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ET-1 and to the endothelin ETB receptor agonist IRL-1620 Godofredo Diéguez Castrillo
was augmented in ischemic vessels. The endothelin ETA
receptor antagonist BQ-123 decreased the sensitivity of the reperfusion, 5-hydroxytryptamine produced contraction in
response to ET-1 similarly in ischemic and control arteries. isolated coronary arteries, which was potentiated by
The endothelin ETB receptor antagonist BQ-788, treatment with ET-1. This potentiation by ET-1 was lower
endothelium removal or L-NAME potentiated the response after ischemia-reperfusion than after control, and the
to ET-1 and to IRL-1620 in control arteries but not in potentiation was reduced by l-NAME, by blockade of
ischemic arteries. Meclofenamate augmented the maximal endothelin ETA receptors with BQ123 and by blockade of
response to ET-1 in control arteries, and reduced it in endothelin ETB receptors with BQ788, but not by the
ischemic arteries. In precontracted arteries, IRL-1620 cyclooxygenase inhibitor meclofenamate. Thus, ET-1 at
relaxed control but not ischemic arteries, and L-NAME or low concentrations could potentiate coronary
meclofenamate abolished this relaxation. Therefore, vasoconstriction, and this effect is reduced after ischemia-
ischemia-reperfusion increases the coronary reperfusion, mediated by both endothelin ETA and ETB
vasoconstriction in response to ET-1 probably due to receptors and is dependent on NO release. This suggests
impairment of endothelin ETB receptor-induced release of that ischemia-reperfusion might induce complex effects on
NO and prostacyclin, to augmentation of the contractile the coronary vascular effects of ET-1 (203).
response to activation of endothelin ETB receptors, and to
increased release of vasoconstrictor prostanoids (200). We have also explored the effects of ischemia-
Studies by others were performed in male Sprague-Dawley reperfusion on the coronary reactivity to other types of
rats, which were subjected to either heart ischemia– substances, the effects of which may be dependent on the
reperfusion (15 min ischemia and 22 h reperfusion), endothelium and may be of interest in the context of
permanent ischemia (22 h) by ligation of the left anterior ischemia-reperfusion. Between these substances are
descending coronary artery, or sham operation (201). diadenosine polyphosphates (ApnAs), which are molecules
Then, the endothelin receptor subtypes mediating that have a chain of 2-6 phosphate groups and they may
vasoconstriction were examined in isolated segments of produce vasodilatation or vasoconstriction of blood vessels
the left anterior descending and the non-ligated septal depending on the particular ApnA in question. In the
coronary arteries. Endothelin ETB receptor-mediated coronary circulation, ApnAs produce vasodilation in pigs
vasoconstriction and receptor protein levels were (204) and in dogs (205) when they are present at nM to
augmented in coronary arteries exposed to ischemia– mM concentrations, as may exist in plasma under normal
reperfusion. In contrast, the ETA receptor-mediated conditions. Platelet activation and platelet release of
vasoconstriction was unaltered in all groups. It is ApnAs, may be involved in the pathophysiology of
suggested that ischemia–reperfusion induces local up- ischemia-reperfusion (206), and the concentration of
regulation of ETB receptors in the smooth muscle cells of ApnAs may increase in coronary venous blood during
coronary arteries in the post-ischemic area. In contrast, in ischemia-reperfusion (207). As these substances can
non-ischemic areas, endothelin ETB receptor function was produce vasodilatation or vasoconstriction depending on
unaltered (201). In a revision published in 2010, Nguyen et the conditions of coronary blood vessels, these compounds
al. (80) suggest that the beneficial role of endothelin ETB could participate in the altered coronary regulation
receptors present under normal conditions may decline associated with ischemia-reperfusion. Apn5A has a long
with age and risk factors for cardiovascular diseases, phosphate chain and it is more likely to produce
revealing smooth muscle ETB-receptors with pro vasoconstriction and therefore, to be involved in the
constricting and proinflamatory activities. coronary vasoconstriction that frequently occurs after
ischemia–reperfusion. Moreover, the production of Ap5A
We also studied the effects of ischemia-reperfusion on in the heart is increased during heart ischemia. Compared
coronary vasculature using isolated, perfused hearts from to control rat hearts, the coronary vasoconstriction to
rats. After 15, 30 or 45 min of global zero-flow ischemia Ap5A was augmented and vasodilation diminished after
and 15 min reperfusion, the coronary vasoconstriction ischemia–reperfusion. After testing the effects of
induced by ET-1 increased after 15 min of ischemia, but antagonists for P2 and P2Ypurinoceptors, L-NAME and
not after 30 or 45 min of ischemia. Inhibition of NO meclofenamate, it is suggested that ischemia–reperfusion
synthesis with L-NAME augmented the vasoconstriction reduces the coronary vasodilatory response and increases
induced by ET-1 in non-ischemic hearts, but not following the coronary vasoconstriction to Ap5A, due to a reduced
ischemia. These results suggest that in this experimental influence of purinergic P2Y receptors and/or to the
preparation, ischemia-reperfusion also inhibits NO production of vasoconstrictor prostanoids (208). The
production, causing an increased coronary response to ET- studies with triphosphate (Ap3A) showed that this
1 after brief ischemias. Longer ischemias may non- substance produces coronary vasodilation in control rat
specifically inhibit coronary vasoconstriction and reduce hearts, which was attenuated following ischemia-
NO production (202). In other series of experiments reperfusion. In this case, the results suggest that the
carried out in isolated, perfused hearts from rats exposed to attenuation of the coronary vasodilatation to Ap3A after
30 min global zero-flow ischemia followed by 15 min ischemia-reperfusion could be due to the functional
reperfusion (203), we found that after ischemia- impairment of purinergic P2Y receptors and K (ATP)
channels, and/or reduced NO release in this condition
34 (209). Tetrataphosphate (Ap4A), in control rat hearts,
@Real Academia Nacional de Farmacia. Spain
