The Compendium June 1996 Small Animal

THERAPEUTICS IN PRACTICE V

Endogenous and Exogenous

Nitric Oxide Donors*

Gerard J. Rubin, DVM
Diplomate, ACVIM (Cardiology
and Internal Medicine)
Animal Internal Medicine Clinic
Dallas, Texas
to endothelium-derived relaxing
factor and vice versa.
Although endogenous nitro-
vasodilators have been used
pharmacologically for more
than 100 years, the mechanism
of their action was unknown
until 1980. Nitrates were better
known for their action as fertil-
derived contracting factors (ED-
CFs), thromboxane-A2, and free
radicals.4 Most relaxants are in-
hibitors of growth, and most
constrictors are stimulators of
growth.2 In response to some
stimuli, the endothelium pro-
duces growth factors that,
combined with platelet and
most of the cells of the body.7,8
The factor is probably a com-
plex that liberates nitric oxide
and may contain a thiol.9 The
major substrate is the amino
acid L-arginine found in cellular
cytoplasm. The dioxygenase
enzyme nitric oxide synthase
(NOS) on stimulation catalyzes

A
survey of scientific ma-
terial written from 1992
to 1995 revealed that
almost 6000 articles on nitric
oxide (NO) and the endotheli-
um-derived relaxing factor
(EDRF) have been published.
The quantity of articles seems
considerable for a small mol-
ecule whose major claim to
fame before 1980 was as an
environmental pollutant from
the exhaust of cars, thus con-
tributing to the formation of
izers and in the manufacturing
of bombs. The discovery of the
importance of nitric oxide in
vascular, neural, phagocytic,
and a myriad of other functions
opened a vast unexplored realm
of pathophysiology and phar-
macology.
The Endothelium
The vascular endothelium,
previously believed to be no
more than a cellular lining with
a barrier role2 of maintaining
macrophage growth factors, oxidation of L-arginine, thereby
are responsible for vascular producing nitric oxide and L-
remodeling. citrulline.10
The endothelium-derived re- Citrulline also is produced
laxing factor is produced in the from glutamine via glutamate
cytoplasm of vascular endothe- and ornithine in the intestinal ep-
lial cells, neurovascular cells of ithelial cells and is transported
■ Endothelium-derived relaxing factor is probably
a complex that liberates nitric oxide or a very
similar substance.
■ Some nonendothelial agents, such as exogenous
nitrovasodilators, can mimic the effects of
KEY POINTS

acid rain and destruction of the
ozone layer.1 Endothelium-de-
rived relaxing factor is believed
to be nitric oxide or a very simi-
lar substance, and much of the
literature uses the terms inter-
changeably. Thus, for the pur-
pose of this presentation, any
reference to nitric oxide should
be interpreted as also referring
*This column is derived from an in-
depth study that includes extensive
referencing. A copy of the study,
along with the references, is avail-
able from the author on request.
the internal integrity of blood
vessels, is now known to be a
prodigious manufacturer of va-
soactive chemicals. The en-
dothelium exhibits all the char-
acteristics of an endocrine
gland.1 The vasorelaxants pro-
duced are the endothelium-
derived relaxing factor, endothe-
lium-derived hyperpolarizing
factor (EDHF), prostacyclin, and
C-type natriuretic peptide (CNP)
(Table One). Vasoconstrictors
produced are endothelin-1, 3
other endothelins, endothelium-
endothelium-derived relaxing factor.
■ Nitrovasodilators have many beneficial effects as
treatment for canine and feline patients with
congestive heart failure and no known incom-
patibility with other common cardiovascular
drugs.
■ Dietary deficiency of arginine may be a contrib-
utory cause of hypertension and thrombosis in
cats.
the central nervous system,5 by the bloodstream to the kid-
vascular smooth muscle cells, neys. Citrulline is converted to
myocardium, 6 endocardium, arginine in the proximal tubules
macrophages, and possibly and made available for nitric

SERIES Susan E. Johnson, DVM, MS

EDITOR The Ohio State University
Small Animal
TABLE ONE
Comparison of Endothelium-Derived Relaxing Factor (EDRF)
and Prostacyclin21
Characteristic
Source
Pathway
Mechanism of action
Half-life
Inhibitors
Stimulus for release
Catabolism
oxide synthesis in other tissue.
Citrulline also is converted to
arginine in endothelial cells and
macrophages.11 The L-citrulline
is recycled back to L-arginine by
incorporation of one nitrogen
from NH3.12 Cats cannot produce
arginine in sufficient quantities
from ornithine or citrulline and
therefore require large amounts
in the diet.13,14
Nitric oxide synthase occurs
in two major forms, constitu-
tive and inducible NOS (iNOS),
and in three major isoforms.
Inducible NOS, also referred to
as isoform II, requires induc-
tion by immunologic stimula-
tion.1 Constitutive nitric oxide
synthases (cNOSs), isoform I
and III, are present under nor-
mal physiologic or constitu-
tional conditions, thus the
designation constitutive. Iso-
form I is produced in neuro-
vascular endothelial cells. 5
EDRF
L-arginine
Nitric oxide synthase
↑ Cyclic guanine
monophosphate
Approximately 6 seconds
Oxyhemoglobin,
methylene blue
Acetylcholine, calcium
ionophore A23187,
wall stress, thromboxane A2,
serotonin, thrombin
Superoxide radicals
Isoform III is produced in car-
diovascular endothelial cells,
endocardium, and myocardi-
um.
The following formula helps
to explain the process:
L-arginine + NOS =
EDRF + L-citrulline
Inhibitors of Nitric
Oxide Synthase
Nitric oxide synthase is inhib-
ited by L-arginine analogues7
(i.e., N G-monomethyl-L-argi-
nine, N G-nitro-L-arginine methyl
ester, and N-iminoethyl- L -
ornithine (Table Two). This inhi-
bition can be overcome by the
addition of L-arginine but not D-
arginine. 15 These inhibitory
agents have been used to define
the effects of nitric oxide by
blocking nitric oxide production
and observing the results. Ex-
amples are:
Prostacyclin
Arachidonic acid
Cyclooxygenase
↑ Cyclic adenosine
monophosphate
Approximately 30 seconds
Aspirin and other
nonsteroidal
antiinflammatory drugs
Acetylcholine, calcium
ionophore A23187,
wall stress, thrombin,
hypoxia
Hydrolysis
■ Induction of an endotheli-
um-dependent constriction
of rabbit aortic rings.16
■ Inhibition of endothelium-
dependent relaxation in-
duced by acetylcholine and
other relaxant substances.16
■ Vascular smooth muscle
constriction by acetylcho-
line.17
■ Increased blood pressure
accompanied by decrease
in the glomerular filtration
rate.18
■ Induction of dose-related
coronary vasoconstriction.19
Inducible nitric oxide syn-
thase is also inhibited by gluco-
corticoid. L-canavanine inhibits
nitric oxide synthase in macro-
phages but not in endothelial
cells, platelets, and the brain.20
Aminoguanidine can be a selec-
tive inhibitor of inducible nitric
oxide synthase.21 N-iminoethyl-
The Compendium June 1996
L -ornithine is a selective in-
hibitor of nitric oxide synthase
in neutrophils.22
Nitrovasodilators
Nonendothelial agents that
mimic the effects of EDRF are
exogenous nitrovasodilators,
atrial natriuretic factor,23 bovine
retractor penis inhibitory factor,
prostacyclin,14 and β-adrenergic
agonists (Table Three).
The pharmacologic and bio-
chemical effects of endotheli-
um-dependent vasodilators and
nitrovasodilators24 are almost
the same.25 Nitrovasodilators
function by releasing nitric ox-
ide independent of L-arginine
and nitric oxide synthase. Three
groups of drugs are considered
to be nitrovasodilators.
The first group is com-
pounds that contain a nitrate
ester bond (R-O-NO2). Some of
the drugs belonging to the ni-
trate ester group are isosorbide
dinitrate (ISDN), isosorbide-5-
mononitrate (IS-5-MN), pen-
taerythritol tetranitrate, and
mannitol hexanitrate.
The second group is nitro-
compounds, which have a car-
bogen-nitrogen bond (R-C-
NO2). Belonging to this group is
nitroglycerin (chemical name:
glyceryl trinitrate).
The third group is nitric-
oxide–containing compounds,
such as nitroprusside and mol-
sidomine. Nitroprusside and
molsidomine can release nitric
oxide spontaneously, while oth-
er compounds require prior in-
teraction with a thiol, such as
cysteine.25
Organic nitrates (ISDN, IS-5-
MN, and nitroglycerin) are initial-
ly converted to nitric acid (HNO3)
intracellularly and subsequently
to S-nitrosothiol (SNO) by the
addition of a sulfhydryl (SH)
group. The S-nitrosothiols and
Small Animal
nitric oxide activate soluble
guanylate cyclase (GC), which
increases cyclic guanine mono-
phosphate (cGMP). Removal of
endogenous nitric oxide produc-
tion or the endothelium en-
hances the sensitivity of the vas-
culature to exogenous nitrates
and catecholamines,26 possibly
because of the up-regulation of
soluble guanylate cyclase.27 Ni-
trovasodilators have greater ac-
tion on coronary arteries than on
peripheral arteries, and veins are
more sensitive than arteries. The
latter effect may be attributable
to arteries producing more en-
dogenous nitric oxide than veins
do.28 It has also been found that
veins are more subject to devel-
oping tolerance to nitrovasodila-
tors than are arteries.29 Of the
three major nitrovasodilators, ni-
troglycerin is more potent than
ISDN, which is more potent than
IS-5-MN.30
Following are two formulas
explaining the process:
Organic nitrates → HNO3
+ SH → SNO
EDRF [SNO or NO] →
↑ GC → ↑ cGMP →
↓ CA++ → ↓ contraction
Nitrovasodilators have many
beneficial effects in a patient
with congestive heart failure.31
They produce venous dilation
and increase venous capaci-
tance, thereby increasing pe-
ripheral pooling of blood.32 The
result reduces left- and right-
sided ventricular end-diastolic
pressure and end-diastolic vol-
ume, thereby unloading the
heart and reducing myocardial
oxygen consumption. The dila-
tion of coronary arteries also
leads to an increase of oxygen
supply to the heart. Afterload
reduction by arterial dilation, re-
duction of arterial impedance,
The Compendium June 1996
and increased arterial compli- stolic filling at a lower filling believed to improve the hemo-
ance boost stroke volume and pressure without affecting sys- dynamic benefits of angiotensin-
therefore cardiac output. As a tolic function.33 converting enzyme inhibitors.34
result, wall stress is decreased Nitrovasodilators have no In Veterans Administration
and oxygen consumption is re- known incompatibility with other Cooperative Vasodilator–Heart
duced. Nitrovasodilators exert a commonly used cardiovascular Failure Trials,35 a combination
relaxing effect on the ventricular drugs and may be used with of hydralazine and nitrates was
myocardium by increasing them, some synergistically. shown to have a favorable ef-
compliance and allowing dia- Chronic nitrate therapy is fect on survival when com-
TABLE TWO
Comparison of Forms of Nitric Oxide Synthase
Constitutive Inducible
Cytosolic Cytosolic
a
NADPH dependent NADPHa dependent
Requires tetrahydrobiopterin Requires tetrahydrobiopterin
Dioxygenase Dioxygenase
L-arginine analogues inhibit L-arginine analogues inhibit
++
Ca and/or calmodulin dependent Ca++ independent
Picomoles of nitric oxide released Nanomoles of nitric oxide released
Short-lasting release Long-lasting release
Unaffected by glucocorticoids Inhibited by glucocorticoids
Isoform I and III Isoform II
a
Nicotinamide adenine dinucleotide phosphate.
TABLE THREE
Comparison of Endothelium-Derived Relaxing Factor (EDRF) and
Nitrovasodilators22
Nitrovasodilator EDRF
Stimulates cGMP Stimulates cGMP
Exogenously administered Endogenously released
Prolonged circulatory effect Transient circulatory effect
Increased activity in coronary disease Decreased activity in coronary
artery disease
Systemically active Locally active
Inhibits smooth muscle growth Inhibits smooth muscle growth
Inhibits myocyte growth Inhibits myocyte growth
Tolerance may develop No tolerance demonstrated
 Small Animal The Compendium June 1996

COMPENDIUM
ON CONTINUING EDUCATION
®
pared with a placebo. A study sium channel activator and
F O R T H E P R A C T I C I N G V E T E R I N A R I A N
of the effect of drugs on ven- a nitric oxide contributor.
Veterinary Technician reprints also available triculoarterial coupling showed Nicorandil acts by dilating
that nitrates delayed the pe- large coronary arteries and
2000 PRICE SCHEDULE* ripheral wave reflection and im- as a preload and afterload
2 4 8 12 16 proved the mechanical efficien- reducer. It causes less toler-
Quantity pages pages pages pages pages
cy of the left ventricle while ance than do the nitrates.38
Black & White hydralazine increased the char- Nicorandil is given orally but
100 $ 108 $ 204 $ 416 $ 604 $ 784 acteristic impedance and short- at this time is not available
500 152 296 616 896 1,156
1000 208 412 868 1,260 1,628 ened wave reflection, thus in the United States.
5000 636 1,264 2,828 4,076 5,160 decreasing the mechanical ef-
10,000 1,172 2,332 5,280 7,596 9,572 ficiency of the heart. 36 It is Use in Veterinary
Color conceivable that trials using Medicine
100 $ 972 $1,408 $2,856 $4,180 $5,380 nitrates without hydralazine I have used nitrates for al-
500 1,152 1,612 3,112 4,704 6,040
1000 1,264 1,840 3,428 5,260 6,852 might result in a more favor- most 50 years in clinical prac-
5000 2,328 3,600 7,140 10,672 12,168 able response. tice, originally at the suggestion
10,000 3,280 5,792 10,640 16,704 18,812 Some available forms of ni- of another practitioner, Dr.
*Price includes UPS Ground Shipping to one location. trovasodilators follow37: Arthur Trayford, to treat old dog
ORDER FORM cough (by prescribing mannitol
Quantity _____________ ❏ Black & White ❏ Color ■ Amyl nitrite is used by in- hexanitrate) and subsequently
❏ With Review Questions ❏ Without Review Questions halation mainly for diagnos- for various forms of diagnosed
tic purposes. heart disease. The old dog
Author _________________________________________
■ Nitroglycerin is available cough was probably caused by
Title of Article ___________________________________ as a sublingual tablet, oral pulmonary edema or mitral re-
______________________________________________ sustained-release tablet, 2% gurgitation.
From Vol. _________________ No. ______________ ointment, transdermal paste, Although reports of the use
and intravenous solution. of nitrovasodilators in veteri-
❏ Compendium ❏ Veterinary Technician
■ Nitroprusside is available for nary medicine39–41 have been
❏ Payment Enclosed (All payments must be in US funds drawn intravenous use only. relatively sparse, a number of
on a US branch of a US bank.)
■ Isosorbide dinitrate is avail- pathologic conditions may be
❏ Purchase Order Attached able as a sublingual tablet, improved by their use. Conges-
Contact Person ___________________________________ chewable tablet, tablets of tive heart failure, especially that
Phone __________________________________________ various sizes, oral spray, attributable to mitral regurgita-
ointment, and intravenous tion, fits this category.
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solution. Early studies42 of dogs have
NAME
■ Pentaerythritol tetranitrate shown that intramural coronary
is available as a sublingual arterial lesions, myocardial
COMPANY OR PRACTICE tablet. necrosis, and myocardial fibro-
ADDRESS
■ Erythrityl tetranitrate is sis (mostly attributable to isch-
available as a sublingual emia) are common findings.
CITY STATE ZIP tablet and an oral tablet. Dogs with heart failure are at
BILL TO: ■ Molsidomine is a syndon- high risk for developing valvular
NAME
imine that releases nitric ox- endocardiosis, arterial lesions,
ide without requiring the and infarcts, which might be
COMPANY OR PRACTICE presence of a thiol group avoided with early treatment us-
ADDRESS
and is less inclined to cause ing nitrovasodilators. The vaso-
tolerance.8 Molsidomine is constrictor effects of congestive
CITY STATE ZIP given orally but at this time heart failure also might be re-
Detach and Mail to: Reprints Department
is not available in the United versed. Inoperable congenital
Veterinary Learning Systems States. cardiac conditions, such as sep-
275 Phillips Boulevard ■ Nicorandil is a nicotinamide tal defects, patent ductus arte-
Trenton, NJ 08618 nitrate that has a dual cellu- riosus with right- to left-sided
No telephone calls accepted.
lar mechanism as a potas- shunts, aortic stenosis, and
The Compendium June 1996
valvular dysplasia, may benefit
from the use of nitrovasodila-
tors. Hypertrophic cardiomyop-
athy may be aided by the use of
nitrovasodilators, but dilatory
cardiomyopathy may not. Dogs
with heartworm disease not
only have pulmonary hyperten-
sion but have endothelial dam-
age as well. It has been demon-
strated that factors in serum
from heartworm-diseased dogs
intefered with endothelium-
dependent relaxation. This de-
creased relaxation is corrected
by addition of nitroglycerin.43
These patients may profit by
adding nitrovasodilators to the
treatment regimen.
Cats are subject to hyperten-
sion as well as to cerebrovas-
cular and caudal aortic throm-
bosis. Nitrovasodilators may be
beneficial in these animals. Cats
have a high dietary requirement
for arginine because they can-
not produce sufficient quanti-
ties from ornithine or citrul-
line.13,14 Dietary deficiency of
arginine may possibly be a con-
tributory cause of the hyperten-
sion and thrombosis diagnosed
in cats.
I have used nitrovasodilators
without observing adverse ef-
fects in animals receiving car-
dioglycosides, diuretics, β-
adrenergic blockers, calcium
blockers, and angiotensin-
converting enzyme inhibitors.
The dose of isosorbide dinitrate
used is from 1⁄ 4 to 1 mg/kg
twice daily in dogs and cats.
The dose of 2% nitroglycerin
ointment is from 1⁄4 to 1 inch
rubbed into hairless parts of the
body (inner thigh or inner ear
pinna) twice daily. Although the
benefits described here have
been anecdotal, the results war-
rant further trials.
The following trial groups are
recommended for a thorough
pharmacologic study of animals
with congestive heart failure:
■ Conventional therapy (i.e.,
digoxin and/or furosemide)
■ Conventional therapy plus
angiotensin-converting en-
zyme inhibitors
■ Conventional therapy plus
nitrovasodilators
■ Conventional therapy plus
angiotensin-converting en-
zyme inhibitors and nitro-
vasodilators
■ Nitrovasodilators and/or
angiotensin-converting
enzyme inhibitors without
conventional therapy.
Conclusion
“The nitrates have not
been included in most of
the trials carried out in
recent years, not because
they have been found to
be ineffective in the syn-
drome, but because they
are generic drugs without
adequate profit margin.”44
“Because nitrates are very
old drugs and are no
longer patented, it is
unlikely that the pharma-
ceutical industry will be
motivated to fund large
placebo-controlled trials
of nitrate therapy.”45
Endogenous and exogenous ni-
trovasodilators have been stud-
ied in detail, and there is little
doubt of the efficacy of nitrova-
sodilators in treating cases of
congestive heart failure.46 The is-
sues that remain to be solved
are the best method of use and
the extent of nitric oxide toxicity
under certain conditions.
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