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Coronary ischemia-reperfusion: role of nitric oxide and endothelin-1. A Review
subsequent studies have confirmed these observations, as types of cells. Interactions between endothelial cells and
brief periods of ischemia, including partial ischemia, cardiomyocytes could be of significance in regulating
impairs coronary vasodilator responses and enhances cardiac function by modulating vascular tone and by
coronary vasoconstrictor responses, and that these stimulating proliferation of neighboring cells. This aspect
alterations are accentuated after prolonged periods of may be of relevance in situations such as ischemia and
ischemia accompanied by myocardial infarction, and they reperfusion (149).
affect both epicardial and microvascular coronary
functional ability (135-140). The mediators of the There are studies showing that NO may be detrimental,
impairment in coronary vasomotor function after ischemia- and also studies showing that NO may be critical to
reperfusion remain uncertain; it may be involved reactive preserve cardiomyocytes function and viability after
oxygen species (138), plaque rupture with embolization of ischemia-reperfusion. In a Review published by R. Bolli in
particulate debris and release of vasoconstrictors 2001 it is indicated that “Of the 92 studies that have
(serotonin, thromboxane (141, 142) ), and inflammatory examined the role of NO in modulating the severity of
mediators, particularly TNFa (143, 144). ischemia-reperfusion injury in unstressed myocardium, the
vast majority (73%) have concluded that NO (either
More recent studies support the idea that NO and ET-1 endogenous or exogenous) has a protective effect, and
play a relevant role at various subclinical and clinical only 12% found a detrimental effect. The proportion of
stages of the coronary artery disease, and particularly after studies supporting a citoprotective role of NO is similar for
myocardial ischemia-reperfusion. The NO/ET-1 axis could in vivo and in vitro preparations” (150). The cardiac
play an important role in pathophysiology of myocardial interstitial NO concentration may increase during early
ischemia-reperfusion and of reperfusion injury, and ischemia and early reperfusion, and this increase may be in
beneficial effects of some therapeutical strategies for part derived from activated NOS isoforms but also from
myocardial reperfusion injury are attributed to NOS-independent pathways. The cardiac interstitial NO
modification of this axis. This particular issue, however, concentration is within the nanomolar range during normal
remains to be resolved and the available results are perfusion. And during ischemia, NOS3 activity is
contradictory. As NO and ET-1 may interact for regulating increased within minutes, and subsequently the NO
the function of coronary vasculature and the myocardium, concentration during early ischemia is increased (151).
the study of these two substances probably should be However, with prolonged myocardial ischemia, NOS3
considered together. NO is produced by both coronary protein expression decreases, and the tissue acidosis
endothelial cells and cardiomyocytes, and the principal attenuates NOS3 activity (153). Within the early seconds
source of this NO is eNOS (NOS3); in cardiomyocites of reperfusion, the NO concentration is increased (154),
NOS1 may be also involved, and expression of both NOS1 and if reperfusion is prolonged, NOS activity and thus NO
and NOS3 in these cells appears to be species-dependent concentration decrease below baseline values (155).
(for this issue, see References 36, 145-148). On the other Decreased NO production during reperfusion have been
hand, NO seems to play a relevant role in the functional suggested by observations indicating loss of NO-
regulation of myocardium under normal conditions and dependent vasodilation in response to Achor bradykinin, or
after ischemia-reperfusion (36, 147-149). Several studies loss of vasoconstriction in response to NOS inhibition (for
demonstrate that biosynthesis of NO by constitutive NOS details, see Reference 146). During myocardial ischemia-
(endogenous NO) plays a critical role in alleviating the reperfusion, reduced production of endogenous NO could
severity of myocardial ischemia-reperfusion as well as leave unopposed coronary vasoconstriction to the presence
reperfusion injury. NO has been known to play various of vasoconstrictors such as ET-1. This disbalance between
functional and pathological roles as an intracellular or NO and ET-1 in turn enhances vascular tone, decreases
intercellular messenger in the heart, and there are data coronary blood flow and exacerbates reperfusion injury.
indicating that NO can both reduce and mediate
myocardial reperfusion injury. NO influences myocardial From the results obtained in a study performed in rat
perfusion by regulating coronary vascular function, hearts, it is suggested that during reperfusion, cardiac
causing a direct vasodilatory effect and modulating function is depressed, despite increased rather than
vascular reactivity to other types of vasoactive stimuli (e. decreased endogenous NO production, largely due to the
g. ET-1). NO can also influence indirectly myocardial prevalence of the deleterious effects of ET-1. These
perfusion by regulating leukocyte–endothelial cell adverse effects of ET-1 can be overcome by antagonism of
interaction, inhibiting platelet adhesion and aggregation, ET-1 receptors or exogenous NO supplied by NO donors
attenuating smooth muscle cell proliferation, and possible (156). In other study performed in anesthetized pigs (157),
modulation of cardiomyocytes function. NO released from it was examined the interaction between the
the endothelium has also been shown to inhibit surface cardioprotective effect of endothelin receptor blockade and
expression of many endothelial cell adhesion molecules NO during ischemia-reperfusion injury. The authors of this
(ECAMs), including P-selectin, E-selectin, VCAM-1, and study suggest that blockade of endothelin ETA receptors
ICAM-1 (for this issue, see Reference147). Also, as produces cardioprotective effects, and that this
cardiomyocytes are surrounded by capillary endothelial cardioprotection is mediated via a mechanism related to
cells it allows for cell-to-cell signaling between these two NO (157).
@Real Academia Nacional de Farmacia. Spain 29
