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In a Review published by R. Schulz et al. in 2004 Godofredo Diéguez Castrillo
(146), the authors remark the importance of endogenous
and exogenous NO when given at the time of reperfusion With regard to mechanisms underly the effects of NO
for vascular and myocardial function, and morphological after ischemia-reperfusion, several hypothesis have been
outcome following ischemia-reperfusion. Administration proposed. In relation to the possible protective role of NO
of NO, NO donors or drugs that enhance NO release during ischemia-reperfusion, it has been proposed that it is
(statins, calcium antagonists, angiotensin-converting- related to the anti-peroxidation effect (156), as well as to
enzyme-inhibitors, dexamethasone) prior to ischemia resistance towards neutrophil adhesion and aggregation
protects the myocardium against ischemia-reperfusion (159). In relation to NO-mediated myocardial injury, it has
injury. This exogenous administration of NO prior to been suggested that it may be primarily related to
ischemia can initiate a preconditioning-like phenomenon. generation of large amounts of oxygen free radicals as
Interestingly, in this study it is suggested that endogenous consequence of an excess of NO, which reacts rapidly with
NO derived from NO-synthase is not involved in oxygen (154). These circumstances may lead to
triggering or mediating the early phase of ischemic reperfusion injury and aggravate the condition (160). A
preconditioning's protection, but it does play a pivotal role study carried out in cultured cardiomyocytes suggests that
for initiating and mediating the delayed phase of ischemic the enhanced production of NO was critical in balancing
preconditioning's protection (146). ATP supply and demand during ischemia, and also in
protecting cardiomyocytes from ischemia-reperfusion
The variation in plasma levels of several factors, injury (161).
including ET-1 and NO, was examined in a rabbit model
of acute myocardial ischemia-reperfusion (158). Rabbits The development of gene-targeted mice has allowed to
were exposed to open-chest surgery and were separated in begin to define the cellular and molecular mechanisms
three groups: group A received sham-surgery, group B was involved in the pathogenesis of acute myocardial
the reperfusion group, and group C was the infarction infarction, although the results from these experimental
group. At 12 h and at 24 h after chest closure, plasma models should be taken with caution. The development of
levels of ET-1 in groups B and C were higher than before mice with genetic manipulations could provide useful
chest surgery, and at 24 h there was no significant information regarding pathologic mechanisms related to
difference between these two groups. NO levels in groups myocardial ischemia-reperfusion injury (for details, see
B and C at 12 h after chest closure were decreased Reference 147). Studies using a model of eNOS transgenic
compared to those before chest surgery. NO levels in mice have demonstrated that eNOS overexpression
group B at 24, 48, and 72 h were lower than those at 12 h, significantly attenuates the extent of myocardial infarct
while those of group C were not significantly changed size following coronary artery ischemia and reperfusion
after 12 h. These results show that ET-1 and NO are (162).
mutually antagonistic vasoactive substances, and that after
myocardial ischemia-reperfusion, sustained reduction of Summarizing, the studies exposed before suggest that
NO may occur, thus suggesting that NO supplement is a the role of NO in ischemia-reperfusion and reperfusion
good clinical choice. Dynamic monitoring and comparison injury is not clear as there are data suggesting that NO may
of plasma levels of ET-1 and NO, as well as of other be beneficial and that it may be detrimental in evolution of
factors, revealed that appropriate intervention of these myocardial ischemia-reperfusion. As hypothesis, it might
factors may reduce reperfusion injury. The authors of this be that at the beginning of reperfusion the presence of NO
same study suggest that plasma ET-1 levels may be used might be beneficial, particularly for coronary vascular
as a reference index for the diagnosis and determining the vasomotion, but at chronic stage its presence might be
prognosis of myocardial infarction. It seems to be that pernicious for heart tissue because of it would facilitate
endogenousET-1 is increasingly released in systemic formation of free radical species.
circulation and coronary circulation, mainly in an
autocrine/paracrine manner by endothelial cells. This study With regard to ET-1, many data suggest that this
of Zhao et al. (158) also showed that 12 h after myocardial peptide is involved in the pathophysiology of reperfusion
ischemia, plasma ET-1 levels increased, while calcitonin injury (67, 68, 163-166), and that it may be also a
gene-related peptide (CGRP) levels decreased. Various significant predictor of reperfusion injury (167, 168).
factors and metabolites produced during the early phase During ischemia-reperfusion, the production of ET-1 is
may have a stimulating effect on endothelial cells, increased, the coronary vasoconstrictor effects of this
increasing the synthesis and release of ET-1, and leading peptide are also increased, and ET-1 enhances myocardial
to both the consumption and the decreased levels of necrosis and arrhythmogenesis (67, 68, 80). Plasma ET-1
CGRP. From this study (158) it can be inferred that NO levels increase 3–4h after the onset of ST segment
mediates reperfusion injury, but it also may reduce elevation myocardial infarction, peak within the first 24h
reperfusion injury through its antagonism on the effects of and remain elevated after 48h (168). High ET-1 values
ET-1. However, this particular issue requires further after percutaneous coronary intervention have been linked
investigation. to poor prognosis, including higher 30-day mortality (168).
In humans, evidence of microvascular injury has been
30 obtained as angiographic scores, primarily by indirect
methods such as the thrombolysis in myocardial infarction
grade flow and myocardial blush grade (169) and more
recently by cardiac magnetic resonance (170). Results
@Real Academia Nacional de Farmacia. Spain
