1461
FiResearch Advances Series
The Nitrovasodilators
New Ideas About Old Drugs
David G. Harrison, MD, and James N. Bates, MD, PhD
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The nitrovasodilators are a diverse group of pharmacological agents that produce vascular relaxation by
releasing nitric oxide. The mechanisms by which these compounds release nitric oxide vary, depending on
their chemical structure. Compounds with lower oxidation states of nitrogen such as nitroprusside,
nitrosamines, and nitrosothiols release nitric oxide nonenzymatically. In the case of nitroprusside, this
involves a one-electron reduction that may occur upon exposure to a variety of reducing agents and tissues
such as vascular smooth muscle membranes. In the case of the organic nitrates, which have higher
oxidation states of nitrogen, the release of nitric oxide in vascular tissue occurs predominantly by a poorly
understood enzymatic process. This interesting property of nitroglycerin is important because it "targets"
its effect to vascular tissues that are capable of this enzymatic process. In the case of the coronary
circulation, nitroglycerin predominantly dilates the larger coronary arteries while having a minimal effect
on coronary resistance vessels <100 gm in diameter. This prevents the development of coronary steal,
which is often encountered with agents that produce intense vasodilation of the coronary resistance
vessels. In this review, the mechanisms by which the nitrovasodilators (particularly nitroglycerin) release
nitric oxide will be considered, and recent studies of nitroglycerin bioconversion in various-sized coronary
vessels will be discussed in detail. (Circulation 1993;87:1461-1467)
KEY WORDs * coronary arteries * microcirculation * cysteine * N-acetylcysteine * methionine
* glutathione
D uring the past decade, a great deal has been
learned about the mechanisms of action of the
pharmacological class of agents known as the
nitrovasodilators. One of the fascinating aspects of this
research is that these drugs for the most part produce
their biological effects by releasing nitric oxide1-4 and
thus in many respects mimic the endothelium-derived
nitric oxide. The most commonly used of these include
nitroglycerin, sodium nitroprusside, and the long-acting
nitrate isosorbide dinitrate. Other pharmacological donors of nitric oxide are isosorbide mononitrate (recently
introduced in the United States), SIN-1 (used principally in Europe), amyl nitrite, and some of the newer
compounds (nicoradil and others) that have additional
properties such as the capacity to open vasodilating K'
channels in vascular smooth muscle. It has become
rather fashionable to state that these pharmacological
agents "replace" the endogenous arginine/nitric oxide
pathway, which may be defective in a variety of diseases.
Although this statement is true in its broadest interpretation, there are important differences between the
endogenous nitric oxide and exogenous nitrovasodilators that should be familiar not only to investigators
From Emory University and Veterans Administration Medical
Center, Department of Medicine, Atlanta, Ga., and the Department of Anesthesia, University of Iowa, Iowa City.
Supported by grants HL-37217, HL-39006, and a Merit Grant
from the Veterans Administration.
Address for correspondence: David G. Harrison, MD, Division
of Cardiology, Department of Internal Medicine, Emory University School of Medicine, PO Drawer LL, Atlanta, GA 30322.
Received November 19, 1992; revision accepted January 27,
1993.
interested in vascular biology but also to the clinician
who uses these drugs. These involve variations in how
these compounds are metabolized to free nitric oxide
and differences in how they behave in various tissues.
This review will summarize some of these newer, important concepts.
Chemistry of the Nitrovasodilators
Nitrogen has five electrons in its eight-electron valence shell, which means that in compounds it can have
oxidation states of -3 to +5.5,6 Although oxidation state
is a purely theoretical concept and not a direct measure
of any physical property of an atom, it is a useful
concept in the discussion of redox reactions. Unlike
many other elements, nitrogen readily forms compounds in each of its possible oxidation states. Examples
of each of these states are presented in Table 1.
As apparent from Table 1, most biological nitrogencontaining compounds have nitrogen in its most reduced form. This includes all amino acids, peptides,
nucleic acids, organic bases, amines, and more than
99% of all the nitrogen present in all organisms. Aside
from the ecological nitrogen cycle carried out mostly by
bacteria, biochemical reactions generally do not change
the oxidation state of nitrogen from -3.
One of the most exciting physiological discoveries of
the past decade, however, is the only established exception to this rule in mammalian biochemistry. It is now
well known that many cells, especially endothelial cells,
neurons, and hematopoietic cells, can oxidize a guanidino nitrogen in arginine (oxidation state, -3) to nitric
oxide (oxidation state, +2) (for reviews, see References
7 and 8). A related discovery first made a decade earlier
1462
Circulation Vol 87, No 5 May 1993
TABLE 1. Compounds With Various Oxidation
States of Nitrogen
-3
-2
-1
0
+1
+2
+3
+4
+5
Ammonia (NH3), amines
(RNH2), amides (RCONH2),
most biological nitrogen
compounds
Hydrazine (N2H4)
Hydroxylamine (NH2OH)
Nitrogen (N2)
Nitrous oxide (N20)
Nitric oxide (NO')
Organic and inorganic nitrites
(RONO and NO2-)
Nitrogen dioxide (NO2)
Organic and inorganic nitrates
(RONO2 and NO3)
NITROSYL
COMPOUND
!
~
STRUCTURE
OXIDATION STATE
._-U
~~
~
TWO
N=O
NITRIC OXIDE
NITRITE
THREE
O=N-O 04
N-O
NITRATE
ORGANIC NITRITE
0
R-O-N=O
NITROSOTHIOL
R-S- N= 0
FIVE
THREE
THREE
0
R-ON +
ORGANIC NITRATE
FIVE
0
0
R-S-N
THIONITRATE
CN
0
FIVE
CN
/
[c'%
CN- Fe-N=0
.
THREE
NITROPRUSSIDE
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is that nitric oxide is the major modulator of the
enzyme-soluble guanylate cyclase, the source of much
and in some cases all of the cGMP inside many cells.2,9
Since cGMP is involved in many important regulatory
pathways, these discoveries have focused much attention on the study of biological nitric oxide.
One result of these studies is a new understanding of
the mechanism of action of some old drugs, the nitrovasodilators. A common feature of these drugs is that
they contain nitrogen in an oxidation state higher than
-3, and the action of these drugs is dependent on the
release of this nitrogen as nitric oxide. The mechanisms
by which nitric oxide release occurs is by no means
similar between the various compounds, and at least in
some instances, may occur via several mechanisms in
the same compound. For some nitroso compounds with
an oxidation state of +3, release of the nitric oxide
occurs via a simple one-electron reduction. In contrast,
compounds with higher oxidation states almost certainly
require enzymatic reduction to release nitric oxide. This
property of nitroglycerin and related organic nitrates
almost certainly is one of the major reasons for some of
the unique properties discussed in this review.
Figure 1 illustrates the structure of a variety of
nitrogen-containing compounds that are either nitrovasodilators or closely related compounds. Also shown are
their oxidation states. Figure 2 illustrates the chemical
structure of nitroglycerin for comparison. Some of the
nitrovasodilators are readily recognized by the clinician,
including amyl nitrite, sodium nitroprusside, the organic
nitrates, and nitric oxide. Others may be less familiar.
The thionitrates have been proposed as an intermediate
of nitroglycerin bioconversion, as have the nitrosothiols.
Some of these compounds such as the nitrosothiols and
nitrosamines are potent vasodilators but are not used
clinically because of chemical instability or potentials
for toxicity that have not been resolved.
Biotransformation of Nitroprusside
An example of a nitroso compound with an oxidation
state of +3 that is a potent vasodilator is sodium
nitroprusside. Despite the fact that this drug has been
widely used clinically for several years, the precise
mechanism by which it released nitric oxide has only
recently been elucidated. It had been reported previously that sodium nitroprusside "spontaneously" re-
CN
CN
FIGURE 1. Chart shows comparison of various nitrosyl
compounds including common nitrovasodilators. Oxidation
states of the nitrogen eventually released as nitric oxide are
shown.
leased nitric oxide, but the studies demonstrating this
point were performed in the presence of light.3 This
concept seemed unlikely, particularly in view of the fact
that solutions of sodium nitroprusside remain relatively
stable when protected from light for prolonged periods.10 To address this issue, we examined the release of
nitric oxide from solutions of sodium nitroprusside
using chemiluminescence.1" In contrast to prior reports,
when protected from light, sodium nitroprusside did not
release detectable levels of nitric oxide. Exposure to
even low levels of light readily elicited the release of
nitric oxide from sodium nitroprusside, and this effect of
light was dependent on intensity. Because of the oxidation state of sodium nitroprusside, we reasoned that
nonenzymatic one-electron reduction would probably
release nitric oxide. Indeed, when solutions of sodium
nitroprusside were exposed to a variety of reducing
agents including dithiothreitol, glutathione, or preparations of hepatic microsomes (which generate reducing
H
H
4M 0
C-0-Nt
0
H
C- O-N
H
C-O-N,
H
,,0
0
FIGURE 2. Chemical structure of nitroglycerin (glycerol
trinitrate).
Harrison and Bates Nitrovasodilators: New Ideas About Old Drugs
equivalents), large quantities of nitric oxide were released. Even red cell membranes and smooth muscle
cell membranes could serve this reducing function.
Another interesting aspect of this process was that
cyanide loss from the sodium nitroprusside molecule
appeared to precede nitric oxide loss, suggesting that
even after reduction, several chemical transformations
of the nitroprusside anion were required before nitric
oxide could be released. The concept that cyanide loss
accompanies nitric oxide release from nitroprusside is
not new.10,12,13 The nitric oxide released is such a
powerful vasodilator, however, that nitroprusside is
effective at doses that do not produce toxic amounts of
cyanide. However, very high doses used to induce
intraoperative hypotension have caused death by cyanide intoxication.14 Similarly, the use of nitroprusside at
high concentrations in experimental situations could
lead to levels of cyanide that may impact on the
experimental outcome.
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Biotransformation of Nitroglycerin
When nitroglycerin is exposed to many mammalian
tissues, (most relevantly vascular smooth muscle), nitric
oxide is released, generally from the C-3 carbon.15 The
precise biochemical process responsible for this has not
been defined. Because nitroglycerin requires a threeelectron reduction to release nitric oxide, it has been
repeatedly suggested that cellular thiols are involved in
this process.1'16-18 Needleman et al17'18 and subsequently
Ignarro et all first proposed that thiols were involved in
the biotransformation of nitroglycerin and that the
formation of a nitrosothiol intermediate was likely.
Indeed, most19-21 but not all22 studies have shown that
manipulation of thiols either in vivo or in vitro influence
responses to nitroglycerin. Whether or not a nitrosothiol
is an intermediate in this process is not shown conclusively by these observations. Sulfhydryl groups may
have other important roles such as serving as cofactors
or donating reducing equivalents that lead to the formation of nitric oxide directly from nitroglycerin.
One consideration is whether the release of nitric
oxide from nitroglycerin is enzymatic or nonenzymatic.
Exposure of nitroglycerin to large concentrations of
various thiol-containing compounds will lead to the
spontaneous hydrolysis of nitroglycerin to glycerol dinitrate and nitric oxide.1'23'24 The most active thiols in this
reaction included cysteine, dithiothreitol, N-acetylcysteine, mercaptosuccinic acid, thiosalicylic acid, and methylthiosalicylic acid.23 Glutathione, the major intracellular source of thiols, is relatively ineffective in releasing
nitric oxide from nitroglycerin in this nonenzymatic
manner.1,23,24 The intracellular concentrations of the
thiols identified to catalyze this reaction are very low or
in most instances nonexistent. In preliminary studies,
we have found that homogenates of vascular smooth
muscle, heated to inactivate all enzyme systems, lose
their capacity to release nitric oxide from nitroglycerin.
Finally, Chung and Fung25 have provided strong evidence that nitroglycerin releases nitric oxide via an
enzyme system attached to the cellular surface membrane. Thus, it would appear that the release of nitric
oxide from reasonable concentrations of nitroglycerin
and thiols almost certainly involves an enzymatic process. The need for sulfhydryl-donating compounds is
not to serve as a substrate for nonenzymatic interac-
tions but
more
likely
as a
1463
cofactor in this enzymatic
process.
Related to this issue is whether or not nitroglycerin
tolerance is caused by depletion of intracellular thiols.
Commonly, the efficiency of nitroglycerin markedly decreases after 18-24 hours. This is in part due to a
decrease in formation of nitric oxide from nitroglycerin,
and several have attributed this to depletion of intracellular sulfhydryl groups.20,26,27 This concept has recently
been challenged, because contrary to what was initially
expected, vascular sulfhydryl groups are not decreased
during the development of nitroglycerin tolerance.28'29
The administration of thiols does enhance vasodilation
produced by nitroglycerin both in vitro and in vivo, but
this is not specific for tolerance. Thiol-donating compounds enhance the effect of nitroglycerin even in the
nontolerant state.30,31
Thus, the role of thiols in the metabolism of nitroglycerin remains quite controversial. Most studies have
suggested that they play an important role in the cellular
biotransformation, but the precise mechanism by which
they work remains unclear. It is unlikely that nitroglycerin tolerance is mediated by thiol depletion.
It has been suggested that the cytosolic glutathioneS-transferases are responsible for the biotransformation
of nitroglycerin to nitric oxide. This is based on the
observation that the glutathione-S-transferases can degrade nitroglycerin (glycerol trinitrate) to glycerol dinitrate32'33 and that certain isoforms of glutathione-Stransferase with this activity are present in vascular
smooth muscle.34 Bromosulfopthalein, an inhibitor of
glutathione-S-transferase, impairs vascular relaxations
to nitroglycerin in isolated vessels.35 This effect is not
specific because bromosulfopthalein also inhibits relaxations to a nitrosothiol, which clearly does not require
enzymatic bioprocessing. The biochemistry of the reaction between nitroglycerin and the glutathione-Stransferases is of substantial interest. According to
well-established biochemical reactions involving glutathione-S-transferases, this enzyme class catalyzes the
attachment of glutathione to one of the nitrate groups
of nitroglycerin and eventually forms an unstable thionitrate.36 This unstable thionitrate is then attacked by a
second glutathione molecule to yield glycerol dinitrite, a
nitrogen oxide, and oxidized glutathione (GSSG).
Whether the nitrogen oxide is released in vascular
smooth muscle as nitric oxide or as nitrite (which is not
vasoactive except at very high concentrations) has,
however, not been established. In recent studies, we
have found that purified preparations of the glutathione-S-transferases release only nitrite from nitroglycerin and do not yield nitric oxide. Furthermore,
manipulations that increase glutathione-S-transferases
activity in vascular homogenates increase the yield of
nitrite while decreasing the yield of nitric oxide from
nitroglycerin.37
Effect of Nitroglycerin on
the Coronary Microcirculation
Some insight regarding the biotransformation of various nitrovasodilators has been gained from studies of
the coronary microcirculation. One of the fascinating
aspects of the pharmacology of nitroglycerin is its effect
on the coronary circulation. In commonly used concen-
trations, nitroglycerin potently dilates the larger coro-
1464
Circulation Vol 87, No S May 1993
% Relaxation
-4
-5
-7
4
Log [Nitroglycerin]
FIGURE 3. Graph shows responses ofvarious sizes ofporcine
coronary microvessels to nitroglycerin. Vessels were grouped as
small (<100 ,m in diameter), intermediate (100-200 ,um in
diameter), and large (>200 gm in diameter). Nitroglycerin
produced only minimal relaxations of coronary microvessels
<100 ,um in diameter. From Reference 40.
-9
4
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nary arteries while producing only a submaximal and
brief effect on coronary flow.38-40 Because coronary
perfusion is predominantly regulated by the coronary
microcirculation, these findings suggest that nitroglycerin has only a minor effect on the smaller coronary
vessels; however, the mechanisms underlying this phenomenon remain unclear. Potential explanations include autoregulatory influences from the adjacent myocardium, which counteract the vasodilatation produced
by nitroglycerin, an absence of guanylate cyclase in the
vascular smooth muscle of coronary microvessels, and
finally, an inability of the smaller coronary microvessels
to convert nitroglycerin to its active vasodilator
intermediate.
In an effort to address these possible explanations for
the heterogeneous effect of nitroglycerin on the coronary circulation, we studied several different sizes of
coronary microvessels using an in vitro microvascular
imaging apparatus.40 This allowed us to control a number of factors that may influence vascular responsiveness such as distending pressure, degree of precon% Relaxation
,
sava~~~azwv
0
c
stricted tone, and presence or absence of other
vasoactive agents. In addition, because the vessels were
studied in vitro, removed from the myocardium, autoregulatory influences of the myocardium could not have
participated in modulation of nitroglycerin's responses.
The results of these initial experiments are depicted
in Figure 3. Interestingly, the response to nitroglycerin
was markedly dependent on vessel diameter. Vessels
>200 ,um in diameter were very responsive to nitroglycerin, whereas those <100 ,m in diameter dilated only
minimally to the highest concentrations of nitroglycerin.
Vessels between 100 and 200 gm in diameter demonstrated an intermediate response to nitroglycerin. Thus,
these in vitro experiments showed that the lack of effect
of nitroglycerin in the coronary microcirculation was
not simply due to autoregulatory influences imparted by
the myocardium on these smaller vessels but that this
phenomenon occurred in vessels dissected free from the
myocardium and studied in vitro.
We sought to determine whether this lack of effect of
nitroglycerin was related to an inability of smaller
coronary microvessels to convert nitroglycerin to its
active vasodilator metabolite. We reasoned that if the
smaller vessels, which do not respond to nitroglycerin,
dilated to either nitric oxide or a nitrosothiol, two
putative metabolites of nitroglycerin, this would provide
evidence that these vessels simply could not convert
nitroglycerin to these vasodilator substances. The results of these experiments are shown in Figure 4. Unlike
nitroglycerin, both nitric oxide and S-nitrosocysteine
elicited potent relaxations of small coronary microvessels. An important observation in these experiments was
that responses of coronary microvessels <100 gm in
diameter to nitric oxide and S-nitrosocysteine were
markedly inhibited by LY83583, a compound that
blocks elevations of cGMP after activation of guanylate
cyclase. Thus, these experiments disproved the hypothesis that diminished responsiveness of coronary microvessels <100 gm diameter to nitroglycerin is due to
an absence or decrease responsiveness of guanylate
cyclase. Because these vessels could respond to putative
metabolites of nitroglycerin, it seemed likely that these
vessels were incapable of converting nitroglycerin to
these more vasoactive substances.
In view of the suggested critical role of thiols in the
biotransformation of nitroglycerin (discussed above),
one reasonable explanation for the inability of coronary
microvessels <100 gum in diameter could have been a
100 MICRONS
a
MICRONS
p200
10
-- &,.0 MICRONS
FIGURE 4. Graphs show responses of coronary microvessels of various sizes to nitric
oxide and the nitrosothiol S-nitroso-L-cysteine. In contrast to the effect of nitroglycerin
on coronary microvessels, these putative metabolites of nitroglycerin produced dilation of
all size class of vessels. From Reference 40.
-6.0
8.0 -7.0
Log M [Nitric oxide]
-5.0
Log M [S-Nltrosocystelnej
Harrison and Bates Nitrovasodilators: New Ideas About Old Drugs
,100 pm diameter
100 Em diameter
% RELAXATION
100
z
0;/4
o-
80
60
--*
Control
0
L-Cystelne (100 AM)
ot
20
0
o
I-
-8
-7
.6
.5
-9
FIGURE 5. Graphs show effect of L-cysteine
the dilation of small coronary microvessels
(<100 gum in diameter) to nitroglycerin. Be-
on
fore the addition of L-cysteine, coronary mi-
o0
40
-9
1465
-8
Log M [NTGJ
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relative deficiency of reduced sulfhydryl groups in the
vascular smooth muscle of these vessels. To test this
hypothesis, we preincubated coronary microvessels
<100 jam and >200 ,um in diameter with L-cysteine.41
Surprisingly, L-cysteine markedly increased the response of smaller coronary microvessels to nitroglycerin. This effect seemed somewhat specific because
L-cysteine had no effect on the response of larger
coronary vessels to nitroglycerin (Figure 5).
In a subsequent study, Kurz et a142 examined the
response of various-sized coronary microvessels to nitroglycerin using a preparation that allows study of the
coronary microcirculation in vivo. As in the in vitro
studies, nitroglycerin dilated arterioles with diameters
>100 gm while having virtually no effect on smaller
coronary microvessels. Furthermore, as in the in vivo
experiments, L-cysteine markedly increased responses
to nitroglycerin in the smaller vessels while having no
effect in larger vessels. Interestingly, unlike L-cysteine,
D-cysteine had no effect. We were concerned that
nitroglycerin might have nonenzymatically combined
with cysteine to form a nitrosothiol extracellularly and
that the uptake of the nitrosothiol might be stereospecific. To examine this possibility, we examined responses of coronary microvessels to both S-nitroso-Lcysteine and S-nitroso-D-cysteine. Both isomers
produced similar potent relaxations of small coronary
microvessels, showing that the effect of L-cysteine was
not simply related to the nonenzymatic formation of a
nitrosothiol (if it had been, one would have expected
that D-cysteine, which also could have nonenzymatically
formed S-nitroso-D-cysteine, would have augmented
responses to nitroglycerin). In subsequent preliminary
experiments, we have found that the effect of L-cysteine
and N-acetyl-cysteine can be prevented by inhibiting
production of glutathione.43 These preliminary experiments suggest that the thiol enhanced by the administration of these agents is probably intracellular glutathione and that glutathione is probably critical in the
bioconversion of nitroglycerin. In these studies, we also
found that the ability of smaller and larger coronary
microvessels to convert L-cysteine to glutathione was
similar. Thus, there does not appear to be major differences between the formation of glutathione in these
different-sized microvessels. One potential explanation
relates to accelerated oxidation of thiols in smaller
vessels, which, being more intimately associated with
-6
-7
*=
p.
-5
crovessels of this size responded minimally to
nitroglycerin. After the addition of L-cysteine,
these vessels became quite responsive to nitroglycerin. L-Cysteine had no effect on vasodilation to other substances and no effect on
coronary microvessels >200 gm in diameter.
From Reference 41.
0.001 vs control
the myocardium than larger vessels, are potentially
exposed to greater oxidative stress.
These experiments examining the effect of nitroglycerin and related compounds on the coronary microcirculation contribute to our understanding of how nitroglycerin interacts with vascular smooth muscle to
produce its vasodilatory effect. By studying a tissue that
normally does not dilate to nitroglycerin, we have been
able to provide cofactors that are potentially critical for
the metabolism of this agent to nitric oxide. These
studies strongly support an important role for intracellular thiols (probably glutathione) as a cofactor in an
enzymatic process. As discussed above, the precise roles
of glutathione and other thiols have not been defined. A
summary of some these interactions are presented in
Figure 6.
Notwithstanding the numerous unanswered questions
left to be addressed about nitroglycerin's biotransformation, it is clear that the unique nature of this compound targets its action in the coronary circulation and
probably in other circulations. This property of the drug
is almost certainly important for its antianginal effects.
Vasodilators that act on the smallest coronary microvessels notoriously induce angina and in fact are often used
to elicit myocardial ischemia as an adjunct to cardiac
imaging.44 The mechanism by which these compounds
induce ischemia probably relates to redistribution of
myocardial perfusion from ischemic regions (the socalled coronary steal phenomenon).45 Because nitroglycerin is selectively converted to its vasoactive metabolite in the larger vessels and to a lesser extent in the
smallest microvessels, it does not share this capacity of
inducing coronary steal. This property probably has
implications regarding the development of newer antianginal nitrovasodilators. It is likely that potent vasodilators of coronary microvessels will be less useful
than substances that require an enzymatic biotransformation similar to nitroglycerin. Compounds with higher
oxidation states of the nitrogens eventually converted to
nitric oxide will be more likely to share this profile of
nitroglycerin's lack of effect on the coronary resistance
circulation. Finally, these observations may have implications regarding strategies of preventing nitroglycerin
tolerance. Several groups have suggested using thioldonating compounds like N-acetyl-cysteine to prevent
or reverse nitroglycerin tolerance. Our data demonstrate that the primary site of interaction of these
1466
Circulation Vol 87, No 5 May 1993
Vascular Smooth Muscle
-
Enzymatic
40
H
H
Glutathione
S-Transferes:
Product Is nitrite.
Activity
increased by
excess GSH
C-0-N,
~,b0
4P0
C-0-N^-
H
H
C-0-N
H
#0
+0
H
n
H
C-O-H
H
C.
;-N
+
N02-
;0
0
C. 0-O No-
H
0.N;
H C
H
Ha,
000
N
Enzymatic
H
0
Unknown pathway. Likely
requires glutathione. Less active
In coronary microvessels c 100
gm (Possibly secondary to
decreased availability of
Non-enzymatic
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
cystelne
dithlothreltbi
N-acetylcystelne
merceptosuccinic acid
thlosalicylic acid
methylthiolsalicylic acid
others
(large concentrations)
N
glutathione) .
L.
N = 0O
uanylate
Cyclase
~0*
FIGURE 6. Chart shows interactions of nitroglycerin, thiols, and vascular smooth muscle. Nitroglycerin can nonenzymatically
interact with a variety of thiol-containing compounds to release nitric oxide, although the concentrations of these thiols necessary
for this interaction are generally not encountered in vivo. The major bioconversion ofnitroglycerin probably occurs via an enzymatic
process. The glutathione-S-transferases predominantly metabolize nitroglycerin to vasoinactive nitrite. An unidentified biochemical
process is responsible for reduction of nitroglycerin to nitric oxide. This process appears to require glutathione or a closely related
thiol. The ability of smaller vessels (particularly coronary microvessels <100 gm in diameter) to convert nitroglycerin to its
vasoactive metabolite appears to be limited compared with larger vessels.
thiol-donating compounds with nitroglycerin is at the
level of the smaller coronary microvessels, and use of
these converts nitroglycerin from a predominant large
vessel dilator to a small vessel dilator. Such an intervention should be viewed with caution, as the resultant
small vessel dilatation may contribute to a coronary
steal phenomenon similar to that observed with other
small vessel dilators.
7.
8.
9.
10.
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Arnold WP, Longnecker DE, Epstein RM: Photodegradation of
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Bates JN, Baker MT, Guerra R Jr, Harrison DG: Nitric oxide
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KEY WORDS * Research Advances Series * pharmacology
vasodilators
The nitrovasodilators. New ideas about old drugs.
D G Harrison and J N Bates
Circulation. 1993;87:1461-1467
doi: 10.1161/01.CIR.87.5.1461
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