evaluated in cats.4 However, direct com-
increase in systolic blood pressure (SBP) induces tissue damage, parative analyses of multiple antihypertensive drug classes are not
mainly in the brain, eyes, heart, and kidney, in animals and feasible in dogs. This study compares the short-term variation in SBP
humans.1-8 Systemic arterial hypertension manifests as a persistent over 4 weeks in hypertensive dogs treated with CCBs, ACEIs, and
increase in blood pressure associated with target organ damage ARBs, either as monotherapy or combination therapy and provides
(TOD).7,9 It is classified according to the risk of future TOD defined by evidence for selecting the appropriate antihypertensive drug for use
the American College of Veterinary Internal Medicine (ACVIM) hyper- in dogs with underlying diseases.
tension consensus statement and the International Renal Interest
Society (IRIS) staging system.1,4,8
Materials and Methods
Clinical manifestations of systemic arterial hypertension in dogs
include retinal hemorrhage, proteinuria, cardiac murmurs, arrhyth-
Animals
mias, and neurologic signs, such as seizures.3,5,6,10,11 Underlying dis-
eases, such as hyperadrenocorticism (HAC), kidney disease, diabetes
We retrospectively evaluated the medical records of 75 client-
mellitus (DM), hyperaldosteronism, pheochromocytoma, and hypo-
owned dogs diagnosed with SBP (
150 mmHg) and prescribed anti-
thyroidism have been reported in dogs.3,12,13
hypertensive drugs. The dogs that were presented for evaluation
Controlling blood pressure is a challenge in progressive hyperten-
between 2017 and 2018 and subsequently diagnosed with systemic
sion.3 Therefore, early and effective treatment is essential to prevent
hypertension were evaluated in this retrospective cohort study. Tran-
hypertensive emergencies and to reduce the risk of TOD.3 The goal of
sient hypertensive dogs with stress were excluded. The SBP in these
treatment is to identify and manage the underlying diseases likely to
dogs was measured weekly for 4 weeks at our teaching veterinary
trigger secondary hypertension and to reduce the severity and possi-
medical hospital. Data on signalment factors and underlying diseases
bility of TOD by steadily decreasing the SBP to values < 150 mmHg.3
were obtained from the medical records. Additionally, TOD was
The major pharmacological classes of antihypertensive drugs
defined as any damage that resulted from the presence of sustained
include angiotensin-converting enzyme inhibitors (ACEIs), angioten-
high SBP and was made diagnosed by ruling out any primary diseases
sin receptor blockers (ARBs), beta-blockers, calcium channel blockers
which could cause hypertension.
(CCBs), and diuretics.14-17 In veterinary medicine, ACEIs and CCBs are
the most widely prescribed antihypertensive drugs.3,18,19 However,
some dogs require multidrug therapy to achieve the target SBP Hypertension Grading
because a single agent is insufficient for effective SBP control.14,17,19
Systemic arterial hypertension was classified as mild (SBP
140 159 mmHg), moderate (SBP 160 179 mmHg), and severe (SBP
*Corresponding author. Ha-Jung Kim, DVM, PhD, Department of Internal Medicine,
College of Veterinary Medicine, Chonnam National University, Address: 77 Yongbong-

180 mmHg) by the guideline of 2007 ACVIM hypertension consen-
ro, Buk-gu, Gwangju 61186, Korea. sus statement and IRIS staging system.1,10 The dogs showing 150-159
E-mail address: kimhj614@jnu.ac.kr (H.-J. Kim). mmHg were classified as mild stage and
180 mmHg were severe.

http://dx.doi.org/10.1016/j.tcam.2022.100674
1938-9736/© 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
2 H.-I. Choi et al. / Topics in Companion An Med 50 (2022) 100674
Blood Pressure Measurements
SBP was measured indirectly using a Doppler-based method
(Ultrasonic Doppler Flow Detector, Model 811-B; Parks Medical Elec-
tronics, Inc, Aloha, OR) following the standardized protocol proposed
by the ACVIM guidelines.1 The SBP was measured after acclimatiza-
tion in a quiet room for 5-10 minutes to reduce the effects of stress.
All measurements were obtained using cuffs that most closely
approximated 30%-40% with the circumference of the forelimb. The
first SBP reading of all dogs was discarded. The subsequent 5 SBP
measurements were recorded, and the arithmetic mean was calcu-
lated.
Treatment Groups
The prescription category was determined by referring to the cri-
teria of "ACVIM consensus statement: Guidelines for the identifica-
tion, evaluation, and management of systemic hypertension in dogs
and cats," and antihypertensive treatment be individualized to the
patient, based on the animal's concurrent conditions.1 Based on the
IRIS guidelines, combination therapy was considered in dogs with
severe hypertension (SBP
180 mmHg).1,8 However, variation was
noted depending on the dog’s condition. For analysis, the cases were
categorized into 5 groups according to the prescribed antihyperten-
sive drug regimen: (1) ACEI (Tritace Tablets, Handok Pharmaceutical
Co., Eumseong, Korea) (0.125 mg/kg ramipril, PO q24h); (2) ARB
(Semintra; Boehringer Ingelheim Promeco, Barrio Xaltocan, Mexico)
(1 mg/kg telmisartan, PO, q24h); (3) CCB (Novalopine Tablets, JW
Pharmaceutical Corp., Danjin, Korea) (0.3 mg/kg amlodipine, PO
q12h); (4) ACEI + CCB; and (5) ARB + CCB. In all cases, the drug was
administered orally.
Assessment of Efficacy
The ACVIM consensus statement defines hypertensive as SBP 160-
179 and severe hypertensive as SBP
180 mmHg. In each case, the
efficacy of the antihypertensive drug regimen was analyzed. To
observe the effect of antihypertensive drugs, the SBP was measured
before commencement of treatment and at 1, 2, 3, and 4 weeks of
treatment. The mean changes in SBP from the baseline values, rate of
decrease in blood pressure, and the proportion of dogs achieving the
target SBP of < 150 mmHg during the 4-week treatment were ana-
lyzed.
Statistical Analysis
The statistical significance of differences was calculated with
GraphPad Prism version 9.2 (GraphPad Software, Inc, La Jolla, CA).
The data were tested for normal distribution by using the Shapiro-
Wilk test. Normal distribution variables were analyzed using analysis
of variance with subsequent Tukey’s multiple comparison test to
establish difference between groups. Paired t-test was used to com-
pare the efficacy with the pretreatment. Non-normal distribution
variables were performed by the Kruskal-Wallis test and Dunn’s mul-
tiple comparison test. In addition, a one-way repeated measures
analysis of variance was used to analyze difference between weeks in
normal distribution. Mean § standard deviation (SD) was used to
describe distribution of continuous variables. Statistical significance
was set at P value <.05.
Results
A total of 805 dogs evaluating at the clinic during the study period
and 75 dogs (9.3%) were found to be hypertensive and treated with
one or more antihypertensive medication. The mean age of the
hypertensive dogs was 10.5 years (SD, range; 2.8, 1-16). Forty dogs
(53%) were aged >10 years. The study group consisted of 41 males (8
intact [11%], 33 castrated [44%]) and 34 females (17 intact [23%], 17
spayed [23%]). The major representative dog breed was the Maltese
(n = 16, 21%), followed by Shih Tzu (n = 15, 20%), Yorkshire Terrier
(n = 11, 15%), Mixed breed (n = 7, 9%), Cocker Spaniel (n = 6, 8%), Poo-
dle (n = 6, 8%), Pomeranian (n = 4, 5%), Schnauzer (n = 3, 4%), Dachs-
hund (n = 2, 3%), and Chihuahua, Boston Terrier, Greyhound,
Miniature Pinscher, and Pekingese (n = 1 each, 1%).
Diseases Underlying Hypertension
HAC (naturally acquired) was the most frequently diagnosed con-
current disease (n = 24, 32%). The diagnoses in these dogs included
HAC alone (n = 14, 19%) and HAC with concurrent left-side congestive
heart failure (CHF) (n = 7, 9%), chronic kidney disease (CKD) (n = 2,
3%), and DM (n = 1, 1%). In addition, CHF (n = 11, 15%), CHF with CKD
(n = 3, 4%), neoplasia (n = 5, 7%), CKD alone (n = 3, 4%), hypothyroid-
ism (n = 1, 1%) and immune-mediated hemolytic anemia (IMHA)
(n = 1, 1%) were also detected. Twenty-seven dogs were classified as
idiopathic because a plausible causal disorder was not identified.
Among CKD patients, prerenal azotemia was excluded by IV fluid
therapy before the evaluation of blood creatinine.10,20 The 8 dogs
diagnosed with CKD were classified as IRIS stage 1 (n = 4) and IRIS
stage 3 (n = 4).10 A total of 4 dogs (50%) were classified as IRIS stage 3
and the remaining 4 dogs (50%) were IRIS stage 1 (n = 4, 50%).
Clinical Signs and Clinicopathologic Abnormalities Indicative of
TOD
The clinical signs of dogs according to the SBP classification were
evaluated. Of the 75 study dogs, 26 showed clinical and clinicopatho-
logic abnormalities, such as proteinuria (n = 9), serial increases in
serum creatinine concentration (n = 8), seizure (n = 6), secondary
glaucoma (n = 2), or epistaxis (n = 1). In particular, 69% (18/26) of the
dogs with evidence of TOD had SBP values > 180 mmHg. Some dogs
were assessed fundic examinations for the earliest signs of TOD. The
primary causes of the manifestations (e.g., nasal neoplasia and pro-
tein-losing nephropathy) were ruled out from the full screening and
specific diagnoses.
Prescribed Antihypertensive Drugs
Of the 75 dogs initially included in the study, 59 (79%) continued
treatment for 4 weeks, including follow-up, whereas 16 (21%) dogs
discontinued the treatment during the same period. Nine cases which
could stop the treatment and 7 dogs discontinued the visit. As a
result, the efficacy of antihypertensive drugs was assessed in a total
of 59 dogs in this study.
Ramipril was used as first-line therapy in dogs with mild hyper-
tension (n = 4, 7%). Dogs with moderate hypertension were most
commonly treated with a combination of ramipril and amlodipine
(n = 13, 22%), followed by ramipril (n = 7, 12%), amlodipine (n = 6,
10%), telmisartan with amlodipine (n = 2, 3%), and telmisartan (n = 1,
2%). In the case of severe hypertension, a combination of ramipril and
amlodipine (n = 16, 27%) was most commonly prescribed as the first-
line therapy, followed by telmisartan and amlodipine (n = 11, 19%),
amlodipine (n = 8, 11%) and telmisartan (n = 7, 12%); ramipril was not
prescribed. The mean characteristics according to medication use are
summarized in Table 1.
Comparison of Pre- and Post-Treatment SBP
First, we wanted to assess the efficacy of various antihypertensive
treatments to decrease SBP within 1 week of therapy. SBP signifi-
cantly decreased with most treatment groups after 1 week of treat-
ment (Table 2). Only dogs in the ramipril treatment group failed to
 H.-I. Choi et al. / Topics in Companion An Med 50 (2022) 100674 3

Table 1
Baseline Mean Characteristics of the Therapy Groups at Index Date

Characteristic Ramipril (n = 11) Telmisartan (n = 8) Amlodipine (n = 14) Ramipril+Amlodipine (n = 29) Telmisartan+Amlodipine (n = 13) P Value

Age (y) 10.63 § 1.92 11.37 § 3.03 9.15 § 2.91 11.27 § 2.73 10.08 § 2.67 >.05
BW (kg) 3.52 § 1.04 7.02 § 2.25 4.56 § 1.35 5.02 § 1.57 5.78 § 2.94 >.05
SBP (mmHg) 158.63 § 2.64 185.75 § 10.69 173.57 § 8.78 177.41 § 11.13 190.38 § 17.39 >.05
HR (rate/min) 148.64 § 16.28 122.5 § 17.5 129.17§ 20.97 135.34 § 19.32 158.33 § 24.44 >.05
Cr (mg/dL) 1.01 § 0.33 0.99 § 0.27 0.71 § 0.14 0.94 § 0.35 1.06 § 0.55 >.05
Serum potassium (mmol/L) 4.29 § 0.39 4.35 § 0.48 4.25 § 0.28 4.57 § 0.44 4.18 § 0.27 >.05
BW: body weight; SBP: systolic blood pressure; HR: heart rate; Cr: serum creatinine concentration.
Data were presented as mean (SD).

Table 2
Comparison of Pre- and 1-Week Post-Treatment Systolic Blood Pressure and Mean Change From Baseline According to Various Antihypertensive Treatment Groups

Treatment Protocols Number Pretreatment SBP Post-Treatment SBP SBP Change From Baseline PValue

Ramipril 11 158.63 § 2.64 155.45 § 6.12 -3.18 § 5.70 .083

Telmisartan 8 185.75 § 10.69 157.50 § 8.75 -28.25 § 5.94 .026
Amlodipine 14 173.57 § 8.78 159.29 § 4.49 -14.29 § 7.24 .005
Ramipril + amlodipine 29 177.41 § 11.13 153.79 § 10.39 -23.62 § 9.86 .007
Telmisartan + amlodipine 13 190.38 § 17.39 146.54 § 11.72 -43.84 § 12.43 .008
Data were presented as mean (SD).

achieve a significant reduction in SBP after 1 week of therapy
(Table 2).
Next, we compared efficacy of various antihypertensive treatments
to decrease SBP over a 4-week treatment period (Fig 1). During the 4
weeks of treatment, all time points (weeks) showed significant differ-
ences among groups (Fig 1A, P < .05). Combination treatment resulted
in a significantly greater reduction in SBP at most time points com-
pared to monotherapy (Fig 1A). The combination of telmisartan and
amlodipine showed the greatest decrease in SBP throughout the 4-
week treatment period (Fig 1A). In the telmisartan group, SBP
decreased more rapidly for 3 weeks compared to ramipril (Fig 1A).
Ramipril alone or when combined with amlodipine resulted in
continued, significant reductions in systemic blood pressure (Fig 1B).
This is contrast to telmisartan alone or in combination with amlodi-
pine in which there was a substantial significant reduction in blood
pressure after 1 week of treatment, but there were no further signifi-
cant reductions after that point during the remainder of the 4-week
treatment period (Fig 1B).
The dogs with severe hypertension (SBP
180 mmHg; n = 42)
were also investigated separately. After 1 week, a significant decrease
in the mean SBP of
20 mmHg was found in all groups treated with
antihypertensive drugs, regardless of the type of drug (Table 3, mean
§ SD and Fig 2). Ramipril was not administered as a monotherapy to
any dog with severe hypertension. In dogs treated with a combina-
tion of telmisartan and amlodipine, the decrease in the SBP was sig-
nificantly greater than that in dogs receiving amlodipine alone or
ramipril combined with amlodipine (Fig 2).
Discussion
The present study retrospectively analyzed the comparative effi-
cacy of antihypertensive drugs in dogs with hypertension. We identi-
fied the common concurrent disorders associated with hypertension
and investigated the effective treatment options according to the
severity of hypertension in dogs.
We found that 69% (18/26) of the dogs with evidence of TOD had
SBP values greater than 180 mmHg. According to other studies, TOD
of the kidney is likely to occur when SBP is >160 mmHg.3,19 Accord-
ing to previously published studies, the SBP is expected to increase in
dogs with specific concurrent disorders.13
Our results show that 32% of the dogs were diagnosed with HAC
alone or HAC concurrent with other diseases. The increase in the SBP
may be attributed to excessive cortisol levels in the systemic circula-
tion.13 One potential reason is that hypercortisolism saturates the
11b-hydroxysteroid dehydrogenase allowing cortisol to bind miner-
alocorticoid receptors, resulting in a cortisol induced apparent miner-
alocorticoid excess in humans.21,22 This feature has been associated
with sodium retention and potassium excretion, which could contrib-
ute to the development of systemic hypertension.23-25 Dogs with
pituitary dependent HAC have decreased aldosterone concentrations
compared to healthy controls, leading to lower serum potassium con-
centrations, higher renal sodium reabsorption, and systemic
hypertension.26,27
Previous studies showed that CKD is a risk factor of systemic
hypertension in dogs.3,10 In comparison with the previous studies,3,10
the proportion of hypertensive dogs in which CKD was diagnosed
was small (n = 8, 10.7%). It is possible that CKD was not diagnosed for
some dogs in the early disease stages, particularly those in stage 1
(e.g., nonazotemic).
Currently, medical management is commonly based on the ACVIM
consensus statement guidelines for the management of hypertension
in dogs and cats.8 Among the 3 classes of drugs used as monotherapy
in our study, amlodipine was used most frequently followed by rami-
pril and telmisartan. The prescription patterns of antihypertensive
drugs in humans differ slightly from our results.28,29
Ramipril alone or in combination with amlodipine resulted in pro-
gressive significant reductions in blood pressure throughout the 4-
week treatment period. In addition, telmisartan monotherapy or
combination therapy resulted in a significant and rapid reduction in
blood pressure after 1-week but did not continue to accrue additional
significant reductions throughout the rest of the treatment period.
Based on the results, the efficacy of ramipril or combined with amlo-
dipine should be monitored serially over time. Meanwhile, caution
must be exercised when administering CCB monotherapy in dogs
due to preferential dilation of the afferent arteriole and subsequent
exposure of the glomerulus to deleterious pressure changes.3,29,30 In
veterinary medicine, comparison of drugs to treat systemic hyperten-
sion have yet to be sufficiently performed, suggesting the need for
further studies.
A few clinical studies have reported the efficacy of combination
therapy in humans treated with telmisartan and amlodipine as the
ARB and CCB, respectively. The combination of these drugs showed a
significant decrease in SBP (up to 50 mmHg).31,32 In our study, the
decrease in SBP following exposure to telmisartan and amlodipine
combination therapy was more significant during the first week than
in other study periods. These results indicate that the combination of
telmisartan with amlodipine is superior in reducing SBP during the
first week of treatment in severely hypertensive dogs. Therefore, in
4 H.-I. Choi et al. / Topics in Companion An Med 50 (2022) 100674

Fig 1. Effects of various antihypertensive regimens (monotherapy and combination therapy) on systolic blood pressure (SBP) in dogs with hypertension (
150 mmHg, n = 59). The
mean decreases in SBP (mmHg) from the baseline value according to the treatment and week (A and B) are shown. Significant differences compared with the prior week: at *P <
.05, **P < .01, ***P < .001.

Table 3
Comparison of Pre- and Post-Treatment 1-Week SBP (mmHg) and Mean SBP Change (mmHg) From Baseline According to Various Antihypertensive Treatment in Severe Hyperten-
sive Dogs

Treatment Protocols Before-Treatment SBP Post-Treatment SBP SBP Change From Baseline P Value

ARBs (n = 7) 188.57 § 9.80* 160.00 § 7.14 28.57 § 6.33 <.05

CCBs (n = 8) 181.25 § 1.86 160.63 § 5.62 20.62 § 4.69 <.05
ACEIs + CCBs (n = 16) 187.5 § 10.31 159.38 § 10.00 28.12 § 8.59 <.001
ARBs + CCBs (n = 11) 196.36 § 15.12 151.36 § 6.69 45.00 § 13.50 <.01
* Values are presented as means § SD.

case of an emergency and suspected TOD in dogs warranting instant
blood pressure control, the combination prescription of telmisartan
and amlodipine may be considered a priority.
The study has some limitations, which include the retrospective
study format, different conditions, and small sample size. The deci-
sions to use certain therapies in dogs based on severity of systemic
hypertension and retrospectively evaluated. The secondary blood
pressure increase caused by the drug was not evaluated in animals
(e.g., steroids or diuretics). Also we followed the 2007 ACVIM Consen-
sus Statement on hypertension, but failed to adopt the new stand-
ards, as the 2018 statement was not released until after our study
was completed. As this study was retrospective and the dogs were
evaluated before the new statement was published, we could not fol-
low the new guidelines.8 Additionally, a CCB as a monotherapy
should be avoided because CCB preferentially dilate the renal afferent
arteriole potentially exposing the glomerulus to damaging increases
in glomerular capillary hydrostatic pressured according to the ACVIM
guideline in 2017.8 There were no dogs with renal problems during
the study in the treatment group, but further studies with update
version of design for hypertensive dogs are needed.
In conclusion, the study results underscore the need for serial
blood pressure monitoring in dogs with underlying diseases that
 H.-I. Choi et al. / Topics in Companion An Med 50 (2022) 100674
Fig. 2. Comparison of hypertensive treatments after 1-week treatment from baseline in severe hypertensive dogs (
180 mmHg, n = 42). The mean decreases in SBP (mmHg) from
the baseline value according to the treatment and week. *P < .05, **P < .01, ***P < .001.
cause hypertension. In addition, the effects of antihypertensive drug
classes differ in the short term, with a greater decrease in the SBP of
dogs treated with combination therapy. The combination of amlodine
and telmisartan might be the optimal choice for short-term interven-
tion in dogs with severe systemic hypertension.
Author Contribution
Conception and design: H.I Choi, H.J. Kim.
Development of methodology: H.J. Kim, I. S. Shin.
Acquisition of data (provided animals, acquired and managed
patients, provided facilities, etc.): H.I Choi, J. Kim.
Analysis and interpretation of data (e.g., statistical analysis, biosta-
tistics, computational analysis): H.I Choi, J. Kim.
Writing, review, and/or revision of the manuscript: H.I Choi,
H.J. Kim, I. S. Shin.
Study supervision: H.J. Kim.
Funding
This work was carried out with the support of Cooperative
Research Program for Agriculture Science and Technology Develop-
ment (Project No. PJ016392) Rural Development Administration,
Republic of Korea.
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