CONICET | Buscador de Institutos y Recursos Humanos

The possibility of a direct mitochondrial action of Na/H exchanger-1(NHE-1) inhibitors decreasing reactive oxygen species (ROS) productionwas assessed in cat myocardium. Angiotensin II and endothelin-1 inducedan NADPH oxidase (NOX)-dependent increase in anion superoxide(O2) production detected by chemiluminescence. Three differentNHE-1 inhibitors [cariporide, BIIB-723, and EMD-87580] with no ROSscavenger activity prevented this increase. The mitochondria appearedto be the source of the NOX-dependent ROS released by the ROSinducedROS release mechanism that was blunted by the mitochondrialATP-sensitive potassium channel blockers 5-hydroxydecanoateand glibenclamide, inhibition of complex I of the electron transportchain with rotenone, and inhibition of the permeability transition pore(MPTP) by cyclosporin A. Cariporide also prevented O2 productioninduced by the opening of mKATP with diazoxide. Ca2-inducedswelling was evaluated in isolated mitochondria as an indicator ofMPTP formation. Cariporide decreased mitochondrial swelling to thesame extent as cyclosporin A and bongkrekic acid, confirming itsdirect mitochondrial action. Increased O2 production, as expected,stimulated ERK1/2 and p90 ribosomal S6 kinase phosphorylation.This was also prevented by cariporide, giving additional support to theexistence of a direct mitochondrial action of NHE-1 inhibitors inpreventing ROS release. In conclusion, we report a mitochondrialaction of NHE-1 inhibitors that should lead us to revisit or reinterpretprevious landmark observations about their beneficial effect in severalcardiac diseases, such as ischemia-reperfusion injury and cardiachypertrophy and failure. Further studies are needed to clarify theprecise mechanism and site of action of these drugs in blunting MPTPformation and ROS release.