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Coronary ischemia-reperfusion: role of nitric oxide and endothelin-1. A Review
observations, antioxidant therapy was considered to be an reported significant reduction of infarct size by inhibiting
appropriate option to prevent such injury. However, both the inflammatory process at the time of myocardial
experimental and clinical studies have reported mixed reperfusion and the inhibition of complement activation,
results with the administration of antioxidant therapy at the corresponding clinical studies using this therapeutic
onset of myocardial reperfusion (234). However, the approach have been largely negative (122).
discovery of mitochondrial-specific antioxidants may be
more effective (235). F) Against late myocardial reperfusion injury. Some
of the described stimulators of myocardial reperfusion
B) Against intracellular Ca2+ overload. Ca2+ injury all appear to operate in the first few minutes of
overload begins during acute myocardial ischemia and is myocardial reperfusion, providing a narrow window for
exacerbated during myocardial reperfusion, and this reducing infarct size in patients. However, several other
overload induces the opening of the mitochondrial important processes such as apoptosis and inflammation,
permeability transition pore. Experimental studies have which are also initiated during ischemia and continue over
shown that pharmacologic antagonists of the sarcolemmal several hours into reperfusion, may contribute to the
Ca2+ channel (236) or the mitochondrial Ca2+ uniporter development of lethal myocardial reperfusion injury.
(237) administered at the onset of myocardial reperfusion, These contributing pathways provide a potential second
reduces infarct size by up to 50%. However, not all therapeutic window for reducing infarct size. However,
experimental studies using this therapeutic strategy have this is a controversial area of research, and some
been positive. Clinical studies of Ca2+ channel blockers experimental studies have failed to demonstrate an
administered at the onset of myocardial reperfusion have increase in infarct size with reperfusion time. Several
not shown beneficial results (238). The identification of experimental studies have reported that administering
the mitochondrial Ca2+ uniporter may result in the cardioprotective agents such as erythropoietin (anti-
discovery of a new class of specific inhibitors for targeting apoptotic), PI3K-?/d inhibitors (anti-inflammatory), and
lethal myocardial reperfusion injury. intracoronary aqueous oxygen, from 30 minutes to 24
hours into myocardial reperfusion may still limit acute
C) To slow the restoration of physiological pH. myocardial infarct size at 72 hours. This may provide an
During acute myocardial ischemia the intracellular pH additional therapeutic window to target late into the
decreases to <7. 0, where as at reperfusion, physiological reperfusion phase (122).
pH is rapidly restored by the washout of lactate and the
activation of the Na+-H+ exchanger, as well as the Na+- G) Antagonists for endothelin ETA and ETB
HCO– symporter. This pH shift contributes to the receptors. As ET-1 may have a relevant role in
cardiomyocyte death of lethal myocardial reperfusion pathophysiology of myocardial ischemia-reperfusion, this
injury by permitting mitochondrial permeability transition has stimulated the possible beneficial effects of
pore opening and cardiomyocyte rigor hypercontracture in endothelin-receptor-blockade to protect the heart against
the first few minutes of reperfusion. Reperfusion of reperfusion injury. However, this research has yielded
ischemic animal hearts with an acidic buffer can reduce unclear results. Respect to this issue, it could be of interest
infarct size (239). Therefore, a potential treatment strategy to take in mind the probable interaction between NO and
for preventing lethal myocardial reperfusion injury would ET-1.
be to slow the normalization of physiologic pH at the time
of myocardial reperfusion or by slowing the process of Efficacy of the non-selective endothelin antagonist l-
myocardial reperfusion, as in the case of ischemic 753037 was examined in a model of canine coronary
postconditioning (122). artery occlusion and reperfusion to assess whether
blockade of both ETA and ETB receptors would enhance
D) The mitochondrial permeability transition pore or reduce myocardial ischemic injury. The results suggest
(MPTP) as a target for cardioprotection. The MPTP is a that this non-selective endothelin antagonist provides
nonselective channel of the inner mitochondrial significant myocardial protection primarily by improving
membrane, the opening of which results in mitochondrial regional myocardial flow distribution following
membrane depolarization and uncoupling of oxidative reperfusion, and demonstrated no detrimental effects
phosphorylation, leading to ATP depletion and cell death. associated with blockade of the ETB receptor (241).
As such, preventing MPTP opening at the time of
reperfusion by administering MPTP inhibitors (e. g., Endothelin ETA and ETB receptor antagonists could
cyclosporin A) at the onset of myocardial reperfusion has be cardioprotective during myocardial ischemia and
been reported in experimental studies to reduce infarct size reperfusion through a NO-dependent mechanism. To
by 40–50% in animal myocardial infarction models (240). investigate whether the ETA and ETB receptor antagonist,
Thus, MPTP may be an important therapeutic target for bosentan, is cardioprotective in atherosclerotic mice,
preventing lethal myocardial reperfusion injury (122). buffer-perfused hearts from apolipoprotein E/LDL
receptor double knockout and wild-type mice were
E) Against inflammatory response. It is unclear subjected to global ischemia and reperfusion. Following
whether the inflammatory response that accompanies an reperfusion, the recovery of left ventricular function was
AMI contributes to the pathogenesis of lethal myocardial equally impaired in wild-type and double knockout mice
reperfusion injury or whether it is a reaction to the acute given vehicle. The ETA/ETB receptor antagonist bosentan
myocardial injury. Although experimental studies have improved recoveries in wild-type and in double knockout
@Real Academia Nacional de Farmacia. Spain 37
