Key result
Ethoxzolamide decreased infarct size by 60% and improved postischemic recovery of myocardial contractile and diastolic relaxation in isolated rat hearts subjected to ischemia-reperfusion.
Why the study?
Having previously shown that inhibiting extracellular carbonic anhydrase isoforms protects against myocardial ischemia-reperfusion injury, the authors aimed to assess the contribution of intracellular isoforms using the cell-permeant inhibitor ethoxzolamide.
Does ethoxzolamide reduce ischemia-reperfusion injury in isolated rat hearts?
Does ethoxzolamide reduce ischemia-reperfusion injury in isolated rat hearts?
Ethoxzolamide protects the myocardium and mitochondria against ischemia-reperfusion injury through p38MAPK- and PKCε-dependent pathways, highlighting carbonic anhydrase as a potential therapeutic target.
ETZ protects myocardium and mitochondria from ischemia-reperfusion injury; leaves open clinical translation of intracellular CA inhibition.
We have previously demonstrated that inhibition of extracellularly oriented carbonic anhydrase (CA) isoforms protects the myocardium against ischemia-reperfusion injury. In this study, our aim was to assess the possible further contribution of CA intracellular isoforms examining the actions of the highly diffusible cell membrane permeant inhibitor of CA, ethoxzolamide (ETZ). Isolated rat hearts, after 20 min of stabilization, were assigned to the following groups: (1) Nonischemic control: 90 min of perfusion; (2) Ischemic control: 30 min of global ischemia and 60 min of reperfusion (R); and (3) ETZ: ETZ at a concentration of 100 μM was administered for 10 min before the onset of ischemia and then during the first 10 min of reperfusion. In additional groups, ETZ was administered in the presence of SB202190 (SB, a p38MAPK inhibitor) or chelerythrine (Chel, a protein kinase C [PKC] inhibitor). Infarct size, myocardial function, and the expression of phosphorylated forms of p38MAPK, PKCε, HSP27, and Drp1, and calcineurin Aβ content were assessed. In isolated mitochondria, the Ca2+ response, Ca2+ retention capacity, and membrane potential were measured. ETZ decreased infarct size by 60%, improved postischemic recovery of myocardial contractile and diastolic relaxation increased P-p38MAPK, P-PKCε, P-HSP27, and P-Drp1 expression, decreased calcineurin content, and normalized calcium and membrane potential parameters measured in isolated mitochondria. These effects were significantly attenuated when ETZ was administered in the presence of SB or Chel. These data show that ETZ protects the myocardium and mitochondria against ischemia-reperfusion injury through p38MAPK- and PKCε-dependent pathways and reinforces the role of CA as a possible target in the management of acute cardiac ischemic diseases.
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Pardo et al. (2021) studied Ischemia-reperfusion injury (n=59). Ethoxzolamide vs. Ischemic control was evaluated on Infarct size (% of risk area) (decreased by 60%, p=<0.05). Ethoxzolamide decreased infarct size by 60% and improved postischemic recovery of myocardial contractile and diastolic relaxation in isolated rat hearts subjected to ischemia-reperfusion.
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