Cellular and Molecular BiologyTM 51, 307-320 ORGANIC NITRATES IN CARDIOVASCULAR DISEASE
Institut für Klinische Pharmakologie, Otto-von-Guericke-Universität, Magdeburg, Germany
✍ Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Heinrich-Heine-Universität,
Fax: +49 211 81 14781; E-mail: email@example.comReceived December 10, 2004, Accepted December 20, 2004, Published September 5, 2005Abstract - Therapeutic activation of the vascular NO/cGMP pathway is induced by a variety of stimuli/mediators including physical activity, supplementation with the precursor L-arginine and organic nitrates which generate NO in the vasculature. The necessity of an enzymatic reduction for NO generation from these drugs as well as differences in the activity of the NO/cGMP pathway within the vascular tree determine the unique hemodynamic changes elicited by organic nitrates. These changes include preferential venodilation, vessel-size specific arterial dilation and improvement of the aortic distensibility and Windkessel-function. Some animal experiments and clinical investigations suggest that nitrates may also be endowed with cardioprotective and/or vasoprotective effects. "Early entry" therapy with nitrates do not significantly improve survial in myocardial infarction but increases the beneficial effects of the ACE- inhibitor enalapril by 50%. Furthermore, nitrates have been shown to improve survival in heart failure, but prognostic effects in stable angina pectoris are unknown. Short-term experimental and clinical investigations suggest that nitrate tolerance induced by nitroglycerin is associated with toxic effects in the vasculature, but this is not true for pentaerythrityl tetranitrate and isosorbide mononitrate. The observed endothelial dysfunction induced by a continuous treatment with nitroglycerin may be an additional risk for patients who receive continuous nitroglycerin to treat conditions such as unstable angina and acute heart failure. In general, nitrates are remarkably safe drugs and are well tolerated. Appropriate clinical trials are needed to answer the question whether nitrates can do more than symptomatic relief in cardiovascular disease. Key words: Nitrates, coronary artery disease, heart failure, L-arginin, nicorandil INTRODUCTION
intima-media thickness in CAD patients and this wasassociated with a significant reduction of the 3-year event
Drugs used in the treatment of CAD fall in two different
rate but did not affect mortality (101). In contrast, clinical
catagories (Table 1). Some of these drugs exert antianginal
data on the effects of nitrates on the prognosis of patients
effects, while others delay the progression of CAD (121).
with stable angina pectoris are still lacking (96,122) and
Antianginal drugs such as nitrates, β-blockers and calcium
although a meta-analysis indicates a small but significant
channel antagonists favourably shift the ratio of myocardial
decrease in CAD-mortality among nitrate treated patients
oxygen demand and supply. They relieve chest pain and
(57), some clinical data raised the suspicion that nitrates may
reduce the duration and frequency of acute ischemic events.
rather increase mortality in CAD (89). Non-antianginal
In addition, β-blockers have been shown to improve survival
drugs are used to improve the outcome of CAD patients
in acute myocardial infarction, while the various types of
(Table 2). During the last 15 years many clinical trials have
calcium channel antagonists have a neutral effect on
repeatedly shown the value of these drugs. In Germany, the
mortality (50,55). The dihydropyridine amlodipine reduced
results of the HOPE trial have led to broaden the indications
Drugs used in the treatment of coronary artery disease (CAD)
Drugs in the treatment of coronary artery disease
Antianginal Drugs Not-antianginal Drugs
inhibitors of platelet aggregation (e.g. aspirin)
calcium channel antagonists (e.g. amlodipine)
Selected clinical trials showing a significantly positive effect of treatment with non-antianginal drugs on the outcome of CAD-
Treatment before Treatment in Treatment after Myocardial Infarction Acute Myocardial Infarction Myocardial Infarction (primary prevention) ("early entry") ("late entry")
of ramipril, which is now also offered to "reduce the risk of
mechanism underlying preferential venodilation is not
myocardial infarction, stroke or cardiovascular death".
completely understood but there is evidence for aninvolvement of endogenous NO-generation. NO can inhibit
HEMODYNAMIC ACTIONS OF NITRATES
enzymatic bioactivation of nitrates and endothelial NOproduction is greater in arteries than in veins (69,75). In vivo
Organic nitrates specifically alter hemodynamics in
studies in rabbits have shown higher NO-generation from
CAD-patients. No other cardiovascular drug is able to
nitrates in veins than in arteries (84). Furthermore, the
induce similar hemodynamic changes. Venous pooling and
steady-state concentration of NO in the vascular wall may
vessel size selective coronary vasodilation are of utmost
reduce the expression of soluble guanylyl cyclase (35,81), a
importance. Other nitrate-like drugs such as molsidomine
key enzyme of the NO/cGMP pathway. This mechanism
also reduce preload (77), while sodium nitroprusside is a
likely reduces arterial vasodilation to nitrates more than
balanced vasodilator which lowers both venous and arterial
tone and induces a rapid and short lasting reduction of blood
The pattern of hemodynamic changes elicited by nitrates
is of particular advantage in CAD patients. It redistributes thecirculating blood volume to splanchnic and mesenteric
blood vessels, reduces pulmonary arterial pressure, left
Venous pooling is evident at low doses of nitrates (Fig. 1)
ventricular end diastolic pressure and systolic ventricular-
which have no influence on peripheral resistance (8). The
wall tension and may increase cardiac output (4).
Hemodynamic actions of glyceryl trinitrate. Reduction of preload is evident at concentrations which have no effect on peripheral
Subsequently, myocardial oxygen demand decreases, while
nitrates (6). This emphasizes the need to closely monitor
oxygen supply, particularly to the endocardium, is improved.
changes of blood pressure in emergency cases such as acute
This resolves and prevents ischemic episodes and quickly
coronary syndromes or decompensated heart failure.
reduces the typical chest pain in angina. In some instances,when preload is already low, these hemodynamic changes
can induce an aggravation of myocardial function mediated
The reduction of myocardial oxygen demand by organic
by the Frank-Starling mechanism (see contraindications).
nitrates is supported by their effects on aortic function. It has
Preferential venodilation also reduces the hepatic venous
been shown that organic nitrates increase aortic distensibility
pressure gradient and portal flow and these effects are
and improve the Windkessel function (130). This reduces the
beneficial in liver cirrhosis (37,73,79).
impedance to the ejection of the left ventricle andsubsequently decreases cardiac workload and oxygen
Vessel-size selective coronary vasodilation
demand. The relative contribution of this activity to the
Nitrates redistribute coronary flow to the ischemic regions
therapeutic effectiveness of organic nitrates is unclear but
of the heart. This was initially observed by measuring the
likely important. Organic nitrates and other NO-donors can
oxygen saturation in large and small arteries of the coronary
also influence myocardial contractility. In isolated
circulation in vivo (132). Later investigations in isolated large
cardiomyocytes nitrates induce a biphasic effect. Low
and small coronary arteries demonstrated that nitrates
concentrations of NO (0.1-1 µM) facilitate myocardial
potently relax large arteries but not coronary resistance
contraction and relaxation, while higher concentrations (>30
vessels (110). The mechanism of this vessel-size specific
µM) induce the opposite effect. In contrast, in vivo studies
vasodilatory activity may involve a lack or a rapid depletion
with nitrates in animal and man showed only positive
of free thiols in the vascular wall (111). The selective
inotropic effects (102,118). In view of the strong vascular
vasodilation of large arteries in the coronary circulation
activity of nitrates, their effects on myocardial contractility
increases myocardial blood flow to ischemic regions where
are rather small and probably of minor importance (67).
resistance vessels are already maximally dilated by adenosinemediated autoregulation. Nitrates induce opposite effects on
EFFECTS OF NITRATES
coronary blood flow than the vasodilator dipyridamol. This
ON PLATELET AGGREGATION
drug relaxes both large and small coronary vessels whichcounteract autoregulatory mechanisms and redistributes
Almost two decades ago it was shown that therapeutic
coronary flow to non-ischemic regions ("steal-phenomenon")
doses of isosorbide dinitrate can reduce platelet aggregation in
which can cause myocardial ischemia in the stetting of
patients with stable angina (27). This observation was
confimed by Diodati et al. who demonstrated similar effects ofsodium nitroprusside and glyceryl trinitrate in stable angina,
unstable angina and myocardial infarction (32,33). Inhibition
Organic nitrates reduce blood pressure. At low doses
of platelet aggregation by organic nitrates is most likely
where preload reduction is almost maximal (Fig. 1) the
mediated by activation of the platelet NO/cGMP pathway
hypotensive effect likely results from the redistribution of the
(115). In addition, it was reported that NO derived from
circulating blood volume (8), while higher doses can cause a
nitrates induces activation of endothelial cyclooxygenase and
direct dilation of larger arterioles resulting in a reduction of
release of antiaggregatory prostanoid prostacyclin (109). The
peripheral resistance and a substantial drop in blood pressure.
contribution of inhibition of platelet aggregation to the
In contrast to organic nitrates, sodium nitroprusside induces a
therapeutic efficacy of nitrates is still controversial but it is
comparable relaxation of arterial and venous blood vessels
likely that these effects might have potential for preventing
and reduce preload and afterload to a similar degree. The
thrombus formation in unstable angina (4).
rapid onset and short duration of action permits a titration ofblood pressure by adjustment of the infused dose (6). CLINICAL EFFICACY
Reduction of blood pressure is harmful for the ischemic
OF ORGANIC NITRATES
heart since it reduces coronary perfusion pressure andsubsequently myocardial oxygen supply. In addition,
The use of organic nitrates in the various settings of CAD
activation of the baroreceptor reflex increases the sympathetic
is largely determined by the pharmacokinetic features.
tone in the heart and leads to enhanced inotropy and
Nitrates can be divided in long acting drugs such as
chronotropy which increases myocardial oxygen demand.
isosorbide mononitrate, pentaerythritol tetranitrate and
Thus, the small effect of organic nitrates on peripheral
molsidomine and short acting drugs such as glyceryl
resistance is important and valuable in ischemic heart disease.
trinitrate, isosorbide dinitrate and sodium nitroprusside (6).
However, it should be noted that there is a great
Short acting nitrates showing a rapid onset of action are used
interindividual variability of the blood pressure response to
to treat acute ischemic attacks, while long acting nitrates are
primarily used to prevent ischemic episodes. However, there
myocardial ischemia in silent angina but the use of nitrates
are sustained-release oral and transdermal formulations of
in this particular setting of CAD is questionable (103,112).
isosorbide dinitrate and glyceryl trinitrate permitting the use of
– Unstable angina pectoris and myocardial infarction: A
these drugs in preventive therapy (96). In addition, intravenous
variety of clinical investigations have shown that nitrates can
glycerol trinitrate and isosorbide dinitrate are commonly used
reduce the frequency and duration of chest pain in unstable
in acute coronary syndromes and heart failure. Furthermore,
angina (43,58,60). Most likely, these effects are mediated by
many clinical reports have indicated beneficial effects of
the their inhibitory activity of nitrates on coronary vasomotor
nitrates in diseases characterized by an increased tone of non-
tone and platelet aggreability. Furthermore, the
cardiovascular smooth muscle tissues (65).
concommitant reduction in left ventricular enddiastolicpressure (LVEDP) enhances the driving pressure for blood
flow to the subendocardium. In unstable angina nitrates are
–Stable angina pectoris: More than 120 years ago
continuously infused at doses adjusted to the disappearance
glyceryl trinitrate was reported to have beneficial effects in
of pain, while at the same time close hemodynamic
stable angina (87) and today this is still the most important
monitoring is necessary to avoid a harmful reduction of
indication. Three different therapeutic strategies can be
blood pressure associated with increased heart rate.
differentiated: a) Treatment of acute anginal attacks; b) short-
Furthermore, it cannot be excluded that in unstable angina
time prevention of anginal attacks when extraordinay pysical
sudden withdrawl or intermittent treatment might precipitate
or mental stress is expected, and c) long-term prevention
during the day to reduce the occurrence and severity of
Nitrate therapy in myocardial infarction is well known
anginal attacks. In any case treatment is initiated to provide
and frequently used to reduce chest pain, pulmonary
symptomatic relief. In contrast, it is not known if this therapy
congestion and sustained hypertension (4,6). As discussed
is associated with improved survival in CAD (see Section
above, these beneficial actions are largely based on the
hemodynamic effects of nitrates. During long-term non-
–Acute treatment and short-term prevention:
intermittent administration for more than a day nitrate
Sublingual glyceryl trinitrate and the slower acting
tolerance develops. Although increasing the dosage will
isosorbide dinitrate are the nitrates of choice to treat acute
restore the hemodynamic and antianginal activity, it must be
anginal attacks (4,6,96), since they promptly relieve chest
considered that severe forms of nitrate tolerance are
pain within minutes. Furthermore, sublingual nitrates are
associated with an increase of vascular superoxide
also useful to prevent anginal attacks if taken a few minutes
production (see below) which may worsen coronary artery
before activities known to possibly cause an atttack.
function and might predispose to a reinfarction. On the other
– Long-term prevention: Long-acting nitrates are
hand, postinfarction treatment with nitrates may help to
still among the drugs of choise to achieve freedom from
preserve diastolic left ventricular function (63). Likewise,
anginal attacks when interventional procedures such as
low dose transdermal nitroglycerin can improve left
PTCA and coronary bypass surgery have failed or are not
ventricular function and prevent left ventricular dilation in
sufficiently effective anymore (4,96). However, it is not
postinfarction patients with a left ventricular ejection fraction
possible to provide a 24 hr protection, since nitrates induce
tolerance when taken continuously (see section NitrateTolerance). Therefore, it is necessary to follow an therapeutic
regimen which includes a daily nitrate pause of
Nitrates, for the most part in combination with
approximately 10 hr. This can be easily achieved by skipping
hydralazine, are an important and often indispensable
nitrate application or removal of a nitrate patch in the
therapeutic option in the treatment of heart failure (6,23).
evening. Effective management of chronic stable angina
Nitrates are considered useful in selected patients,
without development of tolerance using this therapeutic
particularly in those who cannot take an ACE inhibitor
regimen has been proven for glyceryl trinitrate patches (30)
because of hypotension or renal insufficiency (54). As
and standard- and sustained-formulations of isosorbide
already pointed out above, close hemodynamic monitoring
mononitrate (22,98,123). Similar effects have been reported
is necessary to avoid a harmful reduction of blood pressure
with standard- and sustained-release formulations of
associated with increased heart rate. Nitrates are known to
isosorbide dinitrate, although there is some evidence that the
improve left ventricular function and cardiac output and are
beneficial effect of isosorbide dinitrate might decline during
used to prevent or to treat the development of pulmonary
the day (96,97,114). As for sustained-release formulations of
edema. Among nitrates and nitrate-like drugs, glyceryl
isosorbide mononitrate, clinically evident effects resulting in
trinitrate, isosorbide dinitrate and sodium nitroprusside are
better exercise tolerance in patients with angina pectoris
used in acute and chronic heart failure. In case of concomitant
occur one hour after dosing (42). Finally, nitrates have been
myocardial ischemia or established CAD, glyceryl trinitrate
shown to effectively reduce the frequency of asymptomatic
is usually the drug of choice. Another established use of
organic nitrates is an add-on therapy in more severe forms of
inhibitors and statins is likely involved in the beneficial
chronic heart failure to provide symptomatic relief and
effects of these interventions in patients with CAD (41). In
improve the patients quality of life (23).
experimental atherosclerosis organic nitrates such aspentaerythrityl tetranitrate and isosorbide mononitrate can
improve endothelial function and reduce intimal lesion
Pulmonary arterial hypertension is a serious life-
formation and oxidation of LDL (47,82). In addition, an
threatening condition (52,107). A treatment-based
investigation in LDL-receptor deficient mice showed
classification has been suggested that divides the disease into
antiatherosclerotic effects of the NO-releasing nitroaspirin
five different catagories: a) pulmonary hypertension
NCX-4016, while the parent compound acetylsalicylic acid
associated with disorders of the respiratory system and/or
had no effect on atherosclerosis (90). Finally, the nitrate-like
hypoxemia; b) pulmonary venous hypertension; c) chronic
drug nicorandil has been shown to improve the prognosis of
thromboembolic disease; d) pulmonary arterial
patients with stable angina pectoris (124).
hypertension, and e) pulmonary hypertension due to
– Myocardial infarction: In contrast to less life-threatening
disorders directly affecting the pulmonary vasculature (40).
forms of angina, the effects of short-term treatment with
Beside anticoagulation, the condition is treated with
nitrates on survival of patients with myocardial infarction
vasodilator therapy. According to the recently published
have been studied extensively. In 1988, Yusuf et al.
guidelines of the American College of Chest Physicians,
published a meta-analysis on the effects of nitrates in
patients should undergo vasoreactivity testing and those with
myocardial infarction revealing a total reduction of as much
a favourable response to a vasodilator should be considered
as 35% (134). This result was challenged in two large
to receive an oral calcium channel antagonist. Other patients
prospective clinical trials including 77,000 post-infarction
are candidates for pharmacotherapy with bosentan and
patients who received a glyceryl trinitrate patch (46) or an
various prostanoids (7,106). Anew and intensively discussed
oral sustained-formulation of isosorbide mononitrate (57). In
but currently not approved therapeutic option is the use of
both studies there was a trend but no significant effect on
inhaled nitric oxide (74). It appears that this treatment may
survival and similar result emerged from a subsequent meta-
fulfill the need of a drug that acts selectively on the
analysis (57). However, subgroup analysis in GISSI-3
pulmonary vasculature. In contrast, organic nitrates are
showed a significant effect of glyceryl trinitrate on survival
considered to be less efficacious and are not included in
of elderly patients (>70 years) and women. Furthermore,
glyceryl trinitrate significantly improved the beneficial effectof lisinopril on survival (46). It is not known whether these
EFFECTS OF NITRATES ON SURVIVAL
favourable results have been adopted to clinical practice of
IN CARDIOVASCULAR DISEASES
pharmocotherapy of post-infarction patients.
The reasons for the appearant discrepancy between the
results of the initial meta-analysis and the subsequently
– Stable angina: There is no prospective randomised trial
performed prospective clinical investigations have been
on the effects of nitrates on survival in stable angina.
discussed in detail (50,59). One important disadvantage of
Therefore, nitrates are usually considered as pure
GISSI-3 and ISIS-4 is the frequent use of nitrates (up to
symptomatic drugs in the treatment of stable angina.
60%) in the study arms serving as controls for the effects of
Nevertheless, many investigations indicate that nitrates may
nitrates on survival. This is a crucial point, since the
do more than just relieve the symptoms of myocardial
beneficial effects of nitrates have been described to occur
ischemia. Accumulating experimental and clinical data
within the first 24 hr of initiation of treatment (134). Another
suggest that late ischemic preconditioning is triggered and
important factor is the fact that GISSI-3 and ISIS-4 have
mediated by endogenous NO and can be pharmacologically
been conducted after the establishment of significant
recruited by NO-donors such as glyceryl trinitrate (17).
pharmacotherapeutic proceedings in the management of
Furthermore, some of the most important effects that NO
myocardial infarction such as lysis. Finally, the duration of
exerts in the vascular wall are potentially vasoprotective,
treatment (4-6 weeks) might have been too short to show
because these effects contribute to and maintain important
possible significant benefits of nitrates. For example, in
physiological functions such as vasodilation,
secondary prevential trials with statins at least 6 months of
anticoagulation, leucocyte adhesion, smooth muscle
treatment were necessary before the Kaplan-Meier-curves
proliferation, apoptosis and the antioxidative capacity (41).
A large body of evidence suggests that NO produced in thevascular endothelium exerts protective effects against the
development of atherosclerosis and CAD. Improvement of
The results of a randomized controlled clinical trial with
endothelial function and vascular NO-bioavailability by
mild-to-moderate heart failure has demonstrated that a
regular physical activity or pharmacotherapy with ACE-
combination of isosorbide dinitrate and the arterial
vasodilator hydralazine reduces mortality and morbidity in
glyceryl trinitrate was dosed continuously in combination
patients receiving a baseline medication with digoxin and
with low dose L-arginine (700 mg every 6 hr). This study
diuretics (24). The group of patients treated with the
shows a 24 hr antianginal effect of continuously
isosorbide dinitrate/hydralazine combination had significant
administered glyceryl trinitrate. It was concluded that this
improvements of ejection fraction, exercise capacity and
was the result of prevention of tolerance by L-arginine. A
overall mortality as compared with a group of patients
similar prevention of tolerance was seen earlier when
treated with the vasodilator prazosin (α1-adrenoceptor
glyceryl trinitrate and L-arginine was administered
antagonist). After inclusion of angiotensin-converting
intravenously (3) and when oral treatment with folic acid
enzyme inhibitors into the pharmacotherapy of heart failure
was added to continuous transdermal glyceryl trinitrate (44).
it was shown that treatment with enalapril is superior to thenitrate combination (25). In the enalapril arm mortality was
Decreased generation of vascular NO by organic nitrates
28% lower than in the nitrate arm. This favorable effect was
Many efforts have been untertaken to elucidate the
attributable to a reduction in the incidence of sudden death
molecular mechanism underlying nitrate tolerance and
and was more prominent in patients with less severe
several different mechanisms have been shown to be
symptoms (New York Heart Association class I or II). In
involved. The most extensively discussed hypothesis is that
contrast, only the nitrate combination increased body
sulfhydryl depletion of the vascular smooth muscle inhibits
oxygen consumption at peak exercise and it induced in a
generation of NO from organic nitrates (92). However, it
stronger increase of ejection fraction during the first 3
was demonstrated that restoration of thiol levels in the
months of treatment. Nevertheless, there are patients
vascular wall does not reverse in vitro tolerance to organic
showing an insufficient response, a poor tolerability or
nitrates (45). Likewise, it is possible to strongly reduce the
contraindications to ACE-inhibitors so that the nitrate
thiol content of vascular smooth muscle without affecting
combination remains a valuable therapeutic approach (23).
the vasodilator activity of organic nitrates (68). There is also
Despite the considerable debate on raced-based therapeutics
in vivo evidence speaking against the "sulfhydryl-depletion"-
(10), afroamericans (blacks) with heart failure appear to
hypothesis (15). Thus, depletion of vascular free thiols might
represent a particular group of patients with a significant
be associated with nitrate tolerance but is probably not the
reponse to the isosorbide dinitrate/hydralazine combination. A
very recent study with 1050 black patients with severe heart
In contrast, in vitro and in vivo studies provided evidence
for an involvement of impaired vascular nitrate bioactivation
pharmacotherapy therapy for heart failure such as angiotensin-
to NO in nitrate tolerance. Almost two decades ago in vitro
converting-enzyme inhibitors, angiotensin-receptor-blockers,
studies demonstrated that nitrate tolerance is associated with
β-blockers for at least three months before randomization,
reduced vascular bioactivation of nitrates as indicated by a
digoxin, spironolactone, and diuretics showed, that the
lower concentration of the dinitrate metabolites found in
addition of isosorbide dinitrate/hydralazine is efficacious and
tolerant vascular preparations or isolated cells (9,18). As
increases survival these black patients (120).
shown by studies in isolated coronary arteries, the reductionof nitrate bioactivation might be initiated by NO and thus
represent a form of feed-back inhibition (69). These data are
When nitrates are continuously applied, their in vivo
consistant with the results of a recent cDNA mircroarray
vasodilator activity ceases within 17-24 hr. This can be
analysis on the influence of nitrate tolerance on vascular
demonstrated by a reduction of exercise capacity and an
gene expression (127). There was a significantly reduced
increased frequency of anginal attacks (6). In general, nitrate
expression of enzymes such as glutathion-S-transferase or
tolerance is a multifactorial phenomenon (Fig. 2) which also
cytochrome P450 which are known to be involved in
includes a so-called pseudo-tolerance that involves increased
vascular bioactivation of organic nitrates to NO.
circulating levels of vasoconstrictors (65,94). Earlier studies
Although there was no association between reduced
have shown that an eccentric dosing regimen including a
bioconversion of high-dose glyceryl trinitrate in an in vivo
nitrate-free interval of 10-12 hr is a useful therapeutic
study in the rat (72), this well known hypothesis has been
approach to prevent the development of nitrate tolerance.
recently reinforced by a clinical investigation which provided
This has been proven for glyceryl trinitrate (30), and
evidence that a reduced bioactivation of glyceryl trinitrate
different formulations of isosorbide mononitrate
occurs in nitrate tolerance induced by short-term i.v. glyceryl
(22,98,123). Nevertheless, nitrate tolerance is still considered
trinitrate in man (108). In vivo studies in rats and rabbits have
disadvantageous since the eccentric dosing regimen cannot
shown the development of a moderate form of nitrate
provide a 24 hr lasting protection from anginal attacks and is
tolerance characterized by a specific inhibition of vasodilation
associated with a decreased anginal threshold during the
by organic nitrates such as glyceryl trinitrate and isosorbide
nitrate-free interval (95). A potential solution to this problem
mononitrate, while the vasodilator activity of NO itself
may be seen in a recent study (99) in which transdermal
remained (28,83). A recent study proposed the mitochondrial
aldehyde dehydrogenase as an important enzyme for nitrate
Decreased bioavailability of vascular NO
bioactivation and demonstrated its inhibition in the setting of
Recent investigations in rabbits treated with GTN patches
in vitro nitrate tolerance (20). Likewise, the results of a
continuously releasing the drug for 3 days showed the
another report suggest that nitrate tolerance is partially
development of a severe form of nitrate tolerance where both
mediated by inhibition of vascular mitochondrial aldehyde
endothelium-dependent and NO-induced vasorelaxations
dehydrogenase and that mitochondrial reactive oxygen
were markedly impaired. This was associated with other
species contribute to this inhibition (119).
changes of vascular reactivity including increased vascular
However, it should be noted that there are important but
superoxide production induced by angiotensin II stimulated
unexplained steps in this newly proposed mechanism of
activation of NADH/NADPH oxidases and an increased
nitrate bioactivation in mitochondria. For example,
sensitivity to vasoconstrictors such as phenylephrine (85,86).
mitochondrial bioactivation of nitrates yield nitrite anion and
Interestingly, it was suggested that both effects result from
it is unclear how nitrite is reduced to NO. Recently published
activation of protein kinase C by angiotensin II. In
experiments using purified mitochondrial aldehyde
accordance, the angiotensin II receptor antagonist losartan
dehydrogenase showed generation of an activator of soluble
abolished vascular superoxide production and normalized
guanylyl cyclase by glyceryl trinitrate, but the contribution of
endothelium-dependent vasodilation in severe nitrate
this enzyme in mitochiondrial preparations to the
tolerance (71). However, losartan did not completely restore
bioactivation of glyceryl trinitrate appeared rather small (31).
the vascular sensitivity to GTN suggesting that other
Likewise, immunoblot analysis indicate a that the majority of
mechanisms of nitrate tolerance were also involved. This is
vascular mitochondrial aldehyde dehydrogenase is present in
consistant with a study in humans where losartan had no
the cytoplasm and inhibitors of this enzyme such as
effect on the development of nitrate tolerance (80).
cyanamide and propionaldehyde induce a comparable
It has been reported that a damaged form of endothelial
rightwardshift of the concentration-response curves for
nitric oxide synthase, the so-called "uncoupled eNOS", may
nitrates in both tolerant and non-tolerant arteries (31).
also contribute to vascular generation of superoxide in nitrate
Although the identity of the enzyme leading to bioactivation
tolerance (2,3), and there are other observations supporting
of nitrates is still a matter of debate, the findings above further
this hypothesis as recently reviewed (94). In contrast, studies
reinforce the view that nitrate tolerance is indeed at least
in eNOS–/– and eNOS+/+ mice showed no difference in nitrate
partially mediated by impairment of nitrate bioactivation.
tolerance after continuous infusion of glyceryl trinitrate as
Severe Nitrate Tolerance activated renin-angiotensin system strongly impaired vasodilation by nitrates activated vascular protein kinase C impaired vasodilation by NO activated endothelial NADPH-oxidase impaired endothelial function modulated NO-signal transduction increased vascular superoxide production Moderate Nitrate Tolerance impaired vasodilation by nitrates selective reduction of enzymatic nitrate bioactivation No Nitrate Tolerance normal vasodilation by nitrates vascular function
Illustration of the hypothesis that nitrate tolerance is a dynamic event where increasing severity (left side) is mediated by strikingly
different molecular mechanisms (right side). Severe nitrate tolerance increases vascular oxidant stress which and induces endothelialdysfunction, while moderate nitrate tolerance seems to be restricted to a specific impairment of bioactivation of nitrates to NO. Beside NADPH-oxidase uncoupled eNOS might serve as a source of increased vascular oxidant stress (please see chapter Nitrate tolerance).
evidenced by identical reductions of vasodilator responses
nitrate tolerance seem to be restricted to a specific impairment
and vascular cGMP accumulation (128). It should be noted
of bioactivation of nitrates to NO. Thus, nitrate tolerance is
however that this apparent contradiction might be the result
most likely not a simple on-off phenomen but a rather
of compensatory action of vascular neuronal NOS (nNOS) in
dynamic event where increasing severity is mediated by
eNOS–/– mice (53). Another mechanism of nitrate tolerance
strikingly different molecular mechanisms.
that is associated with a decreased bioavailability of NO wassuggested recently (62). This study provided evidence for an
Side effects, contraindications and interactions with other
increased expression of the cGMP-hydrolizing phospho-
diesterase 1A1 in nitrate tolerance, while the cGMP
In general, organic nitrates are remarkably safe and well
hydrolizing phosphodiesterase V was not changed.
tolerated drugs. Important side effects include headache,
In summary, nitrate tolerance is a well documented and
hypotension, flush and nausea (6,65,96). These side effects
clinically important phenomenon in pharmacotherapy with
are directly related to the vasodilator activity of nitrates.
nitrates. It is characterized by a loss of vasodilator activity and
Table 4 lists the side effects of the typical organic nitrate
can be avoided by a nitrate pause of at least 8 h, preferably
isosorbide dinitrate. Headache is the most prominent side
during the night. The molecular mechanism of nitrate
effect and is caused by cerebral vasodilation (93). However,
tolerance is multifactorial and seems to depend on its severity
the mechanism of cerebral vasodilation by organic nitrates
(Fig. 2). In severe nitrate tolerance oxidative stress decreases
seems to differ from that of coronary vasodilation. It has
nitrate bioactivation, the bioavailability of vascular NO and
been reported that the vasodilator efficacy of organic
induces endothelial dysfunction, while moderate forms of
nitrates in isolated cerebral arteries is 100-fold lower than
Side Effect Frequency
at first days of therapy, when dosage is increased,associated with dizziness, drowsiness,reflex tachycardia, feeling of weakness
vomiting, flush, allergic scin reaction (e.g. rash),marked hypotension with increased angina symptoms,collapse (sometimes accompanied by bradyarrhythmia and syncope)
(Please note: not listed is the possiblility that during the treatment with sustained release formulation of isosorbide dinitrate, a temporaryhypoxemia may occur due to a relative redistribution of the blood flow in hypoventilated alveolar areas. Particularly in patients with coronaryartery disease this may lead to a myocardial hypoxia.)
that in isolated coronary arteries, while the reponse of both
cholesterolemia and atherosclerosis (26,126). Therefore, a lot
artery types to NO is essentially the same (78). These data
of studies were conducted to elucidate whether dietary L-
suggest a specific lack of enzymatic bioactivation of nitrates
arginine supplementation can augment NO production in man
to NO in cerebral arteries. One interesting alternative
and thereby improve vascular health (13,16).
mechanism was reported by Wei et al. who found that
Interestingly, the intracellular levels of L-arginine in the
organic nitrates can activate sensory nerve fibres to release
millimolar range far exceed the Km of the NOS enzyme,
calcitonin gene related peptide, which then induces cerebral
which is in the micromolar range, and therefore it is unlikely
vasodilation via the NO/cGMP pathway (129). It is well
that application of L-arginine affects NO production (16).
known that nitrate-induced headache ceases during the first
This phenomenon was called the "L-arginine paradox". The
days of therapy, while other vasodilator actions remain. This
most plausible explanation to solve this paradox may be the
clinical observation also indicates different mechanisms of
presence of the endogenous competitive inhibitor of the
action underlying vasodilation of cerebral and non-cerebral
NOS, asymmetrical dimethylarginine (ADMA). Plasma
blood vessels. A recent report suggests that isosorbide
dinitrate, isosorbide mononitrate and slow release glyceryl
hypercholesterolemia, atherosclerosis, hypertension, chronic
trinitrate induce cluster headache which may be caused by
renal failure, and chronic heart failure. In several studies
central mechanisms involving a decrease of sympathetic
ADMA evolved as a novel cardiovascular risk factor and
administration of L-arginine has been shown to improve
Nitrates are contraindicated in severe hypotension,
endothelium-dependent vascular functions in subjects with
shock, obstructive cardiomyopathy and toxic pulmonary
high ADMA levels (16). Oral L-arginine improves
edema, because their vasodilatory actions would worsen
endothelial function in healthy individuals older than 70
these conditions. Close cardiovascular monitoring is
years (14). The pharmacokinetics of L-arginine have been
recommended if nitrates are administered in acute
investigated, side effects are rare and mostly mild and dose-
myocardial infarction with low filling pressures or in
patients suffering from orthostatic dysregulation.
Today, we have reached phase 2 of the human testing:
Nitrates show just a few interactions with other drugs and
about 500 subjects and patients got oral L-arginine and we
this is of considerable advantage in treatment of more
have results about the effectiveness and safety aspects. The
severly ill cardiovascular patients who need a variety of
problem is the heterogenity of the published studies
drugs. The most important interactions are those resulting in
concerning doses and outcome parameters. Table 3
a magnification of hypotensive effects. This holds true for
summarizes published studies in which L-arginine was
any kind of vasodilatory active drugs such as β-blockers,
applicated in patients with coronary artery disease and
diuretics and calcium antagonists but also for alcohol,
chronic heart failure. For coronary artery disease we had one
neuroleptics and tricyclic antidepressants. For the same
negative: Blum et al. (11) conducted a randomized, double-
reason, patients receiving nitrates cannot take inhibitors of
blind crossover study with 9 g QD for 1 month and assessed
phosphodiesterase V such as sildenafil or vardenafil. This
flow-mediated brachial artery dilation and cell adhesion
latter interaction is of particular importance since the rate of
molecule expression. In this study it was unclear if NO
erectile dysfunction is comparably high in patients with
production was increased. The study subjects were on full
cardiovascular medication with statins and ACE inhibitors,both have been shown to improve endothelial function. In
Other drugs activating the NO/CGMP pathway
addition, β-blockers and aspirin as an antioxidant were used.
During the last decade there have been many reports on
This may have confounded possible effects of L-arginine
activators of the NO/cGMP pathway including L-arginine
itself. In chronic heart failure Chin-Dusting (21) described a
and derivatives, phosphodiesterase inhibitors, NOS-
negative result with 20 g L-arginine for 28 days, whereas
activating β-blockers, NO-independent activators of soluble
Rector et al. (104) showed a significant improvement in
guanylyl cyclase and nitroaspirins (41). In many aspects, the
functional status. It may be that L-arginine may not be useful
pharmacology of the latter two classes of new drugs closely
in later stages of atherosclerosis in which the NOS
resemble that of organic nitrates and their relations to nitrates
expression was decreased by other factors.
will be discussed below. In addition, this paragraph sheds
– Nicorandil: Nicorandil is a nicotinamid ester that activates
some light on clinical data about L-arginine and the nitrate-
two different cellular pathways to induce vasodilation. Early
studies on the effect of nicorandil on coronary cGMP-levels
– L-arginine: L-arginine is the substrate for the enzyme
clearly demonstrated a predominant nitrate-like activity that
nitric oxide synthase (NOS), which is responsible for the
is most likely initiated by an enzymatic generation of NO
production of nitric oxide (NO). Acute and chronic
from the nitrate nitrogen of nicorandil (70). In addition,
administration of L-arginine has been shown to improve
nicorandil was shown to be a potassium channel opener,
endothelial function in animal models of hyper-
although with a much lower potency than cromakalim (131).
The nitrate-like action activates cGMP-dependent protein
one has to await the results of clinical investigations. It is
kinase I and leads to phosphorylation of several proteins such
likely that these drugs will be markted for the treatment of
as phospholamban, 1,4,5-inositoltrisphosphate receptor
hypertension, heart failure and/or CAD. It is not known
associated cGMP kinase substrate (IRAG) and calcium-
whether NO-independent activation of soluble guanylyl
dependent potassium channels (41) which reduces the
cyclase can improve endothelial function and reduce the
intracellular calcium-concentration. In addition, the ATP-
intimal lesion area in experimental atherosclerosis as has been
dependent potassium channel opening activity induces a
reported for organic nitrates (see above). NO was shown to
membrane hyperpolarization that impairs the activation of L-
elicit cGMP-independent and potentially vasoprotective
effects such as a reduction of lipid oxidation, activation of
It is still a matter of debate which of these mechanisms are
potassium channels and antiproliferative activity in vascular
predominant in vivo. However, the nitrate-like hemodynamic
smooth muscle cells (41) and these effects might not be
changes induced by nicorandil together with the knowledge
mimicked by NO-independent activators of soluble guanylyl
that the primarily arteriolar dilator effect initiated by
cyclase. Another important difference to organic nitrates is the
potassium channel openers are rather contraproductive in
strong effect of BAY412272 on platelet aggregation and
CAD strongly speak in favour of a predominant nitrate
bleeding time. Again, it is not known whether this
component (61). Nicorandil induces an antianginal activity
pharmacologic effect is of advantage in CAD. Although
comparable to that of nitrates, β-blockers and specific
inhibition of platelet activation is a useful pharmacologic
calcium channel blockers and does not precipitate a coronary
intervention, increased bleeding time may become a problem,
steal phenomenon. In addition, a large randomized clinical
particularly in combination with aspirin.
trial recently demonstrated beneficial effects of nicorandil on
– Nitroaspirins: Nitroaspirins such as NCX-4016 (2-
the prognosis of patients with stable CAD and additional
(acetoxy)-3-[(nitroxy)methyl]phenyl ester) (Fig. 3) were
cardiovascular risk factors (124). The primary composite
designed to combine pharmacologic effects of organic
endpoint was coronary heart disease death, nonfatal
nitrates and acetylsalicylic acid in one drug. Basically, these
myocardial infarction, or unplanned hospital admission for
drugs resemble the above mentioned direct activators of
cardiac chest pain. Treatment with nicorandil for a mean of
soluble guanylyl cyclase with respect to vasodilation and
1.6 years resulted in a 17% reduction of this endpoint.
inhibition of platelet aggregation (88). Furthermore, it was
Although no firm conclusion can be drawn, it seems possible
anticipated that liberation of NO from these drugs inhibits the
that the nitrate-like action of has contributed to the beneficial
initiation of peptic ulcers by aspirin and improve its
effect of nicorandil in the IONA-study (66).
therapeutic safety and this seems indeed to be the case (36). The liberation of NO from NCX-4016 is a metabolic and not
NO-independent activators of soluble guanylyl cyclase
a spontaneous process (29). This is not surprising since the
In 1994, researchers from Taiwan reported on
generation of NO from a nitrate moiety requires a transfer of
pharmacological activites of YC-1, a new benzylindazol
3 electrons to the nitrate nitrogen. Presumably, NCX-4016 is
derivative. They found that this drug activate the enzyme
metabolized by the same enzymes than organic nitrates,
soluble guanylyl cyclase by a NO-independent mechanism
namely cytochrome P 450 enzymes glutathion-S-transferase
and exerts antiplatelet effects in vivo (64,133). Further studies
and mtALDH, but further studies are needed to answer this
showed that YC-1 also potentiates the effects of NO and that
question. However, the need for enzymatic bioactivation
this is mediated by a stabilization of the active configuration
implies that the NO-generation from NCX-4016 might be
of soluble guanylyl cyclase, presumably via prologation of
reduced by a tolerance phenomenon when the drug is given
the dissociation of NO (38,39). Although the potency of YC-
in a continuous fashion (see above).
1 is too low to consider this compound for clinical
The effects of NCX-4016 on the development of
development, it served as a lead compound in the search of
experimental atherogenesis have also been investigated.
new activators of soluble guanylyl cyclase. This new class of
Cholesterol-fed LDL-receptor deficient mice were given
drugs is much more potent than YC-1 and display useful
NCX-4016 by oral administration. After 12 weeks mice
pharmacologic actions such as vasodilation and inhibition of
treated with NCX-4012 showed a significant reduction of
platelet aggregation (117). A more detailed investigation of
plasma LDL-oxidation, oxidative stress and atherogenesis,
the mechanism of action of these drugs resulted in the
while treatment with aspirin itself had no effect. Thus, these
discovery of a new regulatory site located in the region of the
favourable effects of NCX-4016 can be most likely attributed
cysteins 238 and 243 in the α1-subunit of soluble guanylyl
to the nitrate moiety of NCX-4016. Other studies showed
cyclase (116). The effects of one of the new drugs, namely
protective effects of NCX-4016 in animal models of
BAY412272, has been investigated in hypertensive rats and
restenosis, ischemia-reperfusion and myocardial infarction
was shown to reduce blood pressure and to prolong bleeding
(91,105,125). In summary, nitroaspirins are a new class of
time. Today, it is too early to estimate the possible therapeutic
drugs which may used for the treatment of cardiovascular
value of the new activators of soluble guanylyl cyclase and
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