CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
Benzolamide perpetuates acidic conditions during reperfusion and reduces myocardial ischemia-reperfusion injury
CIOCCI PARDO, ALEJANDRO; DÍAZ, ROMINA G; GONZÁLEZ ARBELÁEZ, LUISA F.; PEREZ, NESTOR G.; SWENSON, ERIK RICHARD; MOSCA, SUSANA M.; ALVAREZ, BERNARDO V.; CIOCCI PARDO, ALEJANDRO; DÍAZ, ROMINA G; GONZÁLEZ ARBELÁEZ, LUISA F.; PEREZ, NESTOR G.; SWENSON, ERIK RICHARD; MOSCA, SUSANA M.; ALVAREZ, BERNARDO V.
JOURNAL OF APPLIED PHYSIOLOGY
AMER PHYSIOLOGICAL SOC
During ischemia, increased anaerobic glycolysis results in intracellular acidosis. Activation of alkalinizing transport mechanisms associated with carbonic anhydrases (CA) leads to myocardial intracellular Ca2+ increase. We characterize the effects of inhibition of CA with benzolamide (BZ) during cardiac ischemia-reperfusion (I/R). Langendorff perfused isolated rat hearts were subjected to 30 min of global ischemia and 60 min of reperfusion. Other hearts were treated with BZ (5 μM) during the initial 10 min of reperfusion or perfused with acid solution (AR, pH 6.4) during the first 3 min of reperfusion. P38MAPK, a kinase linked to membrane transporters and involved in cardioprotection, was examined in hearts treated with BZ in presence of the P38MAPK inhibitor SB202190 (10 μM). Infarct size (IZ) and myocardial function were assessed, and phosphorylated forms of P38MAPK, Akt and PKCε were evaluated by immunoblotting. We determined the rate of intracellular pH (pHi) normalization after transient acid loading in the absence and presence of BZ or BZ+SB202190, in heart papillary muscles (HPM). Mitochondrial potential (∆ψm), Ca2+ retention capacity and Ca2+-mediated swelling following I/R were also measured. BZ, similarly to AR, reduced IZ, improved post-ischemic recovery of myocardial contractility, increased phosphorylation of Akt, PKCε, and P38MAPK, and normalized mitochondrial ∆ψm and Ca2+ homeostasis; effects abolished following P38MAPK inhibition. In HPM, BZ slowed pHi recovery; an effect which was restored after P38MAPK inhibition. We conclude that, prolongation of acidic conditions during reperfusion by BZ could be responsible for the cardioprotective benefits of reduced infarction and better myocontractile function, through P38MAPK-dependent pathways.