CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
Myocardial and mitochondrial effects of the anhydrase carbonic inhibitor ethoxzolamide in ischemia-reperfusion
GONZÁLEZ ARBELÁEZ LF; MOSCA SM; FANTINELLI JC; SWENSON E; CIOCCI PARDO A; ALVAREZ BV
Editorial Office, Physiological Reports
We have previously demonstrated that inhibition of extracellularly orientedcarbonic anhydrase (CA) isoforms protects the myocardium against ischemia-reperfusioninjury. In this study, our aim was to assess the possible further contributionof CA intracellular isoforms examining the actions of the highly diffusiblecell membrane permeant inhibitor of CA, ethoxzolamide (ETZ). Isolated rathearts, after 20 min of stabilization, were assigned to the following groups: (1)Nonischemic control: 90 min of perfusion; (2) Ischemic control: 30 min of globalischemia and 60 min of reperfusion (R); and (3) ETZ: ETZ at a concentration of100 μM was administered for 10 min before the onset of ischemia and then duringthe first 10 min of reperfusion. In additional groups, ETZ was administeredin the presence of SB202190 (SB, a p38MAPK inhibitor) or chelerythrine (Chel, aprotein kinase C [PKC] inhibitor). Infarct size, myocardial function, and the expressionof phosphorylated forms of p38MAPK, PKCε, HSP27, and Drp1, and calcineurinAβ content were assessed. In isolated mitochondria, the Ca2+ response,Ca2+ retention capacity, and membrane potential were measured. ETZ decreasedinfarct size by 60%, improved postischemic recovery of myocardial contractileand diastolic relaxation increased P-p38MAPK, P-PKCε, P-HSP27, and P-Drp1expression, decreased calcineurin content, and normalized calcium and membranepotential parameters measured in isolated mitochondria. These effects were significantly attenuated when ETZ was administered in the presence of SBor Chel. These data show that ETZ protects the myocardium and mitochondriaagainst ischemia-reperfusion injury through p38MAPK-and PKCε-dependentpathways and reinforces the role of CA as a possible target in the management ofacute cardiac ischemic diseases