CHAPTER 27

Vasodilators

RICHARD VULLIET
ASHLEY M. STOKES

INTRODUCTION
Vasodilators are an important adjunctive therapy for heart failure beyond what can be
obtained with digitalis and diuretics. The overall goal of the use of vasodilators is to improve
hemodynamics, reduce edema formation, and to improve cardiac output and tissue perfusion.
This can be accomplished with inotropic agents (Chapter 26) or by dilating the arterioles and
reducing the resistance that the heart pumps against, or by dilating the venules which shifts blood
from the central to the peripheral veins and reduces the ventricular preload, or a combination of
all of these treatments.

The relationship between diastolic filling pressure and stroke volume (also known as
ventricular performance) is shown in Figure 27.1. The normal heart is represented by the solid
line. In heart failure, the patient’s heart with systolic dysfunction is also shown. Administration
of a positive inotropic agent (I) or a vasodilator (V) will increase the performance of a failing
heart, moving the performance to a higher ventricular function curve. More importantly, when
these agents are used together, a greater effect from the combination is observed than would be
obtained by either agent alone. In severe cases, all of these agents can be used together. The
rationale for the use of peripheral vasodilators is to 'unload' the failing heart and reduce its
workload.

One of the major determinates of normal blood pressure is sympathetic tone at the
arterioles. Sympathetic tone of arterioles and veins increases in patients with diminished cardiac
output as a reflex to maintain blood pressure. Increased arteriolar sympathetic tone increases
vascular resistance that the heart is pumping against (afterload). Increased sympathetic venous
tone shifts blood volume from the veins to the central compartment and increases ventricular
return (preload). Although these are normal compensatory adaptations of the circulatory system
in patients with severely failing myocardium, these changes can be detrimental if they persist as
they will eventually lead to volume overload hypertrophy.

In association with heart failure, there is a typical cascade of events that occurs. Heart
failure results in decreased cardiac output, hypotension, and decreased perfusion of tissues. The
body’s reactions (compensatory mechanisms) are aimed to increase blood pressure and include

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both acute and chronic alterations. First, the sympathetic nervous system is stimulated to increase
heart rate and cause vasoconstriction. On a more chronic basis, the renin-angiotensin system is
activated due to decreased perfusion to the kidneys. Stimulation of this system results in
vasoconstriction and increased sodium and water retention. Short term, these compensatory
mechanisms are beneficial for maintenance of homeostasis. Long term, the heart becomes
overworked due to the increased vascular resistance and increased blood volume.

THERAPEUTIC OVERVIEW
Blood pressure is generated by the pumping action of the heart which forces blood from
the arteries through the tissue capillaries into the veins where it is returned to the heart. We have
identified what normal blood pressure is from measuring it in normal healthy individuals. For
clinicians, relevant questions are usually posed as “what is abnormal blood pressure?” or more
specifically “what is adequate (or more importantly inadequate) blood pressure?” Adequate
blood pressure is usually determined by evaluating tissue perfusion (color of mucous membranes
or capillary refill time). A myriad of physiological mechanisms attempts to maintain blood
pressure within “normal” limits in patients with cardiovascular disease. Most of these
mechanisms are active in patients that are candidates for vasodilator therapy. Many vasodilator
drugs can interfere with these mechanisms and alter blood pressure to potentially improve tissue
perfusion (or alternatively, make it worse). Philosophically, one might question whether
“normal” blood pressure is the optimal blood pressure for the cardiac-compromised patient?
Astute clinical judgment and frequent patient assessment are required for the optimal use of these
agents.

In most species, normal mean arterial blood pressure is approximately 90 to 110 mm of

Hg and venous blood pressure is about 5 to 0 mm of Hg. This pressure differential provides
enough reserve for the individual’s body to adjust the flow of the blood to adequately perfuse
tissues to accommodate the activity level of the individual. In the normal individual, cardiac
reserve can be used to increase cardiac output sufficient to maintain this pressure differential if
necessary. Perfusion of the tissues will be maintained, albeit reduced, as the arterial-venous
pressure differential is reduced down to about 50 to 60 mm of Hg. At this point, the perfusion of
the coronary, cerebral and renal vascular beds is reduced to the point where clinical signs
become evident. However, consider the patient with a compromised heart that is pumping at
near maximal effort against a mean of 100 to 110 mm of Hg. Can tissue perfusion be improved
in this patient by reducing the pressure that the compromised heart is pumping against? The
short answer is a qualified “yes”, depending upon the cardiovascular status of the specific
patient.

Indications for Vasodilators

One of the major goals in treating congestive heart failure is to increase cardiac output by
decreasing pressure that the heart is pumping against1-3. The most common indication for
therapy with vasodilators in veterinary medicine is congestive heart failure, secondary to mitral
regurgitation3. Vasodilators can also be effective in patients with aortic stenosis. In humans,
vasodilators are also used to treat coronary artery disease, certain types of hypertension, and
diseases of the vascular beds, such as Raynoud’s syndrome (vascular spasms)1, 2. These later
diseases are rare in veterinary patients. Although hypertension is not as prevalent in veterinary

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species as in humans, it is becoming recognized as a clinical syndrome in canine and feline
patients3.

Vasodilators relax the smooth muscle of the arterioles, venules or both. The exact site of
action at which these agents work depends on the administered dose. These agents are classified
based on their site of action, chemical structure and/or mechanism of action.

Arteriolar Dilators
Arteriodilators dilate systemic arterioles. Systemic arteriolar resistance is reduced when
systemic arterioles are dilated (decreased afterload). Resistance equals arterial blood pressure
divided by the blood flow (R = BP / Flow). When the resistance to blood flow is reduced, 1)
blood pressure can decrease with the same blood flow or 2) blood pressure stays the same with
an increase in blood flow. Blood pressure often stays the same, and blood flow increases when
a normal dog receives an arteriolar dilator. This is caused by reflex stimulation of the
sympathetic nervous system in an attempt to maintain homeostasis. Sympathetic stimulation of
the heart increases both contractility and heart rate, leading to an increase in cardiac output
which normalizes blood pressure. This is why an effective dose of many vasodilators will result
in only a modest decrease or no change in blood pressure and/or a slight increase in heart rate.

Venodilators
Venodilators dilate systemic veins, which shifts blood to the peripheral circulation and
decreases venous return to the heart (decreases preload). When venous return is reduced,
diastolic pressures are reduced. Elevated diastolic pressures are associated with left heart failure
and produce transudation and leakage of the fluid from the pulmonary capillary beds. This is
termed “pulmonary edema”. Likewise, right heart failure leads to the formation of peripheral
edema. Under these conditions, venodilators can decrease edema formation by decreasing
central venous pressure. Although the mechanisms of action of venodilators and diuretics are
different, their effects on the cardiovascular system are similar. Instead of decreasing venous
return through a decrease in blood volume (as with diuretics), venous return is decreased via
peripheral blood “pooling”.

Mixed Vasodilators
Most vasodilators work by relaxing vascular smooth muscle. The specific site of action
often times depends upon the administered dose. Some of the agents work preferentially on
arteriolar smooth muscle. Others produce their actions primarily on the venous smooth muscle.
Some vasodilators dilate both arteriolar and venous smooth muscle at about the same dose.
These agents are termed mixed vasodilators.

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 A comparison of various classes of agents and their actions on the cardiovascular system
is presented in Table 27.1.

Table 27.1. VASODILATOR DRUGS USED TO TREAT HEART FAILURE

MECHANISM OF PRELOAD AFTERLOAD

DRUG CLASS VASODILATING ACTION REDUCTION REDUCTION

Organic nitrates (Nitroglycerin) Nitric oxide-mediated +++ +

vasodilation
Nitric oxide donors Nitric oxide-mediated +++ +++
(Nitroprusside) vasodilation
Angiotensin converting enzyme Inhibition of angiotensin ++ ++
inhibitors (Enalapril) generation, decreased
bradykinin degradation
Angiotensin receptor blockers Blockade of angiotensin ++ ++
(Iosartan) inhibitors receptors
Phosphodiesterase (Milrinone, Inhibition of cyclic AMP ++ ++
Inamrinone, Pimobendan) degradation
Direct-acting (Hydralazine) Unknown + +++
Subtype-selective α1-adrenergic Selective α1-adrenergic receptor +++ ++
receptor antagonists (Prazosin) blocker
Non-subtype-selective α- Non-selective α-adrenergic +++ +++
adrenergic receptor receptor blockade
antagonists (Phentolamine)
Vasodilating β/α1 adrenergic Selective α1-adrenergic receptor ++ ++
receptor antagonists blockade
(Carvedilol)
Ca2+ channel blocking drugs Inhibition of L-type Ca2+ + +++
(Amlodipine) channels
β-adrenergic receptor agonists Stimulation of vascular β2- + ++
(Isoproterenol) adrenergic receptors

Complications from Vasodilator Therapy

Although a role for vasodilator therapy in treating heart failure has been established, the
use of these agents is not without concern. These agents share several side effects and potential
complications that will be discussed as a group in this section. The two major complications of
vasodilator therapy are hypotension and reflex-enhanced sympathetic activity1-3. These side
effects are frequently encountered following the use of vasodilators, and frequent blood pressure
monitoring is recommended. Hypotension is a common side effect of nearly all of the
vasodilator agents. It can result as a dose-dependent extension of the specific pharmacological
actions of the agent. If this occurs, it can often be corrected by dose adjustment. It may be result
from decreased clearance of the agents due to impaired renal or hepatic clearance common in
cardiac-compromised patients. If adjustment of the dose is necessary because of compromised
renal or hepatic clearance, further adjustment may be necessary as normal clearance returns
following therapeutic intervention.

The second type of side-effects is enhanced sensitivity to the actions of certain drugs.
Most commonly these are agents that interfere with the normal autonomic response. As

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discussed in Chapter 25, the cardiovascular system is exquisitely regulated to the needs of the
body. If blood pressure is lowered because of compromised cardiovascular function, the
sympathetic nervous system may be activated to maintain blood pressure caused by lowered
cardiac output. It is most commonly manifest as an increase in heart rate or increase in vascular
tone. For example, a cardiac-compromised patient will have enhanced sympathetic stimulation
and altered patterns of blood distribution, as a normal response to the disease. The response to
adrenergic blocking agents will most likely be more severe in the patient with increased tone
than in patients that do not generate a strong sympathetic response. Other specific side effects
that occur will be presented following a discussion of the specific agents.

SPECIFIC VASODILATORS
Arteriodilators
Hydralazine
Hydralazine (Apresoline®) (Figure 27.2) is one of the most potent and specific arteriolar
dilators4, having little effect on the venous compartments. The primary indication for
hydralazine in veterinary medicine is mitral regurgitation that is refractory to other treatments
such as ACE inhibitors and diuretics5, 6. Hydralazine dilates systemic arterial beds, decreases
peripheral vascular resistance and lowers resistance to left ventricular ejection. This results in a
decrease in cardiac size and wall tension which can lead to a decrease in O2 consumption1, 2. It
has been used successfully in feline and canine patients with ventricular septal defects and aortic
regurgitation3. It will decrease vascular resistance to about 40% of normal compared with ACE
inhibitors, which only decrease resistance by about 25%. Hydralazine decreases vascular
resistance in renal, mesenteric, coronary, and cerebral beds more that skeletal muscle tissues7. In
dogs with mitral regurgitation, a therapeutic dose will decrease mean arterial blood pressure from
100 to 110 mm to about 60 to 80 mm Hg5, 6.

Administration of hydralazine causes direct relaxation of arterial smooth muscle without

relaxing the venous smooth muscle2. The molecular mechanism by which hydralazine produces
this action is unknown is spite of the fact that it was one of the first anti-hypertensive agents used
in the United States2, 3. The current proposed mechanism of action is by a reduction in the
movement of calcium in smooth muscle cells thereby reducing contraction. Administration of
hydralazine elicits a strong sympathetic stimulation (increase in heart rate, contractility and renin
secretion as well as fluid retention) which serves to counteract its’ antihypertensive actions2.

Hydralazine’s plasma half life is only 2-4 hours8. However, its’ duration of action is 11
to 13 hours so that it is administered every 12 hours3. The effective dose is 0.5 to 3 mg/kg/ every
12 hours, but it must be titrated. The initial dose should be 0.5 mg/kg and if there is no response,
the dose should be increased in 0.5 mg/kg increments. Some dogs will respond to 1 mg/kg,
while others may require 2-3 mg/kg3. The average sized cat should be started at 2.5 mg and this
may be increased up to 10 mg per cat3. The therapeutic dose can lower mean arterial blood
pressure from 100 to 110 mm Hg to 60 to 80 mm Hg3. It is useful to monitor blood pressure 1 to
2 hours following the administration of hydralazine, looking for the expected decrease in BP8, 9.
It is well absorbed on oral administration but is rapidly metabolized by the liver. Its
bioavailability varies from 20% to 60%. The effective plasma concentration is approximately
100 ng/ml3. Hydralazine is available in injectable and oral formulations.

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 The most common adverse reaction is hypotension with a reflex tachycardia. Usually,
the hypotension is manifest as weakness and lethargy. It is usually not treated and will resolve
upon withdrawal or reduction of the dose of hydralazine. It can lead to renal failure and death if
severe. GI disturbances can occur in up to 50% of treated animals, and are usually severe
enough to prevent the use of the drug again. Hydralazine can produce a lupus-like syndrome in
humans following chronic use2.

Phenoxybenzamine
Phenoxybenzamine (Dibenzyline®) is an alpha-adrenergic blocking agent that has been
termed a “chemical sympathctomy”(see Chapter ??). The most predominant effects are seen in
arterial blood flow to the skin which explains its primary use as a treatment for equine laminitis.
Other uses in dogs and cats include treatment of urethral sphincter hypertonus and
pheochromocytoma-induced hypertension, especially before surgery. In contrast to many of the
agents discussed in this chapter, phenoxybenzamine should used with caution in animals with
chronic heart failure due to resulting tachycardia. In horses with colic or other conditions
associated with hypotension phenoxybenzamine should be not be used. An oral formulation is
most commonly used for small animals and for large animals, although IV administration is also
cited for horses(see reference for Robinson 1987 below).

Robinson, N.E. 1987 Table of Common Drugs: Approximate Doses. In Current Therapy in
Equine Medicine, 2. Edited by N.E. Robinson. 761. Philadelphia: W.B. Saunders.

Phentolamine
Phentolamine (Regitine®) is a nonselective alpha-adrenergic blocking agent that is very
similar in action to phenoxybenzamine(see Chapter ??). Phentolamine has also been shown to
block recptors for the vasoconstrictor 5-HT (serotonin)( see reference below for Curro and
Greenberg 1983). Also similar to phenoxybenzamine, phentolamine can be used in the treatment
of hypertension secondary to excessive catecholamine release from pheochromocytomas in dogs.
An IV formulation is available for small animal use. Large animal clinical use has not been
reported.

Curro, F. A. and S. Greenberg (1983). "Differential inhibition of 5-hydroxytryptamine (5-HT)

mediated contraction of rat thoracic aortae by phentolamine and tolazoline: correlation with
inhibition of 5-HT binding and calcium ion." Methods Find Exp Clin Pharmacol 5(2): 107-20.

Venodilators

Nitroglycerin
Nitroglycerin (Nitrostat®, Nitrol®, Nitrobid®) (more correctly glyceryl trinitrate) is an
ester of nitric oxide. In its concentrated form, nitroglycerin is explosive. However, the medical
grade is diluted to approximately 2 to 10% with inert carriers, such as propylene glycol, alcohol
or lactose, which makes it non-explosive. In human medicine, nitroglycerin is used primarily for
low output CHF and to reduce pulmonary congestion and edema. Nitrates, which produce
systemic venodilation, have been suggested for symptomatic relief in dogs and cats with heart

27-6
failure10. This indication has not been documented in veterinary medicine, although there are
anecdotal reports of efficacy in canine patients3. Nitroglycerin is hydrolyzed to nitric oxide in
the vascular smooth muscle. The nitric oxide activates guanylate cyclase, the enzyme that
converts GTP to cyclic GMP11. Cyclic GMP activates cyclic GMP dependent protein kinase and
by steps that are currently not known, leads to the dephosphorylation of the light chains of
myosin12. The phosphorylation of myosin regulates the tone of the smooth muscle cell and
decreasing the amount of phosphorylated myosin leads to relaxation of the smooth muscle12 as
shown in Figure 27.2.

Low doses of nitroglycerin produce venodilation that results in decreased end diastolic
pressures, reduced preload, and decreased ventricular chamber sizes with slight, if any, reduction
in systemic arterial resistance. This will divert blood from pulmonary to systemic vasculature
and relieve pulmonary congestion with a modest change in cardiac output. Systemic arterial
pressures may fall slightly or remain unchanged due to reflexive mechanisms. Higher doses will
cause further venous pooling and may dilate selective arteries. Certain arterial beds are more
sensitive to the effects of nitroglycerin than others and this sensitivity is based on the levels of
the metabolizing enzymes that convert nitroglycerin into nitric oxide. In humans, the arteriolar
dilation of the face, neck, and meningeal arteries account for the flushing and headache,
respectively that is observed following nitroglycerin administration. This selectivity may
account, in part, for the anti-anginal properties of nitroglycerin in humans.

Nitroglycerin may be administered by numerous routes, including intravenous, oral, or

transdermal. The IV route will produce rapid effects and may result in higher concentrations that
will have slightly different effects on the body. At low concentrations, venodilation
predominates. At higher doses, arteriolar dilation may also occur. Once in the plasma,
nitroglycerin has a short half-life of 1 to 4 minutes, so to maintain effective concentrations, the
drug must be given as a continuous drip. Intravenous doses have not been established in
veterinary patients3. The starting dose for humans is 5 Φg/min per 70 kg human2. The dose is
adjusted upward in 10 to 20 μg/min increments until the desired effect is achieved. Presumably,
similar results will be obtained in veterinary patients when dosed according to allometric scaling.

Because of the short half-life, nitroglycerin is given orally as a sustained release

preparation. Although it is well absorbed, its bioavailability is very low (around 10%) due to
rapid metabolism by the liver. Small dogs are given 2.5 mg every 12 hours up to a maximum of
6.5 mg every 8 hours. In medium to large dogs, nitroglycerin is started at 6.5 mg every 12 hours
with a maximum dose of 9 mg every 8 hours3. Cats are treated the same as small dogs3. It
should be noted that nitroglycerin has a high affinity for plastic products. It should be dispensed
in glass bottles and stored at between 15 and 30Ε C. During administration with standard IV
sets, it has been estimated that 40 to 80% of a diluted nitroglycerin solution will be absorbed
onto the polyvinyl chloride tubing. Special non-PVC tubing sets are available for nitroglycerin
administration3.

Nitroglycerin can be administered by the transdermal route using either patch or paste
formulations. A 2% paste is available for direct application to a hairless area of the skin, usually
the thorax or the pinna of the ear. In horses, nitroglycerine is commonly used in the treatment of
laminitis and is administered transdermally at the level of the fetlock over the palmar digital

27-7
vessels. The person applying the nitroglycerin should be advised to wear gloves since
transdermal absorption will occur in the person applying the ointment as well as the patient. The
most common complaint from inappropriate transdermal absorption of nitroglycerin is a
profound headache. However, in controlled blinded studies performed at the University of
California at Davis, the paste was found to be no different than the petroleum jelly control
(Vaseline) when cardiac output, pulmonary capillary wedge pressure or systemic arterial
pressures were monitored by a blinded observer3.

The adverse effects of nitroglycerin can be predicted from its known pharmacological
actions. It may cause a reflex tachycardia if severe hypotension is present. In addition,
nitroglycerin is known to decrease renal blood flow. Nitroglycerin can worsen renal and cardiac
blood flow in a cardiac patient with compromised renal blood flow. In horses, rare adverse
effects have been noted when used as described above. Repeated or continuous administration of
nitroglycerin in small and large animals will result in tolerance. Tolerance is a common problem
in humans and up to 70% of people given nitroglycerin intravenously will demonstrate some
form of tolerance10. While the exact mechanism of tolerance is not known, intermittent
administration of nitroglycerin may prevent its development. However, because of the short
half-life of nitroglycerin, intermittent administration may also reduce its’ therapeutic benefit. In
humans, concurrent administration of hydralazine with nitroglycerin appears to prevent the
occurrence of tolerance2.

Isosorbide dinitrate/mononitrate
Isorbide dinitrate and isosorbide mononitrate (Isordir®, Isorbid®, Monoket®) are
organic nitrates that work similar to nitroglycerin. Both agents are primarily venodilators;
however, isosorbide mononitrate (Monoket®) is the biologically active form and is therefore the
suggested form for administration. They are extensively used in human patients with angina.
Both drugs are available in oral formulations. Neither drug has been extensively studied in
veterinary patients3.

Isoxsuprine
Isoxsuprine (Vasodilan®) is primarily a venodilator that works through the direct
relaxation of vascular smooth muscle. It is also known to stimulate beta-adrenergic receptors
although this is not though to contribute to its vasodilatory effects. Isoxsuprine is also thought to
decrease blood viscosity and decrease platelet activation and aggregation (see Chapter 31). The
primary uses for isoxsuprine are for the treatment of navicular disease and laminitis in horses(see
references Erkert 2002 and Turner 2002 below). Isoxsuprine is administered orally and is
absorbed rapidly and completely. It usually requires long-term BID administration (21 days)
followed by SID administration for 14 days and then administration every other day. If no
response is seen after 6 weeks, then consider discontinuing. There is a significant first-pass
effect that may actually result in low bioavailability of the drug. The elimination half-life is 2.5 –
3 hours following intravenous administration. The adverse effects and contraindications
associated with isoxsuprine are unclear. The most common adverse effect is CNS stimulation in
horses. Hypotension is another uncommon adverse effect.

Erkert RS, Macallister CG. Isoxsuprine hydrochloride in the horse: a review. J Vet Pharmacol
Ther 2002;25:81-87.

27-8
Turner AS, Tucker CM. The evaluation of isoxsuprine hydrochloride for the treatment of
navicular disease: a double blind study. Equine Vet J 1989;21:338-341.

Mixed Arteriolar / Venous Dilators

Prazosin
Prazosin (Minipress®) (Figure 27.4) was originally developed as an anti-hypertensive
agent for humans2. The hemodynamic effects of prazosin have not been fully elucidated in
clinical veterinary medicine3. Prazosin is not commonly used in veterinary medicine; however
its most common uses are for pulmonary and systemic hypertension. It preferentially blocks the
α1 receptor, and on initial dosing, will lower systemic blood pressure by decreasing endogenous
vascular tone2. In patients with a failing heart, the vascular system is under α1 stimulation to
maintain system blood pressure. Prazosin blocks the α1 receptors, reducing this sympathetic
tone, and a severe paradoxical hypotension may result (see Chapter ??). In humans, the
vasodilating properties of prazosin are reduced after 2 to 4 days, most likely because of
activation of the renin–angiotensin-aldosterone system2. Prazosin has also been used in cats for
relief of functional urethral obstruction. It should be used with caution in animals with chronic
renal disease. Prazosin is available in an oral formulation. The starting dose for dogs is 1 mg
every 8 hours in dogs that weigh less than 15 kg and 2 mg every 8 hours in dogs greater than 15
kg 3. Cats and smaller dogs, as noted by the difference in dosing for dogs under 15 kg, should
especially be monitored for severe hypotension during administration of prazoxin.

Nitroprusside
Nitroprusside (Nitropress®) (sodium nitroferricyanide) is a potent arterio- and veno-
dilator that is metabolized in the blood vessels to nitric oxide. The nitric oxide then activates
guanylate cyclase leading to an increase in smooth muscle cGMP which then leads to relaxation
of the vascular smooth muscle and vasodilation11, 12 (see Figure 27.2). However, the enzyme that
generates nitric oxide from nitroprusside is different than the enzymatic pathway activated by
nitroglycerin2. This accounts for the difference in potency at different vascular sites, and the
lack of tolerance to nitroprusside, while nitroglycerin is well known to produce tolerance2.

Nitroprusside is used to treat hypertensive emergencies. It does this by rapidly relaxing

vascular resistance and improving cardiac output without increasing cardiac workload. In
humans, following myocardial infarction, nitroprusside will improve left ventricular function
while reducing myocardial O2 demand and producing only a slight reflexive increase in heart
rate. The cardiovascular effect of nitroprusside is a prompt relaxation of both arteriolar and
venous smooth muscle which will decrease preload and systemic blood pressure (afterload),
leading to an increase in cardiac output. In small animals, it is used to treat acute congestive
heart failure by decreasing both preload and afterload3. In these cases, it can be combined with
dobutamine due to the synergistic effects between these two agents resulting in increased cardiac
output and reduced pulmonary wedge pressure. It is also used in humans to produce hypotension
and reduce bleeding during critical surgical procedures2.

Nitroprusside is administered as a continuous IV infusion because of its short half-life (1-

2 min). A 5% dextrose solution should be used for powder dissolution and for administration.
No other medications should be added to the nitroprusside solution. There is very little lag time

27-9
between the onset of administration and the cardiovascular response. Initially, nitroprusside is
administered IV at a dose of 2 to 10 μg/kg/min and the response can be adjusted by adjusting the
dosing rate3. Nitroprusside will decompose in light and it should be protected from light by
covering the administration bottle with an opaque wrapper (usually aluminum foil). The solution
is normally a light-brown color, if discolored to a dark brown, blue, red or green color the
solution should be discarded3.

The adverse effects of nitroprusside include hypotension and cyanide poisoning

associated with long term infusion (> 16 hours). Hypotension can be prevented by close
monitoring of hemodynamics of the patient (i.e. blood pressure monitoring). Nitroprusside is
metabolized to cyanide which, if it accumulates in the body, will be toxic. The toxic
accumulation of cyanide has been reported in humans dosed at a rate greater than 5 μg/kg/min2.
Normally, cyanide is metabolized in the liver to thiocyanate, but this depends on the presence of
thiosulfates. A toxic accumulation of cyanide may first appear as a lactic acidosis due to an
inhibition of oxidative phosphorylation and decreased ATP production. Thiocyanate can also
reach toxic levels if nitroprusside is infused for greater than 24 to 48 hours, and if there is renal
impairment2. A common treatment for cyanide poisoning is IV sodium thiosulfate.

Pimobendan

Pimobendan (Vetmedin®) is the newest FDA-approved mixed artio- and venodilator for the
treatment of canine congestive heart failure. Pimobendan is a benzimidazole-pyridazinone
derivative with positive inotropic and vasodilator properties via phosphodiesterase III inhibitor
activity, similar to that of amrinone and milrinone, which reduces the breakdown of cAMP. The
increase of cAMP leads to increased intracellular calcium resulting in smooth muscle relaxation
in both arteries and veins. The increased intracellular calcium causes a different result in cardiac
muscle leading to enhanced myocardial contractility (inotropic effects). Therefore, in cases of
hypertrophy, aortic stenosis, or other conditions where an increase in cardiac output is
contraindicated, pimobendan is not recommended. It should be noted that pimobendan should
not be used alone or used as a substitute for current therapies; concurrent therapy with diuretic
agents and/or digoxin is strongly recommended. Currently, pimobendan is only available as
chewable tablets for dogs. The bioavailability of this oral formulation is approximately 60% and
it is eliminated in the feces. It is given orally at a dosage of 0.2 to 0.6 mg/kg daily divided into
two doses given 12 hours apart. It has best GI absorption if given 1 hour before meals.
Pimobendan use in cats is not approved and one report of its use in limited feline cases found no
beneficial effect beyond currently available therapies.

Angiotensin Converting Enzyme (ACE) Inhibitors

Renin is an enzyme synthesized in the juxtaglomerular cells of the macula densa region
of the kidney, which controls the volume of circulating fluids13. As shown in Figures 27.5 and
27.6, circulating renin converts plasma angiotensinogen, synthesized in the liver, into
angiotensin I (see Chapter 22). Angiotensin I (inactive) is then converted into angiotensin II
(active) by Angiotensin Converting Enzyme, a dipeptidyl carboxypeptidase, commonly
abbreviated as ACE. Angiotensin II will activate two distinct receptors, angiotensin receptor 1
(AT1) and angiotensin receptor 2 (AT2). Both receptors are G-protein coupled and are found

27-10
extensively throughout the body. The release of renin into the systemic circulation is controlled
by: 1) NaCl reabsorption of the macula densa, 2) blood pressure changes sensed by the pre-
glomerular vessels and 3) activation of β1 receptors on the juxtaglomerular cells. For a more
extensive review see Jackson13. Most of the cardiovascular actions of angiotensin II are thought
to be mediated by activation of the AT1 receptor13. The major physiological actions of increased
levels of angiotensin II are: 1) an increase the secretion of ADH which increases in the
reabsorption of water and increases the plasma volume, 2) an increase in sympathetic nervous
system tone which increases vascular resistance; 3) direct contraction of selected blood vessels,
and 4) increased circulating levels of aldosterone, which decreases sodium excretion and
potassium reabsorption (see chapter 22). ACE is also responsible for the breakdown of
bradykinin as well as metabolizing angiotensin II and this explains some of the side effects
associated with ACE inhibitors.

When purified angiotensin II is injected into the body, it produces a myriad of effects on
the circulatory system. One of the most striking is the pressor effect for which angiotensin was
named. This pressor effect is mediated by the combination of angiotensin II with the AT1
receptor. Angiotensin II increases peripheral resistance by a combination of direct actions on the
vessels themselves, and by indirect actions. In general, it will combine with AT1 receptors on
both arteriolar and venous smooth muscle cells to cause vasoconstriction. The specific actions of
angiotensin II may vary depending upon the specific vascular bed, the concentration of AT1
receptors, the circulating concentration of angiotensin II and the species being tested.
Angiotensin II also enhances noradrenergic transmission by facilitating norepinephrine release,
blocking the uptake of norepinephrine, and enhancing the vascular response to norepinephrine.
Angiotensin II also acts on the CNS to increase sympathetic tone to the peripheral vasculature,
increasing vascular resistance.

Angiotensin II causes a dramatic reduction in the amount of Na+ ion and water that are
secreted by the kidney, while increasing the excretion of K+ ion. Angiotensin II also stimulates
the cells of the zona glomerulosa of the adrenal cortex to secrete aldosterone. Aldosterone acts
on the distal and collecting tubules to increase the retention of Na+ ion and increase the excretion
of K+ and H+ ions (see chapter 29). It also reduces renal blood flow by constricting the renal
vascular smooth muscle, enhancing noradrenergic neurotransmission and increasing sympathetic
tone via increases in CNS mediated enhancement of sympathetic tone.

To counteract many of the responses cited above, ACE inhibitors are commonly used in
patients with failing hearts. In addition to vasodilation, they have effects on important
neurohumoral and renal compensatory mechanisms associated with heart failure. These
inhibitors bind to ACE at the same site as angiotensin I and prevent its conversion to angiotensin
II. The net result is a decrease in circulating levels of angiotensin II13. Thus, they act as
arteriodilators and venodilators, and they decrease the plasma aldosterone concentration, all of
which can help a failing heart. The administration of ACE inhibitors will produce a peripheral
vasodilation which decreases blood pressure (decreases afterload) and shifts blood from central
veins to peripheral veins (decreases preload)13. They also decrease aldosterone secretion, which
decreases Na+ reabsorption, which in turn reduces blood volume and contributes to the reduction
in preload. In addition, they can decrease ACE activity which leads to an increase in bradykinin
levels which can also cause vasodilation. In addition, they will decrease sympathetic nervous

27-11
tone, which also decreases peripheral resistance and cardiac work. Quite often ACE inhibitors
are administered concurrently with diuretics and serve as the cornerstone treatments of canine
DCM and feline HCM. Captopril and enalapril are the most commonly used ACE inhibitors in
veterinary medicine and they will be discussed separately below3. In hypertension secondary to
renal disease, treatment with an ACE inhibitor is indicated because it will treat the hypertension
and may slow the progression of the renal disease3.
Most of the ACE inhibitors are administered orally in veterinary practice and have better
bioavailability when administered on an empty stomach. Side effects occasionally seen with
these agents include vomiting, diarrhea, and anorexia. Newer and more commonly used agents
appear to have fewer of these side effects. An interesting finding with the ACE inhibitors is that
the clinical improvements are usually more dramatic than the hemodynamic and
echocardiographic improvements. All animals receiving these agents should be monitored for
hypotension, electrolyte imbalances, and for renal function 3-7 days from the initiation of
administration. Afterwards, periodic monitoring should continue, especially monitoring of BUN
and creatinine. It should be noted that ACE inhibitors cross the placenta and have been shown to
cause decreased fetal weights and increased fetal/maternal death; therefore, these agents should
be used with caution in pregnant animals.

Captopril
Captopril (Capoten®) inhibits ACE by competing for the angiotensin I binding site (see
Chapter 22). Administration of captopril results in an arteriolar and venous dilation and a
decrease in circulating aldosterone concentrations14. Captopril is thought to improve all stages of
heart failure. It improves exercise tolerance, reduces blood pressure, and prolongs survival in
humans. It improves dogs with mitral regurgitation and dilated cardiomyopathy15, 16. Captopril
can be used in patients with CHF that are refractory to digitalis or demonstrate severe toxicity to
cardiac glycosides3.

In the dog, captopril is given orally at a dose of 0.5 to 1 mg/kg every 8 hours. Doses
greater than 2 mg/kg every 8 hours should be avoided3. It is about 75% bioavailable following
oral administration and this bioavailability is reduced to about 40% in dogs that are fed near the
time of drug administration17. The half-life is approximately 3 hours18. Drug effects are
apparent within 1 hour and usually last for up to 4 hours19. It is usually dosed at 0.5 to 1.5 mg/kg
every 8 hours in cats. Captopril is metabolized in the liver, but the parent drug and its
metabolites are eliminated in the urine. Captopril is excreted in the urine via a renal tubular
transport process. Increasing dosing interval is recommended in patients with renal
compromise3.

Adverse effects of captopril include excessive hypotension which is uncommon unless

using high doses13. This can lead to ataxia and syncope. Glomerular lesions and renal failure
have been noted at doses slightly higher (2 to 4 mg/kg every 8 hours) than the clinical dose13.
Anorexia and other signs of GI distress are common side effects in both the canine and feline3.
For this reason, Enalaril and Benazepril are more often used currently in dogs.

Enalapril maleate
Enalapril maleate (Enacard®, Vasotec®), like all ACE inhibitors, blocks the conversion
of angiotensin I to angiotensin II. Enalapril is the inactive ethyl ester of enalaprilat. Following

27-12
absorption, enalapril is hydrolyzed in the liver to the active form enalaprilat. Enalapril is similar
to captopril but it has a longer duration of action. Enalapril is eliminated in the kidneys (40%)
and feces (36%)3.

Enalapril is dosed at 0.5 mg/kg PO once a day and if the desired response is not observed
the frequency can be changed to every 12 hours. Enalapril concentrations peak about two hours
after administration and the duration of activity is about 12 to 14 hours3. In experimental dogs, a
dose of 0.3 mg/kg inhibited the pressor response to administered angiotensin I (weakly active
and rapidly metabolized to angiotensin II, which is much more active) by about 75%20. This
inhibition lasts for about 6 hours. A dose of 1 mg/kg produced about the same degree of
inhibition (approximately 80%) but the duration of inhibition was longer20. Enalapril has also
been studied in dogs with experimentally-induced mitral regurgitation20. The conclusion of this
study was that the dose of 0.5 mg/kg was the correct dose, although it was not clear whether the
frequency should be every 12 hours or every 24 hours3.

Several other studies have examined the safety and efficacy of enalapril in dogs. In fact,
enalapril is probably one of the best studied veterinary drugs in terms of clinical trials. These
studies21-23 all use acronyms to describe their purposes (IMPROVE-Invasive Multicenter
Prospective Veterinary Evaluation of Enalapril; LIVE-Long term Investigation of Veterinary
Enalapril study; COVE-Cooperative Veterinary Enalapril study) and have enrolled many dogs at
multiple veterinary medical centers. The IMPROVE study used 58 dogs and found that the dogs
on enalapril with dilated cardiomyopathy improved clinically and had better mobility when
compared to placebo. This was not true for dogs with mitral regurgitation21. In the COVE study,
211 dogs were studied at 19 centers22 in a blinded manner. Dogs with dilated cardiomyopathy
improved in overall evaluation, class of heart failure, mobility, activity and degree of pulmonary
edema at 14 and 28 days. At 28 days, there was improvement in appetite, cough, and demeanor.
In dogs with mitral regurgitation, significant improvement was noted in activity, mobility, cough
and overall evaluation. In the LIVE study23, 24, the dogs from the IMPROVE and COVE study
were continued on either placebo or enalapril for up to 15 months. In this study, the dogs that
were administered enalapril remained in the study for longer periods of time. Most of the benefit
from this treatment was observed in the first 60 days23, 24. After that, enalapril-treated and
placebo treated dogs died or developed intractable heart failure at a similar rate. The results of
these three studies clearly indicate benefit from enalapril treatment despite what appears to be
minimal changes in hemodynamic parameters3. For the treatment of CHF in dogs, enalapril is
often given concurrently with diuretics (furosemide) and cardiac glycosides.

Enalapril is available in oral (most commonly used) and injectable formulations. The
most common use of the injectable form is for the treatment of cardiogenic shock. In horses, the
oral formulation has been used; however the first-pass effects are unknown. The adverse effects
of enalapril are similar to those reported for captopril13. Chronic enalapril toxicity is restricted to
the kidney due to 40% of this agent being excreted renally. Healthy dogs given 15/mg/kg daily
did not show any signs of renal toxicity while those given 30 to 60 mg/kg/day showed a dose
related increase in renal toxicity3. The renal toxicity is exacerbated by hypotension25. As noted
in the general ACE inhibitor information above, 3-7 days after the administration of enalapril is
initiated monitoring for azotemia, electrolyte imbalances, and hypotension should occur.

27-13
 Other ACE inhibitors
The success of captopril and enalapril has spawned a search for improved ACE
inhibitors. Several have been recently approved for use in humans. Lisinopril (Prinivil®,
Zestril®), a lysine derivative of enalaprilat, is one of the newer, longer acting ACE inhibitors26.
It does not require metabolic activation. Its bioavailability is between 25 and 50% and is not
affected by feeding. A dose of 0.3 mg/kg inhibits the pressor actions of angiotensin I by 75% at
3 hours, which decreases to 60% at 6 hours and is about 10% at 24 hours. A dose of 1 mg/kg
inhibits ACE by 90% at 4 hours, by 90% at 6 hours, and remains at 40% inhibition at 24 hours.
The recommended dose for lisinopril in the dog is 0.5 mg/kg every 24 hours3. Lisinopril’s side
effects and adverse reactions are similar to those of other ACE inhibitors13.

Benazepril (Fortekor®, Lotensin®, Lotrel®) is a prodrug like enalapril that requires

metabolic activation to form benazeprilat. Benzaprilat has been studied in dogs with
experimentally induced heart failure27. Benazeprilat at 30 μg/kg IV decreased peripheral
resistance 30% and aortic pressure by about 30% with no increase in cardiac output. Although
this drug has not been extensively studied in veterinary patients, its use is becoming more
common for CHF and hypertension with a starting dose of between 0.125 and 1 mg/kg
(veterinary formulation (Fortekor®) stated dose of 0.25 – 0.5 mg/kg) orally every 24 hours. It is
approved for use in dogs in Canada and the UK3. In cats, higher doses may be required with the
veterinary formulation (Fortekor®) stated dose of 0.5 – 1.0 mg/kg orally every 24 hours.

Angiotensin II Receptor Blockers

The therapeutic benefits of ACE inhibition are well established in both veterinary and
human therapeutics. Since the product of ACE activity is angiotensin II, which combines with
angiotensin receptors, an angiotensin receptor blocker should have therapeutic activity
comparable to (or perhaps better) an ACE inhibitor (See Figure 27.8)13. This strategy has been
pursued by the pharmaceutical industry and several angiotensin II receptor antagonists
(specifically targeted against the AT1 receptor) are currently approved for the treatment of
hypertension in the humans. This class of agents is more effective at inhibiting the angiotensin
mediated response and has the added advantage that they do not potentiate the activity of
bradykinin13. ACE inhibition results in potentiation of bradykinin because ACE also inactivates
circulating bradykinin. Very little is known about the use angiotensin II receptor blockers in
veterinary patients at present.

Calcium Channel Blockers

Calcium channel blockers are an important family of agents for lowering peripheral
vascular resistance and treating hypertension. Since vascular smooth muscle contraction is
dependent upon intracellular calcium concentrations, inhibition of the influx of calcium should
reduce the contraction of smooth muscle cells. In support of this concept, calcium channel
blockers do reduce the amount of calcium that reaches intracellular sites. They relax arterial
smooth muscle, and this decreases peripheral resistance and leads to a lowering of blood
pressure28 (see Chapter 27.7). Calcium channel blockers have a pronounced effect on arterial
smooth muscle but little effect on venous smooth muscle. However, they can also affect many

27-14
other tissues that depend on the calcium ion and their use in the clinics has been tempered
somewhat by side effects and the presence of more selective drugs that produce similar
hemodynamic actions with reduced side effects.

There are five structural classes of calcium channel blockers (representative agents given
in italics): phenylalkylamines (verapamil), dihydropyridines (nifedipine, amlodipine, et al.),
benzothiazepines (diltiazem) and diarylaminopropylamine ethers (bepridil)29. While all of
these agents will relax arterial smooth muscle, the dihydropyridines are the most potent for this
indication. While nifedipine has a negative inotropic action on the heart in vitro,it relaxes
vascular smooth muscle at a concentration much lower than those that cause direct effects on the
heart. Following oral administration, arteriolar resistance and blood pressure are lowered,
contractility and ventricular function remain unchanged, and cardiac output is increased while
working against a lower resistance. Venous tone is unchanged. Other dihydropyridines produce
similar hemodynamic changes29.

The use of calcium channel blockers has been limited due to lack of demonstrated
efficacy. In addition, while hypertension, one of the major indications for these agents, is a
major human disease, it is less frequently encountered in veterinary species3. In general,
hypertension in veterinary species is frequently secondary to some other underlying disease and
treatment of the primary disease, rather than the associated hypertension, is preferred. An
exception to this is hypertension secondary to renal disease. In cats with this condition,
amlodipine is effective in lowering systemic arterial pressure30, 31.

The most common side effect associated with calcium channel blockers is hypotension30.
This is especially true with the dihydropyridines. In humans, the most common side effects
include dizziness, headache, nausea,edema formation and hypotension. In veterinary patients,
most of these side effects would not be noticed on routine physical exams3.

Amlodipine
Amlodipine (Norvasc®) (Figure 27.8) is a second generation calcium channel blocker
with selectivity for the L-type calcium channel. Amlodipine has more of an effect on arteriolar
dilation and results in decreased afterload. It appears to be the drug of choice for treating
hypertension secondary to renal disease in cats and perhaps in dogs3. Additionally, this agent
has been used to treat hypertension associated with hyperthyroid thyrotoxic cardiomyopathy. In
a large scale clinical trial in humans, amlodipine was found to reduce death related to dilated
cardiomyopathy, but not in patients with ischemic heart disease32.

Amlodipine is well absorbed orally with a bioavailability of about 90% in the dog33. The
drug plasma concentrations peak at about 6 hours after dosing. About 45% of the drug is
excreted in the urine and 45% in the feces. The plasma half life is approximately 30 hours
following IV administration33, 34. The oral dose is estimated to be between 0.05 to 0.2
mg/kg/day3.

β Adrenergic Receptor Blockers

β-adrenergic blocking agents were not expected to have an anti-hypertensive effect when

27-15
administered to human patients. However, an anti-hypertensive effect has been subsequently
demonstrated for propranolol and all other β blockers, that is clearly mediated through β
receptor blockade. This effect, while counterintuitive (see Chapter 9) appears to be mediated by
a reduction in the secretion of renin and a decrease in angiotensin II2. While some success with
β blockers has been reported in dogs with experimental mitral regurgitation35, little is known
about β blockers in veterinary patients, and most information is largely anecdotal3.

REFERENCES

1. Ooi, H and Colucci, W. Pharmacological Treatment of Heart Failure. In Goodman

and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed., Eds Hardman, J. and
Limbird, L., pp. 901-932.

2. Oates, J. A. and Brown, N. J. (2001). Antihypertensive Agents and the Treatment of

Hypertension. In Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed.,
Eds Hardman, J. and Limbird, L., pp. 871-900.

3. Kittleson, M. (1998). Management of Heart Failure. In Small Animal Cardiovascular

Medicine, Eds. Kittleson, M. and Kienle, R., pp. 149-194.

4. Yamamoto, J., Trippodo, N.C., and Ishise, S. (1980). et al: Total vascular pressure-volume
relationship in the conscious rat. Am J Physiol, 238:H823.

5. Kittleson, M.D., Hamlin, R.L. (1981). Hydralazine therapy for sever mitral regurgitation in a
dog. J Am Vet Med Assoc, pp. 179:903.

6. Kittleson, M.D., Eyster, G.E. and Olivier, N.B. (1983). et al: Oral hydralazine therapy for
chronic mitral regurgitation in the dog. J Am Vet Med Assoc, pp. 182:1205.

7. Spokas. E.G. and Wang, H.H. (1980). Regional blood flow and cardiac responses to
hydralazine. J Pharmacol Exp Ther. pp. 212:294.

8. Kittleson, M.D. and Hamlin, R.L. (1983). Hydralazine pharmacodynamics in the dog, Am J
Vet Res, pp. 44:1501.

9. Kittleson, M.D., Johnson, L.E. and Oliver, N.B. (1985). Acute hemodynamic effects of
hydralazine in dogs with chronic mitral regurgitation. J Am Vet Med Assoc pp. 187:258.

10. Hamlin, R.L. (1991). Evidence for or against clinical efficacy of preload reducers. In
Hamlin RL, ed., The Veterinary Clinics of North America. Vol. 21, ed. 5, Philadelphia, WB
Saunders.

11. Murad, F. (1986). Cyclic guanosine monophosphate as a mediator of vasodilation. J. Clin.

Invest., pp. 78: 1-5.

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12. Waldman, S. and Murad, F. (1987). Cyclic GMP synthesis nad function. Pharmacol. Rev,.
39: 163-196.

13. Jackson, E.K. Renin and Angiotensin. In Goodman and Gilman’s The Pharmacological
Basis of Therapeutics. 10th ed., Eds Hardman, J. and Limbird, L., pp. 809-842.

14. Vidt, D.G., Bravo, E.L. and Rouad, F.M. (1982). Captopril. N Engl J Med, pp. 306:214.

15. Blackford, L.W., Golden, A.L. and Bright, J.M. (1990). et al: Captopril provides sustained
hemodynamic benefits in dogs with experimentally induced mitral regurgitation. Vet Surg, pp.
19:237.

16. Kittleson, M.D. (1986). Positive inotropic agents and captropril. Proceedings of the Ninth
Annual Kal Kan Symposium. Vernon, Calif, Kal Kan Foods, Inc, p. 19.

17. Fox, P.R., Sisson,D,D. (1995). Angiotensin-converting enzyme inhibitors. In Bonagura JD,
ed: Current veterinary therapy. XII. Small animal practice, Philadelphia, WB Saunders.

18. Singhvi, S.M., Peterson, A.E. and Ross, J.J. (1981). et al: Pharmacokinetics of captopril in
dogs and monkeys. J Pharm Sci, pp. 70:1108.

19. Kittleson, M.D., Johnson, L.E. and Pion, P.D. et al: The acute haemodynamic effects of
captopril in dogs with heart failure. J Vet Pharmacol Ther, pp. 16:1.

20. Benitz, A.M., Hamlin, R.L. and Ericsson, G.F. (1991). Titration of enalapril dose for dogs
with induced heart failure. Proc Annu Vet Med Forum, pp. 879 (abstract).

21. IMPROVE Study Group: Acute and short-term hemodynamic echocardiographic, and
clinical effects of enalapril maleate in dogs with naturally acquired heart failure: results of the
Invasive Multicenter PROspective Veterinary Evaluation of Enalapril study. J Vet Intern Med,
pp. 9:234.

22. COVE Study Group. (1995). Controlled clinical evaluation of enalapril in dogs with heart
failure: results of the Cooperative Veterinary Enalapril Study Group. J Vet Intern Med, pp.
9:243.

23. Ettinger, S.J., Benitz, A.M. and Ericsson, G.F. (1994). Relationship of enalapril with other
CHF treatment modalities Proc Annu Vet Med Forum, pp. 251.

24. Fox, P.R. (1992). The effect of drug therapy on clinical characteristics and outcome in dogs
with heart failure, Proc Annu Vet Med Forum, pp. 592.

25. MacDonald, J.S., Bagdon, W.J. and Peter, C.P. (1987). et al: Renal effects of enalapril in
dogs. Kidney Int Suppl, 20:S148.

26. Sweet, C.S. and Ulm, E.H. (1988). Lisinopril. Cardiovasc Drug Rev, pp. 6:181.

27-17
27. Nakazawa, M., Sawanobori, T. and Iwasaki, K. (1991). et al: Hemodynamic effectsof
benazeprilat in the anesthetized dog with acute left ventricular failure, Jpn J Pharmacol, pp.
56:369.

28. Lehmann, H., Hochrein, H., Witt, E. and Meis, H. (1983). Hemodynamic effectsof calcium
antagonists. Review. Hypertension, 5: II66-II73.

29. Kerins, D.M., Robertson, R.M., and Robertson, D. Drugs used for the treatment of
Myocardial Ischemia. In Goodman and Gilman’s The Pharmacological Basis of Therapeutics.
10th ed., Eds Hardman, J. and Limbird, L., pp. 843-870.

30. Henik, R.A., Snyder, P.S. and Volk, L.M. (1997). Treatment of systemic hypertension in
cats with amlodipine besylate. J Am Anim Hosp Assoc, pp. 33:226.

31. Snyder, P.S. (1997). Blinded clinical trial of amlodipine in cats with hypertension. J Vet
Intern Med, pp. 11:139 (abstract).

32. Packer, M., O’Conner, C.M. and Ghali, J.K. (1996). et al: Effect of amlodipine on
morbidity and mortality in severe chronic heart failure. Prosepective Randomized Amlodipine
Survival Evaluation Study Group,. N Engl J Med, pp. 335:1107.

33. Stopher, D.A., Beresford, A,P. and Macrae, P.V. (1988). et al: The metabolism and
pharmacokinetics of amlodipine in humans and animals. J Cardiovasc Pharmacol, 12(suppl
7):S558.

34. Beresford, A.P., Macrae, P.V. and Stopher, D.A. (1988). Metabolism of amlodipine in the
rat and the dog: a species difference,. Xenobiotica, pp. 18:169.

35. Tsutsui, H., Spinale, F. and Nagaatsu, M. (1994). et al.: Effects of Chronic beta-blockade
on the left ventricular and cardiomyocyte abnormalities of chronic canine mitral regurgitation. J.
Clin. Invest., pp. 93: 2639.

SUGGESTED READINGS

1. Adams, H. R. (2001). Digitalis and Vasodilator Drugs. In VeterinaryPharmacology and

Therapeutics,. 8th ed., Ed H. R. Adams, pp. 453-481.

2. Boothe, D. M. (2001). Therapy of Cardiovascular Diseases. In Small Animal Clinical

Pharmacology and Therapeuti, . Ed. D. M. Boothe, pp. 553-601.

3. Kittleson, M. (1998). Management of Heart Failure. In Small Animal Cardiovascular

Medicine, Eds. Kittleson, M. and Kienle, R., pp. 149-194

27-18
4. Kienle, R. and Kittleson, M. (1998). Pulmonary and Systemic Arterial Hypertension. In
Small Animal Cardiovascular Medicine, Eds. Kittleson, M. and Kienle, R., pp. 433-448.

5. Oates, J. A. and Brown, N. J. (2001). Antihypertensive Agents and the Treatment of

Hypertension. In Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed.,
Eds Hardman, J. and Limbird, L., pp. 871-900.

6. Ooi, H and Colucci, W. Pharmacological Treatment of Heart Failure. In Goodman and

Gilman’s The Pharmacological Basis of Therapeutics, 10th ed., Eds Hardman, J. and Limbird, L.,
pp. 901-932.

27-19