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Coronary ischemia-reperfusion: role of nitric oxide and endothelin-1. A Review

2.5. Interaction between NO and ET-1 system, and with increased ET-1 plasma levels. From a
study performed in hearts from young (3 months old),
The functional interaction between NO/ET-1 deserves aged (24 months old) and aged rats after 3 months of
attention for its implication in the regulation of vascular caloric restriction, it is suggested that aging is
function under normal and some pathological conditions. accompanied by alterations in myocardial and coronary
The release of ET-1 is inhibited by NO from the responses to ET-1, that may be related to changes in
endothelium (83, 101), which make NO and ET-1 expression of NO synthases and/or endothelin receptor
functionally closely interdependent, with a strong subtypes, with some of these changes being prevented by
inhibitory effects of ET-1 on NO-mediated dilation, and caloric restriction (109).
vice versa (102-104). Endothelial dysfunction is
associated with a decline in the contribution of NO in The relation between NO and ET-1 may be also
favor of greater influence of ET-1 on vascular function, altered during hypotension. In anesthetized goats, during
and this phenomenon seems to be more evident in the acute hypotension induced by constriction of the caudal
coronary circulation under certain pathological vena cava, it was found that: 1) under normotension, ET-
conditions (80). This alteration in the balance between 1 and AVP, intracoronarily injected, decreased coronary
NO and ET-1 under certain conditions may be one of the vascular consuctance (CVC) by up to 56% for ET-1 and
aspects underly dysfunction of the coronary circulation 40% for AVP; 2) under non-treated hypotension, the
with deleterious consequences for the myocardium (78, decreases in CVC byET-1 were augmented
80). approximately 1. 5 fold, and those by AVP were not
modified; 3) this increase in CVC by ET-1 was not
Alterations in the NO/ET-1axis can lead to disbalance affected by L-NAME and was reversed by
in vascular endothelial function, resulting in pathological meclofenamate, and 4) the coronary effects of AVP were
changes (105). With regard to this, it has been not modified by any of these treatments. Therefore, acute
demonstrated that intracoronary infusion of BQ123 hypotension increases the coronary vasoconstriction in
resulted in beneficial effects on coronary diameter and response to ET-1 but not in response to AVP, and this
coronary blood flow in patients with coronary artery increased response to ET-1 may be related to both
disease (106). Other observations also support the idea inhibition of NO release and release of vasoconstrictor
that in patients with coronary artery disease, less NO is prostanoids (110).
produced and more ET-1 would contribute to vascular
tone (80), and this hypothesis was tested in patients with The data exposed above suggest that NO and ET-1
coronary artery disease where it was proved that ET-1, play a relevant role in the regulation of the coronary
via endothelin ETA receptors, contributed to the circulation, and that a functional intereration between
reduction of endothelial dilatory response (107). Other these two substances could be of relevance in the control
study in patients with coronary artery disease shows that coronary vacular tone. When it is compared the role of
blockade of endothelin ETA receptors or blockade of NO in the coronary effects of ET-1 and AVP, the data
both endothelin ETA and ETB receptors improved the suggest that the interaction between NO and ET-1 is
endothelium-dependent dilation in coronary arteries greater that the interaction between NOand AVP in the
(108). Data from other studies also suggest that when regulation of the coronary circulation (see Figure 7).
more severe is atherosclerosis in coronary arteries, more
importance has ET-1 in the control of coronary artery Summarizing, the alteration in NO/ET-1 axis may
tone, thus functional contribution of this peptide appears play a relevant role on pathogenesis of coronary artery
to rise with the severity of coronary artery disease (80). disease, and thisaxismay be a target for therapeutic
interventions in some pathological conditions (e. g.,
Other circumstance in which interaction between NO atherosclerosis, myocardial ischemia-reperfusion) (Figure
and ET-1 may be altered is during aging. This condition 8).
may be associated with alterations in the cardiovascular

Figure 8. A) Schematic representation of a transverse section of a normal artery showing the layers of the artery wall, the release of NO
and ET-1 by endothelial cells, and chemical structure of these two substances. B) Schematic representation of changes in the relative role
of NO and ET-1 in the regulation of vascular tone after aging, cardiovascular risk factors and some cardiovascular diseases (CVD).

@Real Academia Nacional de Farmacia. Spain 25