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Coronary ischemia-reperfusion: role of nitric oxide and endothelin-1. A Review
continuity due to erosion, fissure, or endothelial rupture. facilities is limited, thrombolytic therapy is still
Endothelial dysfunction and damage is a main factor for
the formation of atheromatous plaques and development
of coronary artery disease. Many clinical trials have
suggested that lifestyle and pharmacologic interventions
are effective in attenuating atherosclerotic disease
progression and events development in coronary
vasculature. Thus, preventing the appearance of
atherosclerosis coronary plaques or their progression
should be the first line of action against the disease.
The atheromatous plaques, by producing severe
stenosis and/or thrombosis of a coronary artery, may
induce a pronounced reduction (>80%) of coronary blood
supply in the distal territory of myocardium supplied by
the artery affected, thus causing acute myocardial
infarction (AMI). This entity frequently occurs in persons
>45 years old, of which 1? /3 die within 28 days after
beginning clinical symptoms. Studies of sex differences
in long-term mortality after AMI have reported mixed
results. Main determinants in evolution of patients with
AMI are individual factors (e. g., age of patient), size of reperfusion may also damage myocardium exposed to
infarct, and time elapses between symptoms felt by
patient and instauration of an effective treatment. The
treatment should be directed to salvage the maximum
amount possible of myocardium, by applying the
adequate treatment as early as possible. Ischemic
myocardial injury may also occur in clinical conditions
such as heart transplantation, cardiac bypass, and
coronary stenting after acute myocardial infarction (for
details, see References 1-5).
The incidence and fatality rates of an AMI are going
down in developed countries as a result of better
prevention and treatment. Basic and clinical researchers
agree that the most effective treatment of AMI is timely
(early) reperfusion by opening the stenosed/thrombosed
coronary artery, thus restoring the blood flow to the
ischemic myocardial territory. Timely restoration of
blood flow to the ischemic zone of the myocardium
limits infarct size and reduces mortality, and this
reperfusion can be performed in patients, either by using
thrombolytic agents (6) or percutaneous coronary
angioplasty (7), and both of these procedures were
initiated around 1975 (8). AMI is a dynamic process that
frequently reaches the total extension of myocardium
necrotized within 6h after initiating the artery occlusion. The present Review focus on myocardial ischemia-
Myocardial reperfusion intents to stop expansion of
myocardial damage, and this procedure represents a
major step in treatment of patients with AMI.
Reperfusion therapy is one of the most successful
therapies of modern medicine. Today, primary
percutaneous coronary angioplasty is the preferred
strategy if the procedure can be performed by an
experienced team within 90–120 min after the patient
first presents (8). It is preferred because it can confer
more rapid and complete revascularization, induces
revascularization in a larger number of infarct-related
coronary arteries and is associated with fewer bleeding
complications. However, because access to invasive
@Real Academia Nacional de Farmacia. Spain
employed in many centers worldwide (8). In advanced
countries, patients are now receiving the benefits of
reperfusion therapy, and reducing time between
symptoms onset and reperfusion therapy, is at present
one of the main goals in the management of patients with
AMI (9).
Also, basic and clinical researchers agree that not all
it is favorable with myocardial reperfusion, and as
Braunwald and Kloner written at 1985, myocardial
reperfusion is “a double edge sword” (10). Whereas it is
very difficult to study the pathogenesis of human
coronary syndromes such as AMI, experimental models
have provided good reproducible means to explore
different aspects of the events that occur after myocardial
ischemia-reperfusion. Around the 1960s, R. B. Jennings
and cols. brightly demonstrated in laboratory animals the
consequences of a temporary occlusion of a coronary
artery, as well as those of reperfusion by releasing this
coronary occlusion (11, 12). They observed that
ischemia, and this damage is added to myocardial
damage caused by ischemia itself, and it known as
reperfusion injury (13). This phenomenon has been also
described in the clinical setting (10).
The coronary circulation plays a crucial role in the
development of the effects of ischemia-reperfusion on the
heart tissue. Indeed, the coronary circulation is the cause
of the consequences of interruption of blood supply to
cardiac tissue, as coronary artery disease is culprit of this
interruption, and also it is victim of these consequences
of blood flow deprivation as ischemia-reperfusion
damages not only cardiomyocytes but also coronary
vasculature. Furthermore, the coronary circulation is also
protagonist in the process of reperfusion aimed to reduce
the consequences of ischemia-reperfusion. Therefore, the
coronary circulation should be considered with attention
as it could play a central role in path physiology of
myocardial ischemia-reperfusion and reperfusion injury,
and also should be considered as a target of therapeutical
strategies for cardioprotection (14). However, spite of
relevance of the coronary circulation in ischemia-
reperfusion and reperfusion injury, this vasculature has
received little attention in literature about this issue (14).
reperfusion, paying particular attention to the coronary
circulation and to role of nitric oxide and endotheli-1 in
the regulation of this vascular bed under normal
conditions and after ischemia-reperfusion. Also, it will be
considered therapeutical strategies for ischemia-
reperfusion injury, with greater mention to antagonists
for endothelin receptors.
2. THE CORONARY CIRCULATION
2.1. General considerations
Over the past several decades, the major factors
determining myocardial perfusion have been elucidated,
and this knowledge has been incorporated in the
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