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Coronary ischemia-reperfusion: role of nitric oxide and endothelin-1. A Review
be mediated by both endothelin ETA and ETB receptors; during ischemia-reperfusion. Brar et al also suggest that
endothelin ETB receptors situated in the endothelium may the protective effect of urocortin on the endothelial cells
reduce their function probably due to endothelium damage, during ischemia-reperfusion may be mediated by
whereas those situated in smooth muscle cells of coronary activation of protein kinase C, as an inhibitor of this
arteries acquires a high role and thus contributing, together enzyme, chelerythrine, abolished the improvement of
with endothelin ETA receptors, to the adverse coronary endothelial function by urocortin (249). Gordon et al.
effects of ET-1. Thus, the treatment with blockers of both (254) also found that the protection by urocortin against
endothelin ETA and ETB receptors may protect the ischemia-reperfusion in adult rat cardiomyocytes was
myocardium and coronary vasculature against the adverse attenuated by chelerythrine. Also, our results partly agree
effects of ischemia-reperfusion, and in consequence it may with those of Lawrence et al. (255), who showed
reduce reperfusion injury. involvement of protein kinase C epsilon in the prevention
of mitochondrial damage during ischemia-reperfusion.
H) Urocortin. This substance is a 40 amino-acid However, in the studies of Gordon et al. (254) and
peptide which has a high degree of structural homology Lawrence et al. (255), KATP channels were also involved,
with the peptide corticotrophin-releasing factor (CRF), and a phenomenon that was not observed in our study. It may
has marked cardiovascular effects. In the heart, exogenous be supposed that urocortin action may share some
urocortin produces coronary vasodilation (248). Also, it mechanisms, but not others, in endothelial and myocardial
has been demonstrated that urocortin production may be cells. In conclusion, our results suggest that relatively low
increased in cardiac cells exposed to ischemia and that concentrations of urocortin may protect endothelial
exogenous urocortin may protect myocardium during function in the coronary circulation against deleterious
coronary ischemia (249), and that urocortin reduces the effects of ischemia-reperfusion through activation of
infarct area in the ischemic and reperfused rat heart (250). protein kinase C. Urocortin might act as an endogenous
Several mechanisms may be involved in this protective protective factor in the heart during coronary ischemia-
effect of urocortin in the myocardial cells (251). To reperfusion, and identification of its protective
explore the action of urocortin on the adverse effects of mechanisms on endothelial function may help to prevent
ischemia-reperfusion on coronary vasculature, hearts from the coronary vascular dysregulation that occurs after heart
rats were perfused at constant flow and then exposed to 15 ischemia (252, 253). With respect to this, it is remarkable
mins ischemia followed by 15 mins reperfusion. In one that a recent study in humans (256) provided the first
series of experiments, we found that the coronary evidence that human urocortin prevents the development
relaxation to urocortin was reduced after ischemia- of atherosclerosis by suppressing endothelial cell
reperfusion. Treatment with a low threshold concentration inflammatory response and proliferation, macrophage
of urocortin, administered before ischemia and during foam cell formation, and vascular smooth muscle cell
reperfusion, improved the coronary relaxation to Ach after migration and proliferation. Thus, human urocortin might
ischemia-reperfusion. Therefore, this condition impairs the serve as a novel therapeutic agent for atherosclerotic
coronary vasodilation to urocortin and produces cardiovascular diseases (256).
endothelial dysfunction, and this endothelial dysfunction
may be improved by urocortin (252). 5. CONCLUSIONS
In other series of experiments (253), we observed that Acute coronary syndromes (e. g., acute myocardial
the urocortin-induced improvement of the coronary infarction (AMI) ) are the most lethal of cardiovascular
relaxation to Ach after ischemia-reperfusion was not diseases, but the mortality rates of these syndromes are
modified by treatment with tetraethylammonium, blocker going down in developed countries as a result of better
of Ca2+ dependent-potassium channels; glibenclamide, prevention and treatment. The most effective treatment of
blocker of K (ATP) channels; L-NAME, blocker of NO AMI is timely (early) reperfusion of the myocardial
synthesis; or meclofenamate, blocker of cyclooxygenase, ischemic zone. However, not all it is favorable with
but it was abolished by chelerythrine, blocker of protein myocardial reperfusion as this procedure may also damage
kinase C Thus, it is suggested that urocortin may protect myocardium, which is known as “reperfusion injury”.
coronary endothelial function during ischemia-reperfusion
by activation of protein kinase C. Therefore, urocortin may The present Review pays particular attention to the
act as an endogenous protective factor of the heart during coronary circulation and to the role of NO and ET-1 in the
ischemia. These protective effects of urocortin may act on regulation of this circulation under normal conditions and
the endothelial function (252) as well as on the myocardial after ischemia-reperfusion. Also, it is considered
function (249, 250) during ischemia-reperfusion. Urocortin therapeutical strategies for ischemia-reperfusion injury,
may activate ATP-sensitive and Ca2+-sensitive potassium with special mention to antagonists for endothelin
channels in cardiac myocytes and in vascular smooth receptors. The coronary circulation plays a crucial role in
muscle cells, respectively. However, we found that neither pathophysiology of ischemia-reperfusion and reperfusion
glibenclamide nor TEA modified the urocortin-induced injury, after all it is the cause and victim of this condition.
improvement of the coronary endothelial function, Ischemia-reperfusion damages not only cardiomyocytes,
suggesting that these channels do not seem to be involved but also coronary vasculature. The damage to this
in the protective effect of urocortin on endothelial cells vasculature may vary from functional impairment of
@Real Academia Nacional de Farmacia. Spain 39
