Beneficial Actiohs of Nitrates in

Cardiovascular Disease
Jonathan Abrams, MD

Nitroglycerin and the long-acting nitrates have been with lower systolic and diastolic pressures. These
used in cardiovascular medicine for > 100 years. changes are caused by a redistribution of the circu-
Nitrates are widely utilized for the various angina1 fating blood volume away from the heart to the ve-
syndromes and are also used in congestive heart fail- nous capacitance system, with a fall in venous return
ure and patients with left ventricular dysfunction. The to the heart. The afterload or arterial effects of nitrates
potential mechanisms for relief of myocardial isch- are also useful in decreasing myocardial oxygen con-
emia with nitrates are multiple. The nitrovasodilators sumption. Considerable evidence confirms a variety of
are a related group of drugs that result in the forma- mechanisms whereby nitrates increase coronary
tion of nitric oxide (NO) within vascular smooth mus- blood flow, including epicardial coronary artery di-
cle cells. NO stimulates the enzyme guanylate cyclase, lation, stenosis enlargement, enhanced collateral size
which results in increases in cyclic guanosine mono- and flow, improvement of endothelial dysfunction,
phosphate and vasodilation. In the presence of ath- and prevention or reversal of coronary artery vaso-
erosclerosis, endothelial dysfunction is ubiquitous and constriction. These effects help increase nutrient cor-
associated with decreased NO availability, probably onary blood flow to zones of myocardial ischemia.
due to increased destruction of NO by free radical Recent data with the nitroglycerin patch confirm that
anions. Nitrovasodilators, including the nitrates, sup- myocardial ischemia is decreased after nitrate admin-
ply exogenous NO to the vascular wall and improve istration. Nitroprusside, another nitrovasodilator, is a
the vasodilator state. When nitrates are administered, commonly used intravenous agent for lowering arte-
endothelial-dependent stimuli cause relaxation rather rial pressure and left ventricular filling pressure. This
than constriction in the setting of endothelial dys- drug is highly effective for the treatment of acute or
function. Nitrates also have antiplatelet effects, and severe hypertension and congestive heart failure.
recent evidence confirms that these drugs decrease However, there are data suggesting that nitroprusside
platelet aggregation and thrombosis formation. This may be deleterious in the presence of acute myocar-
may play an important role in the therapy of acute dial ischemia, perhaps by shunting blood away from
unstable myocardial ischemia, including unstable an- zones of jeopardized myocardial blood flow. There-
gina and myocardial infarction. Nitrate hemodynamic fore, nitroprusside cannot be recommended to treat
effects have been long known. They are primarily myocardial ischemia; intravenous nitroglycerin should
modulated through a decrease in myocardial work be used in this context.
that results from smaller cardiac chambers operating (Am J Cardiol 1996;77:3 1C-37C)

itroglycerin (NTG) and the long-acting ni- of action of the nitrates as they relate to the clinical
N trates are used by physicians for a variety of
cardiovascular conditions (Table I). The primary
syndromes for which these agents are used.

role of these drugs is in the prophylaxis and treat-
ment of myocardial ischemia in subjects with cor-
onary atherosclerosis. Less well known is their ef-
ficacy in ameliorating the signs and symptoms of
congestive heart failure and left ventricular dys-
function. In intravenous formulation, NTG is used
to treat severe hypertension and to control blood
pressure in the operating room during certain sur-
gical procedures. Important advantages of the ni-
trates relates to their many mechanisms of action;
their proven efficacy in many cardiovascular dis-
eases; and their reassuring safety and adverse ef-
fect profile. The dominant negatives of nitrate ther-
apy include headache and nitrate tolerance. The
latter is discussed in detail elsewhere in this sym-
posium. Table II outlines the various mechanisms
From the Department of Medicine [Cardiology), University of New
Mexico School of Medicine, Albuquerque, New Mexico.
Address for re rints. Jonathan Abrams, MD, Department of Med-
icine, University o P New Mexico School of Medicine, 22 1 1 lomas
Boulevard NE, Albuquerque, New Mexico 8713 1.
NITRATES AND MYOCARDIAL
ISCHEMIA
The initial utilization of NTG in medicine was for
acute attacks of angina pectoris. This indication re-
mains the most important role for these agents. Thus,
sublingual or oral spray NTG or, less commonly,
sublingual isosorbide dinitrate (ISDN) remain the
worldwide gold standards for relief of angina1 chest
pain. Intelligent preadministration of these drugs be-
fore anticipated physical activity or emotional stress
is an important but infrequently utilized approach to
the prevention of angina. Most of the known mech-
anisms of nitrate action can be invoked as being im-
portant in preventing or eliminating myocardial isch-
emia. It is likely that different actions are more (or
less) important in individual patients, in whom there
are a variety of ways for myocardial ischemia to be
triggered. Several recent reports of transdermal NTG
in patients with chronic stable angina demonstrate
the potency and efficacy of nitrates in alleviating
exercise-induced myocardial ischemia.“* Although

0 1996 by Excerpto Medica, Inc. 0002.9149/96/$15.00 31c

All rights reserved. PII SOOO2-9149(96)00186-5
 TABLE I Clinical Indications for Nitrates

Condition Comments

l Acute attacks of angino pectoris Highly effective

l Prophylaxis of chronic stable angina
l Unstable ongino
l Acute myocardial infarction
-Control of chest pain and ischemia
-Hypertension, acute heart failure
-Routine 24-48 hour infusion of
intravenous NTG
l Post-MI left ventricular remodeling
l Chronic congestive heart failure
l Acute heart failure/pulmonary edema
l Hypertension
Comparable efficacy to calcium and beta blockers. Tolerance o problem
Intravenous nitroglycerin (NTG) very useful
Often effective: use sublingual, intravenous NTG. Caution to avoid hypotension
Very useful; intravenous or high-dose topical
little positive data; consider in large anterior myocordial infarction (MI)
Limited positive data. Uncertain benefits
Useful adjunct to angiotensinconverting enzyme (ACE) inhibitors-can use with hydrolozine.
Consider for all symptomatic subjects on ACE inhibitors and digitalis
Highly effective-especially intravenous NTG
Useful in intravenous formulation. limited positive doto in systolic hypertension of the elderly
in oral formulotion

TABLE II Mechanism of Action of Nitrates: Relationship to Clinical Indications*

Acute attacks and prophylaxis of stable angina pectoris Decreased myocordiol oxygen consumption
-Decreased LV dimension
-Decreased LV filling pressure
-Decreased LV systolic pressure
-Decreased vascular impedence
Increased coronary blood supply
-Epicardial coronary artery dilation
-Coronary stenosis enlorgement
-Improved coronary endotheliol function
-Dilaton of coronary collaterals or small distal coronary vessels
Unstable angina Same OS above, plus ontiplotelet antithrombotic action
Acute myocardial infarction Same as above, plus antiplatelet ontithrombotic action
Congestive heart failure
Systolic dysfunction Decreased LV and RV dimensions (few data in congestive heart failure)
Decreased LV and RV filling pressure
Decreased orterial pressure
Decreased systemic vascular resistance
Decreased PA and RA pressure
Improved endothelial function
Coronary artery disease patients: increased coronary blood flow
Diastolic dysfunction Decreased mitral regurgitation
Decreased LV filling pressure
Hypertension Decreased systolic blood pressure
Decreased systemic vascular resistance
Decreased LV prelood, uncertain importance

* LV = left ventricular; PA = pulmonary artery; RA = right otrial; RV = right ventricular.

these studies do not provide insight as to the pre- rently under investigation. This discussion will em-
cise mechanisms of NTG action in reducing myo- phasize NTG, nitroprusside, ISDN, and isosorbide-
cardial ischemia in a given subject, they carefully 5mononitrate (ISMN) .
document and quantitate the magnitude of im- Cellular mechanisms: NTG, as the prototype com-
provement in ischemia reduction that is induced by pound, is a short-lived agent with a half-life of sev-
the drug (Figure l).’ Another recent study con- eral minutes. It is rapidly converted to NO at or
firms earlier work suggesting that nitrates improve near the plasma membrane of the vascular smooth
nutrient coronary blood flow to regional zones of muscle cell. For years it was believed that NTG
myocardial ischemia.3 goes through a stepwise denitration process re-
sulting in the release to NO, but it appears that
NTG directly forms either NO itself or a nitrosy-
MECHANISMS OF ACTION OF THE lated entity known as a nitrosothio14 (Figure 2).
NITROVASODIIATORS The conversion of NTG (and the other nitrates) to
The nitrovasodilators are a related group of drugs NO is enzymatic. The enzyme has been partially
that result in the formation and release of nitric oxide characterized; of potential importance, a thiol moi-
(NO) from the parent molecule (Table III). A va- ety forms part of the enzyme structure.” Nitrate ox-
riety of metabolic or biochemical steps exist for these ide or nitrosothiols formed from NTG activate the
agents; some (the organic nitrates) are enzymatically cytoplasmic enzyme guanylate cyclase (Figure 2).
converted to NO. Nitroprusside and molsidomine This catalyzes the formation of cyclic guanosine
form NO directly. Many new NO donors are cur- monophosphate from guanosine diphosphate. Cy-

32C THE AMERICAN jOURNA1 OF CARDIOLOGY@ VOL. 77 MAY 30, 1996

 clic guanosine monophosphate, a second messen-
ger, induces a shift in intracellular calcium within
the sarcoplasmic reticulum, resulting in a transient
fall in intracellular calcium and subsequent vaso-
relaxation.6 Nitroprusside and molsidomine pro-
duce NO in a nonenzymatic fashion; nitrate toler-
ance does not appear to be a problem with these
compounds.
Endothelial function: It has been known for some
time that arterial vasomotor function is predomi-
nantly related to phasic release of a NO-like sub-
stance from endothelial cells. NO itself (or a close
intermediate) is produced in endothelial cells in
response to vascular shear stress or a variety of
receptor-mediated stimuli (e.g., serotonin, thrombin,
histamine). This process, which is mediated by I SmJDvl mJDY2 mum1 muDv2
a putative endothelium-derived relaxing factor
FIGURE 1. Nitroglycerin patch efficacy in reducing exercise-in-
(EDW, ’ is responsible for vasodilation of large duced ischemia in patients with angina. Mean and individual po-
arteries and the microcirculation. Prostacyclin, a tient changes in exercise-induced left ventricular (1~) perfusion
cyclic adenosine monophosphate-mediated vaso- defects from study 1 (baseline placebo patch) to study 2 (active
dilator, is also involved in endothelial cell regu- nitrate versus lacebo patch). Nitroglycerin patch therapy signifi-
lation of vasodilation. cantly reduc fxr the mean quantitative thallium perfusion defect
size compared with placebo therapy (‘p = 0.04). Bold lines indi-
EDRF (NO) is involved in other important cate the 7 patients receiving active patch therapy who reduced
functions of the endothelium, including antiplate- their perfusion defect size by 2 10% (absolute). (Reprinted with
let and antithrombotic activity and processes that permission from I Am Co// Car&o/.‘)
impede or suppress smooth muscle cell prolifera-
tion and atherosclerosis. Although most available
data regarding EDRF involves its vasodilating ac- TABLE III Nitrovasodilators
tions, many believe that normal or abnormal EDRF Exogenous
production or degradation is intimately related to Currently available in the United States
fundamental characteristics of the vascular wall it- Nitroglycerin
self, including smooth muscle cell function and lsosorbide dinitrate
Isosorbide5mononitrate
atherogenesis.’ Sodium nitroprusside
Endothelial dysfunction and nitrates: Abnormal en- Not available or approved in the United States
dothelial function has been well documented in cor- Nicorandil (also a K’ channel blocker)
onary atherosclerosis. Most of this research involves Molsidomine (converted to SIN-l, the active moiety, in the
endothelial modulation of vasomotor function and liver)
Nitrosothiols [research only)
documents impaired vasodilator responses to a va- Endogenous
riety of stimuli in the presence of abnormal endothe- Endothelium-derived relaxing factor (nitric oxide or closely
lial function in atherosclerotic blood vessels. The related compound)
dominant finding in such studies is a derangement of
maximal or normal dilator capacity. In the presence
of overt atherosclerosis, and also in apparently nor- exogenous endothelial-dependent stimuli (e.g., ace-
mal arteries in subjects with diabetes, high choles- tylcholine, reactive hyperemia) are proportional to
terol, hypertension, or heart failure, endothelial va- the degree of atherosclerosis. Coronary stenosis con-
sodilator capacity is impaired.’ The administration striction is an advanced form of endothelial dys-
of NTG or other nitrates results in normal or near- function; it is likely that transient decreases in the
normal vasodilation, presumably because the nitrate caliber of atherosclerotic lesions are important trig-
directly supplies NO to the vascular endothelium and gers of myocardial ischemia.
smooth muscle in the media.*-” It is believed that Nitrates, through their capacity to provide NO di-
endothelial dysfunction in humans is often caused rectly to the arterial media, are categorized as en-
by accelerated destruction of EDRF and NO, prob- dothelial independent vasodilator agents.‘-” Thus,
ably due in part to the presence of excess oxygen- NTG, nitroprusside, and the other organic nitrates
free radical activity.” result in predictable near-normal coronary vasodi-
Patients with an elevated low density cholesterol, lation in the presence of endothelial dysfunction.
hypertension, or a history of smoking often have an This has led to the concept that nitrates act as ex-
impairment of endothelial vasodilator responsive- ogenous EDRF-like agents, supplying or replenish-
ness. Further, the presence of overt atherosclerosis ing NO to the vessel wall when normal NO avail-
is an important marker that endothelial dysfunction ability is diminished by disease processes.*-” This
is present; the greater the severity of the atheroscle- construct points to the potentially unique role of ni-
rotic process, the more the impairment of endothe- trovasodilators in patients with vascular disease, hy-
lial-modulated vasodilation. Abnormal responses to pertension, or heart failure, states often associated

A SYMPOSIUM: NITRATES IN HEART FAllURE 33C

 ENOOTHELIUM VASCULAR SMOOTH MUSCLE
1
NO
RSH ,I
S-nitrosothiol’
J and phannacokinetics
(RSNO) - RSNO::
. .
Endothelium
-dependent *EDRF
vosodi lotors
with NO penia. Of interest, in the presence of normal
or intact endothelial function, NTG appears to have
a lessened vasodilator capability, perhaps in part re-
lated to continuous basal release of NO by the en-
dothelial cell layer decreasing the potential maximal
vasorelaxation induced by nitrate-derived NO.
In any case, the concept of exogenous EDRF
(NO) supplied by NTG and the organic nitrates, is
useful, and helps explain the efficacy of these rather
old-fashioned drugs in patients with vascular abnor-
malities. 8-‘“,‘2,13Prevention or reversal of coronary
artery and atherosclerotic lesion vasoconstriction, l3
or overt coronary spasm, are more readily explained
in the context of NO supplementation from an ex-
ogenous pharmaceutic NO donor.
Nitrates and thrombosis: It has been long recog-
nized that NTG and other organic nitrates have an
antiaggregatory effect on platelet function. The re-
sults of early experiments were controversial, how-
ever, and the actual importance of nitrate antiplatelet
action has been clouded by uncertainty. In recent
years, however, considerable evidence has become
available supporting a robust role for these agents in
interfering with platelet function and subsequently
decreasing platelet thrombotic activity. A variety of
animal and human studies have confirmed important
nitrate antiplatelet actions in this regard.14-17
Although it is difficult to attribute a beneficial
contribution of nitrates in chronic stable angina re-
lated to platelet and antithrombotic actions, it is ob-
vious that a significant anti-platelet-thrombotic ef-
fect could be important in patients with unstable
angina or acute myocardial infarction. These so-
called syndromes of acute myocardial ischemia are
associated with focal and perhaps generalized en-
dothelial dysfunction; platelets help initiate the
thrombotic cascade leading to intraluminal or mural
thrombus and ongoing platelet-thrombin activation,
which would be favorably affected by nitrate anti-
platelet. activity. Such nitrate actions would lead to
34C THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL. 77
FIGURE 2. Nitrovasodilators, endo-
thelium-dependent vasodilators, and
vascular smooth muscle relaxation.
EDRF = endothelium-derived relaxing
factor; GC = guanylate cyclase; GTP
= guanosine triphosphate; NO = ni-
tric oxide; R’SH and RSH = 2 distinct
pools of intracellular
groups; R’SSR’ = disulfide
sulfhydryl
roups.
(Re rinted with permission !r om Ko-
wa Puk E, Fung H-L. Pharmacology
of nitrates. In:
Abrams J, Pepine C, Thadani U, eds.
Medical Therapy of lschemic Heart
Disease: Nitrates, Beta Blockers, and
Calcium Antagonists. Boston: Little,
Brown, 1992: 152.)
I /
*
decreased coronary artery spasm or vasoconstriction,
particularly at or near the site of intimal disruption.
These nitrate effects, in addition to a nitrate related
decrease in myocardial oxygen consumption and in-
crease in nutrient coronary blood flow, should be
salutary in such patients.
HEMODYNAMIC ACTIONS
Nitrates dilate veins, arteries, and arterioles
through the previously described cascade of intra-
cellular events leading to NO production and acti-
vation of cyclic guanosine monophosphate (Figure
2). In the smaller, distal vessels of the microcircu-
lation, NTG and the organic nitrates appear to have
little vasodilator capacity, perhaps because the en-
zyme responsible for nitrate bioconversion to NO is
not present in these vessels.9 Veins take up nitrates
more avidly than arteries, and venodilation is pro-
nounced at lower plasma concentration of nitrate.
Nitroprusside is a potent vasodilator; at relatively
low infusion rates, nitroprusside is more active than
NTG in dilating arteries and arterioles. Further, ni-
troprusside relaxes the microcirculation and is more
likely to decrease coronary resistance than NTG (see
below ) .
The classic view of nitrate hemodynamic actions
relates to pronounced venodilation with an increase
in blood volume in the venous capacitance beds. In
effect, nitrates induce an autotransfusion of blood
away from the heart and lungs to the splanchnic and
peripheral circulations. Less blood returns to the
right heart; preload falls, and cardiac output and
stroke volume typically decrease. NTG is a potent
and reliable agent for decreasing left and right ven-
tricular filling pressure in the normal heart, as well
as in subjects with congestive heart failure and high
pulmonary capillary pressure. Concomitant nitrate
actions on pulmonary and aortic compliance and im-
pedance result in decreasesin systolic pressure in the
central circulations. Thus, pulmonary artery and aor-
MAY 30, 1996
FIGURE 3. Hemodynamic changes
(A) in hemodynamic variables after
bolus intravenous nitroglycerin in
normal (group 1) (n = 9; E./E, < 1)
(solid bars), hypertensive ( roup 2a)
(n = 9; E,/E,,> 1; ejection L ction
>40%) (hatched bars), and heart fail-
ure (group 2b) (n = 9; E./E.,> 1;
ejection fraction <40%) (open bars)
subiects. Prelood changes, defined OS
o decrease in end-diastolic volume
(EDV) ore greatest in roup 1 and in-
termediate in group 2% . Afterload
changes defined OS a decrease in ef-
fective aerial elastance (E,), are
greatest in groups 20 and 2b. In-
creases in stroke volume (Sv) consis-
tent with predominant afterlwd L
effects ore seen in groups 2a and 2b. Systo llic blood pressure (BP) decreased in all groups but to a lesser extent in group 2b.
*p ~0.05 versus group 1. tp <0.05 versus group 20. (Reprinted with permission from J Am co// Cardio/,‘q

tic systolic pressure falls with a relatively small de- becomes quite clear when one recognizes the im-
cline in diastolic pressures. Peripheral arterial vaso- portant physiologic effects of nitrates in this condi-
dilation contributes to an overall reduction in arterial tion. Nitrates are beneficial in heart failure, although
impedance and blood pressure. In the normal heart large amounts of these drugs are usually necessary
decreased left and right ventricular preload contrib- to achieve desired hemodynamic goals.
ute to the decrease in cardiac output and blood pres-
sure. CORONARY BLOOD SUPPLY
Nitroprusside is more potent in the arterial cir- NTG, and presumably the other nitrates, have sig-
culation than NTG on a per milligram basis and de- nificant actions on the coronary circulation (Table
creases arterial pressure to a greater degree than II). These are less well recognized than nitrate ef-
NTG. At high infusion rates and plasma concentra- fects on peripheral veins and arteries. The coronary
tions, however, intravenous NTG becomes more po- vasodilating actions of the nitrates probably play a
tent as a dilator of arteries and arterioles, and the significant role in the prevention and relief of myo-
drug’s hemodynamic effects become comparable to cardial ischemia in many patients with coronary ar-
nitroprusside. The decreases in left ventricular and tery disease. Although epicardial coronary artery va-
right ventricular preload and afterload translate into sodilation has been long recognized, and beneficial
smaller ventricular chamber size, with lower intra- nitrate effects on coronary collateral size and flow
cardiac systolic and diastolic pressures. These mul- are well known, several mechanisms of action of ni-
tiple actions result in decreased diastolic and systolic trates in the coronary bed have only recently been
left ventricular wall stress, and lower myocardial en- confirmed. These include the salutary effects on cor-
ergy demands.” In the presence of normal left ven- onary endothelial dysfunction, discussed before,8-‘0
tricular systolic function, stroke volume and cardiac coronary atherosclerotic stenosis dilation or enlarge-
output usually decline following NTG administra- ment, I3 and increased regional coronary blood flow
tion. However, in the setting of left ventricular sys- to viable myocardium downstream from a total cor-
tolic compromise, increased systemic vascular resis- onary artery obstruction via collateral and distal ves-
tance, or an elevated afterload, nitrates allow the left sel vasodilation.*’
ventricle to empty more efficiently, and stroke vol- It is quite difficult if not impossible to dissect out
ume may increase due to nitrate “unloading” ef- the benefits of NTG vis-a-vis decreasedmyocardial ox-
fects. I9 Nitroprusside is even more potent in this re- ygen consumption versus increased regional or nutrient
gard. A recent study suggests that the effects of NTG myocardial blood flow in a given patient with coronary
on left ventricle dimensions and stroke volume may
be, in part, determined by the underlying state of the
circulation. Thus, nitrate hemodynamic actions in the TABLE IV Hemodynamic Effects of Nitrates in the Normal
normal heart are different from that in the impaired Circulation and in Congestive Heart Failure with Left Ventricular
left ventricle with contractile dysfunction, or in hy- Contractile Dysfunction
pertensive patients who have an increased resting af- Normal
terload (Figure 3 ) .l9 LV CHF
Several differences in nitrate hemodynamic ef-
Blood pressure Decrease No change or modest decrease
fects are demonstrable in different physiologic states Heart rate Increase No change
(Table IV). It is important for the clinician to be LV filling pressure Decrease Decrease
aware of the diversity of nitrate actions related to the Stroke volume Decrease No change or modest increase
underlying status of the circulation. Further, the rel- CHF = congestive heart failure; LV = left ventricular.
evance of nitrate therapy in congestive heart failure

A SYMPOSIUM, NITRATES IN HEART FAILURE 35c

 lieve that nitroprusside should be avoided in the set-
ting of acute myocardial ischemia so as to revent a
possible “coronary steal” phenomenon27l2ii Present
guidelines do not include nitroprusside as an anti-
ischemic agent in acute myocardial infarction or un-
stable angina.29However, for patients with myocar-
dial ischemia complicated by hypertension or acute
heart failure, nitroprusside remains an effective and
rapid acting nitrovasodilator of considerable potency
Late Treatment and safety so long as central aortic hypotension is
avoided. In the absence of acute ischemia, nitro-
--O--O--,,’
prusside is an ideal drug for treatment of acute pul-
monary edema and decompensated heart failure.

NITRATE TOLERANCE
70 ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ This subject is considered elsewhere in this sup-
0 I 2 3 4 5 6 7 6 9 IO II plement. However, many nitrate actions are attenu-
12 13
WEEKS ated in the presence of nitrate tolerance. Nitrates
must and should be prescribed in a tolerance-avoid-
FIGURE 4. Intravenous nitroprusside in acute myocardial infarc- ance manner, with an appropriate nitrate-free inter-
tion. Approximately 400 patients in each group, nitroprusside val and pulsed dosing regimen. However, when in-
versus placebo. Cumulative percentage of patients surviving after
early treatment (within 9 hours of onset of acute myocardial in-
travenous NTG is given for acute myocardial
farction) and late treatment (later than 9 hours). (Reprinted with infarction or unstable angina, one should not rou-
permission from N Engl I Med.25) tinely stop the infusion in an effort to reverse or pre-
vent the appearance of nitrate tolerance. Rebound
vasoconstrictor forces and the withdrawal of favor-
artery disease.Perhaps both actions come into play in able hemodynamic action are potentially hazardous
most subjects. Nevertheless, the recognition that ni- consequences of abrupt cessation of intravenous
trates improve coronary blood flow to regions of myo- NTG in this setting. Intravenous NTG should be ta-
cardium subtended by a coronary stenosis or obstruc- pered slowly in patients with acute myocardial in-
tion represents an enhanced understanding of these farction or ischemia while the subject is being
valuable agents.Prevention or reversal of coronary ep- switched to oral therapy.
icardial artery and microcirculatory vasoconstriction as
well as stenosis vasodilation may be quite important in NITRATE FORMULATIONS
certain individuals. At present, NTG, ISDN, and ISMN are the only
organic nitrates that can be recommended. The
INTRAVENOUS NITRATES: choice of agent depends on a number of factors, in-
NITROGLYCERIN AND cluding the drug’s pharmacokinetic profile, available
NITROPRUSSIDE dosing or delivery systems, physician preference,
Sodium nitroprusside is a more potent arterial va- and cost. There are no reliable data to suggest im-
sodilator than NTG, and nitroprusside has an impor- portant differences among these compounds in clin-
tant dilating effect on the coronary microcirculation. ical effectiveness, potency, or likelihood of tolerance
Although the hemodynamic profile of nitroprusside induction. Further, it is presumed (but unproven)
helps explain its greater efficacy in lowering blood that the beneficial endothelial and peripheral circu-
pressure or in the therapy in decompensated conges- latory effects and direct coronary actions are similar
tive heart failure, 2’ serious questions have been among the available nitrate formulations. The side
raised as to whether nitroprusside is completely safe effect profiles appear to be comparable. Fortunately,
in the presence of coronary artery disease. It is pos- for patients and physicians, NTG and the organic
sible that the dilator actions of nitroprusside on the nitrates remain reliable and predictable pharmaceutic
resistance vessels of the coronary circulation may compounds that have multiple beneficial effects and
allow for an unwanted diversion of coronary blood considerable efficacy in clinical medicine.
flow away from zones of potential or actual myo-
cardial ischemia subtended by a tight coronary ste-
nosis. This concept has some basis in older animal 1. Mahmarian JJ, Fenimore N, Marks GF, et al. Transdermal nitroglycerin patch
and human data during acute infarction.22-24 Further, atherapy reduces the extent of exercise-induced myocardial &hernia: results of
double-blind, placebo-controlled trial using quantitative thallium-201-tomog-
a multicenter trial in acute myocardial infarction raphy. J Am Co11 Cardiol 1994;24:25-32.
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glycerin therapy in angina pectoris. Clinically effective without tolerance or
given a 48-hour nitroprusside infusion, treated rebound. Circulation 1995;91: 1368-1374.
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however, demonstrated a survival benefit with an flow with typical nitroglycerin in patients with coronary arterial disease. Cir-
culation 1995;91:1381-1388.
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