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Coronary ischemia-reperfusion: role of nitric oxide and endothelin-1. A Review
effect might be related to alteration of release of NO and min reperfusion in anesthetized goats, untreated and
prostanoids. treated with L-NAME or meclofenamate. Coronary
occlusions of 5- and 10-s duration produced hyperemic
In pages 26 and 27, we have commented two studies responses that depended on occlusion duration. After
from our laboratory where we found that under normal ischemia-reperfusion, these hyperemic responses were
conditions AVP produces marked coronary diminished, and this diminution was dependent on duration
vasoconstriction and that this vasoconstriction may be and severity of ischemia. These effects of ischemia-
mainly mediated by vasopressin V1 receptors, and it is reperfusion were not affected by inhibition of NO
modulated by NO, but not by prostanoids (98). In the other synthesis with L-NAME, and were reversed with
study, we compared the coronary effects of ET-1 and meclofenamate. The hyperemic response reduction during
AVP, and the results show that ET-1 produce higher reperfusion after prolonged ischemia, but not after brief
vasoconstrictor effect than AVP. From this study, it is also ischemia may be related at least in part to increased
suggested that NO may play a more relevant role for production of vasoconstrictor prostanoids (193).
modulating the coronary vasoconstriction by ET-1 than by
AVP, and that cyclooxygenase products may not be Episodes of myocardial ischemia may occur in humans
involved in the coronary effects of these two peptides under situations such as transient arterial hypotension.
(100) (See Figure 7). We then examined the coronary From experiments in anesthetized dogs it has been
effects of AVP and its interaction with NO and prostanoids reported that the coronary reactivity to ET-1, but not to
during ischemia and reperfusion. During partial coronary angiotensin II is increased during low coronary perfusion
occlusion, the coronary vasoconstriction in response to pressure, which may contribute to coronary ischemia after
AVP was attenuated in non-treated animals, and this reduced coronary perfusion (194), and that ET-1 does not
attenuation was reversed by L-NAME and was modify the coronary response to decreased coronary
accentuated by meclofenamate. At 30 min of reperfusion perfusion pressure after coronary stenosis (195).
after this partial coronary occlusion, the vasoconstriction Hemorrhagic shock in rats is accompanied by decreased
with AVP was as in the control and this vasoconstriction perfusion of the heart (and other organs), together with
was not affected by L-NAME or meclofenamate. These increased ET-1 levels in plasma (196). As a result, the
results suggest that: 1) during partial ischemia, the authors suggest that ET-1 is involved in the decreased
coronary vasoconstriction with AVP is attenuated, with perfusion of vital and peripheral tissues during
preservation of the modulatory role of NO and probable hemorrhagic shock (196). Experimental observations have
involvement of vasoconstrictor prostanoids in this shown that ET-1 (197) and AVP (187) may increase in
vasoconstriction; and 2) during its reperfusion, the plasma during some types of hypotension. It seems that
coronary reactivity to AVP recover, but the modulatory under normotension NO may be more relevant in
role of NO in this reactivity may be attenuated. The modulating coronary vasoconstriction by ET-1 than by
significance of these results may be that the endothelial AVP (191), and that NO and ET-1 mutually affect the
function in modulating coronary reactivity to AVP is very production and action of each other in the blood vessel
sensitive to reperfusion after partial, moderate ischemia, wall (198). We performed experiments in anesthetized
and that AVP may also contribute to the adverse effects of goats where blood flow through the left circumflex
ischemia-reperfusion on coronary vasculature (191). In coronary artery was measured electromagnetically, and
other series of experiments, we found that at 60 min of hypotension was induced by constriction of the caudal
reperfusion after 15 min total occlusion of the circumflex vena cava. ET-1 and AVP were directly injected into this
coronary artery, the coronary vasoconstriction in response coronary artery before (normotension) and during
to AVP was increased during reperfusion in non-treated, hypotension in animals non-treated and treated with L-
was not changed in L-NAME-treated and was decreased in NAME, meclofenamate, or both inhibitors. The results of
meclofenamate-treated animals. Therefore, this study these experiments suggest that hypotension increases the
suggests that during reperfusion after a short, total coronary vasoconstriction in response to ET-1 but not to
ischemia, the coronary vasoconstriction in response to AVP. This increased response to ET-1 may be related to
AVP is increased, probably due to both attenuation of the both inhibition of NO release and of vasoconstrictor
modulatory role of NO and the release of vasoconstrictor prostanoids release. This study also suggests that in the
prostanoids (192). This idea is in line with that proposed coronary circulation, the functional interaction between
by others (189, 190), and both of them suggest that AVP NO and ET-1 may be greater than that between NO and
should be considered as a factor involved in AVP (199).
pathophysiology of myocardial ischemia-reperfusion,
although its role could be of less significance than that of To extend our knowledge of the coronary effects of
ET-1. ET-1 after ischemia-reperfusion, the left anterior
descending coronary artery of anesthetized pigs was
We also explored the coronary vasodilator reserve after subjected to 30-min occlusion followed by 60-min
ischemia-reperfusion examining the hyperemic response reperfusion. Then, rings distal (ischemic arteries) and
after brief coronary occlusions. To this, partial (60 min) or proximal (control arteries) to the artery occlusion were
total (15 and 60 min) occlusions of the left circumflex taken from this artery and prepared for isometric tension
coronary artery were induced, followed in each case by 60- recording. The sensitivity of the contractile response to
@Real Academia Nacional de Farmacia. Spain 33
