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mice. Similar effects were observed for the recovery of left Godofredo Diéguez Castrillo
ventricular end-diastolic pressure, developed pressure and
dP/dt. Bosentan improved the recovery of coronary flow in Left ventricular hemodynamic variables were measured
both double knockout and wild-type mice. Recovery of in the Langendorff-perfused model after 40- and 20-
coronary flow was significantly higher in the double minute regional or global ischemia, followed by 30-minute
knockout mice given bosentan than in the wild-type group. reperfusion. Wild-type and ETB-deficient rats were
ET-1 impaired recovery of coronary flow in both wild-type compared. Left ventricular dysfunction was more
and double knockout mice though this effect was more prominent in ETB-deficient rats, particularly after regional
pronounced in the double knockout mice. Coronary ischemia. Infarct size was smaller in wild-type than ETB-
outflow of NO during reperfusion was enhanced in both deficient rats after 40 minutes of regional ischemia-
double knockout and wild-type mice following bosentan reperfusion. Although the recovery of left ventricular
administration. Therefore, the ETA/ETB receptor function was poorer after 40-minute ischemia-reperfusion,
antagonist bosentan may protect the atherosclerotic mouse end-diastolic pressure in ETB-deficient rats was higher
heart from ischemia-reperfusion injury. The observation after 20 than after 40 minutes of regional ischemia-
that endothelin receptor blockade and stimulation have a reperfusion. It is concluded that ETB receptors exert
greater effect on coronary flow in atherosclerotic hearts cytoprotective effects in the rat heart, mainly after regional
indicates an increased activation of the endothelin system ischemia-reperfusion. Longer periods of ischemia suppress
in atherosclerotic coronary arteries (242). the recovery of left ventricular function after reperfusion,
but the role of ETB receptors may be more important
In our laboratory we have compared the effects of during the early phases (244).
antagonists for endothelin ETA and ETB receptors on the
action of ischemia-reperfusion on endothelial and In rabbits subjected to 1 h of coronary artery occlusion
myocardial function. The study we carried out in followed by 3 h of reperfusion, left ventricle unloading
anesthetized goats, in which 30 min of partial or total was initiated 15 min prior to reperfusion and was
occlusion followed by 60 min of reperfusion of the left maintained during reperfusion. Animals were treated with
circumflex coronary artery was induced in animals treated the ETA receptor antagonist BQ123. In parallel, isolated
with intracoronary administration of saline (vehicle), BQ- rabbit cardiomyocytes subjected to simulated ischemia-
123 (endothelin ETA receptors antagonist) or BQ-788 reperfusion with or without ET-1 or BQ123, intracellular
(endothelin ETB receptors antagonist). During reperfusion calcium and cell death were assessed with flow cytometry.
after partial occlusion, coronary vascular conductance and From the results of this study, the authors suggest that
left ventricle contractility were decreased after saline or components of reperfusion injury involve ET-1 release
BQ-788, and they normalized after BQ-123. In these three which stimulates calcium overload and apoptosis.
groups of animals, the coronary effects of Ach and sodium Intravenous ETA receptor blockade prior to reperfusion
nitroprusside during reperfusion were as under control. may be a protective adjunct to reperfusion therapy in acute
During reperfusion after total occlusion, coronary vascular myocardial infarction patients. Thus, endogenous ET-1
conductance and left ventricle function were decreased released during acute myocardial infarction might mediate
after saline, and they normalized after BQ-123 or BQ-788 ischemia-reperfusion injury by stimulating increased
treatment. In these three groups of animals, the coronary intracellular calcium concentration, and apoptosis (245).
effects of Ach but not those of sodium nitroprusside during
reperfusion were decreased after saline, and they reversed In patients with type 2 diabetes and coronary artery
after BQ-123 or BQ-788 treatment. Therefore, selective disease it has been observed that both selective ETA and
antagonists of endothelin ETB and ETA receptors may dual ETA/ETB receptor antagonists improve endothelium-
produce similar protection of coronary vasculature and dependent vasodilatation. ETB receptor blockade increases
myocardium against reperfusion after severe ischemia. basal blood flow but does not additionally improve
Selective antagonists of endothelin ETB receptors, endothelium-dependent vasodilatation (246). Safety and
contrarily to those of endothelin ETA receptors may be feasibility of selective ETA receptor blockade in ST-
ineffective to protect coronary vasculature and elevation acute coronary syndrome (STE-ACS) within a
myocardium against reperfusion after mild ischemia. larger randomized trial was assessed in patients. Patients
Probably it may be more beneficial the use of antagonists with posterior-wall STE-ACS were randomly assigned to
for both subtypes of endothelin receptors (243). In addition receive intravenous BQ-123 or placebo over 60 min,
of antagonists for ETA receptors, the use of antagonists for starting immediately prior to primary percutaneous
ETB receptors is supported by studies performed in pig coronary intervention. Twenty-four hour Holter recordings
coronary arteries (202) in which it seems to be that were performed during hospitalization for STE-ACS and
ischemia-reperfusion increases the coronary after 6–8 weeks. The predefined primary endpoint was the
vasoconstriction in response to ET-1 probably due to documentation of ventricular tachycardia and/or late
impairment of endothelin ETB receptor-induced release of potentials at follow-up. Based on the analysis of long-term
NO and prostacyclin, to augmentation of the contractile ECG data, short-term administration of BQ-123 after AMI
response to activation of endothelin ETB receptors, and to was safe (247).
increased release of vasoconstrictor prostanoids.
The studies shown before support the idea that ET-1
38 could play a relevant role in the adverse effects of
ischemia-reperfusion on the myocardium, including
coronary vasculature. These adverse effects of ET-1 may
@Real Academia Nacional de Farmacia. Spain
