Endogenous and Exogeneous Nitric Oxide Donors

8/14/2019 Endogenous and Exogeneous Nitric Oxide Donors

1/6

Asurvey 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 fromthe exhaust of cars, thus con-

tributing to the formation of

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

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 betterknown for their action as fertil-

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 EndotheliumThe vascular endothelium,

previously believed to be nomore than a cellular lining with

a barrier role2 of maintaining

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-

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

macrophage growth factors,

are responsible for vascular

remodeling.

The endothelium-derived re-

laxing factor is produced in the

cytoplasm of vascular endothe-

lial cells, neurovascular cells of

Susan E. Johnson, DVM, MSThe Ohio State University

The Compendium June 1996 Small Animal

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

oxidation of L-arginine, thereby

producing nitric oxide and L-

citrulline.10

Citrulline also is produced

from glutamine via glutamate

and ornithine in the intestinal ep-

ithelial cells and is transported

SERIESEDITOR

the central nervous system,5

vascular smooth muscle cells,

myocardium,6 endocardium,

macrophages, and possibly

by the bloodstream to the kid-

neys. Citrulline is converted to

arginine in the proximal tubules

and made available for nitric

I Endothelium-derived relaxing factor is probablya complex that liberates nitric oxide or a very

similar substance.I Some nonendothelial agents, such as exogenous

nitrovasodilators, can mimic the effects ofendothelium-derived relaxing factor.

I Nitrovasodilators have many beneficial effects astreatment for canine and feline patients withcongestive heart failure and no known incom-patibility with other common cardiovasculardrugs.

I Dietary deficiency of arginine may be a contrib-utory cause of hypertension and thrombosis incats.

KEYP

OINTS

Endogenous and ExogenousNitric Oxide Donors*

THERAPEUTICS IN PRACTICE V

Gerard J. Rubin, DVMDiplomate, ACVIM (Cardiology

and Internal Medicine)Animal Internal Medicine Clinic

Dallas, Texas

*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.


2/6

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

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 NitricOxide Synthase

Nitric oxide synthase is inhib-

ited by L-arginine analogues7

(i.e., NG-monomethyl-L-argi-

nine, NG-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:

Small Animal The Compendium June 1996

I Induction of an endotheli-

um-dependent constriction

of rabbit aortic rings.16

I Inhibition of endothelium-

dependent relaxation in-

duced by acetylcholine and

other relaxant substances.16

I Vascular smooth muscle

constriction by acetylcho-

line.17

I Increased blood pressure

accompanied by decrease

in the glomerular filtration

rate.18

I 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-

L-ornithine is a selective in-

hibitor of nitric oxide synthase

in neutrophils.22

NitrovasodilatorsNonendothelial agents that

mimic the effects of EDRF areexogenous nitrovasodilators,

atrial natriuretic factor,23 bovine

retractor penis inhibitory factor,

prostacyclin,14 and-adrenergicagonists (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. Threegroups 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-

oxidecontaining 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 ascysteine.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

TABLE ONEComparison of Endothelium-Derived Relaxing Factor (EDRF)and Prostacyclin21

Characteristic EDRF Prostacyclin

Source L-arginine Arachidonic acid

Pathway Nitric oxide synthase Cyclooxygenase

Mechanism of action Cyclic guanine Cyclic adenosinemonophosphate monophosphate

Half-life Approximately 6 seconds Approximately 30 seconds

Inhibitors Oxyhemoglobin, Aspirin and othermethylene blue nonsteroidal

antiinflammatory drugs

Stimulus for release Acetylcholine, calcium Acetylcholine, calciumionophore A23187, ionophore A23187,wall stress, thromboxane A2, wall stress, thrombin,serotonin, thrombin hypoxia

Catabolism Superoxide radicals Hydrolysis


3/6

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,

and increased arterial compli-

ance boost stroke volume and

therefore cardiac output. As a

result, wall stress is decreased

and oxygen consumption is re-

duced. Nitrovasodilators exert a

relaxing effect on the ventricularmyocardium by increasing

compliance and allowing dia-


stolic filling at a lower filling

pressure without affecting sys-

tolic function.33

Nitrovasodilators have no

known incompatibility with other

commonly used cardiovascular

drugs and may be used withthem, some synergistically.

Chronic nitrate therapy is

believed to improve the hemo-

dynamic benefits of angiotensin-

converting enzyme inhibitors.34

In Veterans Administration

Cooperative VasodilatorHeart

Failure Trials,35 a combination

of hydralazine and nitrates wasshown to have a favorable ef-

fect on survival when com-

TABLE TWOComparison of Forms of Nitric Oxide Synthase

Constitutive Inducible

Cytosolic Cytosolic

NADPHadependent NADPHadependent

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

aNicotinamide adenine dinucleotide phosphate.

TABLE THREEComparison of Endothelium-Derived Relaxing Factor (EDRF) andNitrovasodilators22

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


4/6


pared with a placebo. A study

of the effect of drugs on ven-

triculoarterial coupling showed

that nitrates delayed the pe-

ripheral wave reflection and im-

proved the mechanical efficien-

cy of the left ventricle whilehydralazine increased the char-

acteristic impedance and short-

ened wave reflection, thus

decreasing the mechanical ef-

ficiency of the heart. 36 It is

conceivable that trials using

nitrates without hydralazine

might result in a more favor-

able response.

Some available forms of ni-

trovasodilators follow37:

I Amyl nitrite is used by in-halation mainly for diagnos-

tic purposes.

I Nitroglycerin is available

as a sublingual tablet, oral

sustained-release tablet, 2%

ointment, transdermal paste,

and intravenous solution.

I Nitroprusside is available for

intravenous use only.

I Isosorbide dinitrate is avail-

able as a sublingual tablet,

chewable tablet, tablets of

various sizes, oral spray,

ointment, and intravenous

solution.

I Pentaerythritol tetranitrate

is available as a sublingual

tablet.

I Erythrityl tetranitrate is

available as a sublingual

tablet and an oral tablet.

I Molsidomine is a syndon-

imine that releases nitric ox-

ide without requiring the

presence of a thiol groupand is less inclined to cause

tolerance.8 Molsidomine is

given orally but at this time

is not available in the United

States.

I Nicorandil is a nicotinamide

nitrate that has a dual cellu-

lar mechanism as a potas-

sium channel activator and

a nitric oxide contributor.

Nicorandil acts by dilating

large coronary arteries and

as a preload and afterload

reducer. It causes less toler-

ance than do the nitrates.38

Nicorandil is given orally but

at this time is not available

in the United States.

Use in VeterinaryMedicine

I have used nitrates for al-

most 50 years in clinical prac-

tice, originally at the suggestion

of another practitioner, Dr.

Arthur Trayford, to treat old dog

cough (by prescribing mannitol

hexanitrate) and subsequentlyfor various forms of diagnosed

heart disease. The old dog

cough was probably caused by

pulmonary edema or mitral re-

gurgitation.

Although reports of the use

of nitrovasodilators in veteri-

nary medicine3941 have been

relatively sparse, a number of

pathologic conditions may be

improved by their use. Conges-

tive heart failure, especially that

attributable to mitral regurgita-

tion, fits this category.

Early studies42 of dogs have

shown that intramural coronary

arterial lesions, myocardial

necrosis, and myocardial fibro-

sis (mostly attributable to isch-

emia) are common findings.

Dogs with heart failure are at

high risk for developing valvular

endocardiosis, arterial lesions,

and infarcts, which might be

avoided with early treatment us-ing nitrovasodilators. The vaso-

constrictor effects of congestive

heart failure also might be re-

versed. Inoperable congenital

cardiac conditions, such as sep-

tal defects, patent ductus arte-

riosus with right- to left-sided

shunts, aortic stenosis, and

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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 notonly 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, -adrenergic blockers, calcium

blockers, and angiotensin-

converting enzyme inhibitors.

The dose of isosorbide dinitrate

used is from 14 to 1 mg/kg

twice daily in dogs and cats.

The dose of 2% nitroglycerin

ointment is from

1

4

to 1 inchrubbed 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:

I Conventional therapy (i.e.,

digoxin and/or furosemide)

I Conventional therapy plus

angiotensin-converting en-zyme inhibitors


nitrovasodilators


angiotensin-converting en-

zyme inhibitors and nitro-

vasodilators

I Nitrovasodilators and/or

angiotensin-converting

enzyme inhibitors without

conventional therapy.

ConclusionThe 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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