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Na⁺/H⁺ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action

Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina

Submitted 6 May 2008 ; accepted in final form 15 September 2008

The possibility of a direct mitochondrial action of Na⁺/H⁺ exchanger-1 (NHE-1) inhibitors decreasing reactive oxygen species (ROS) production was assessed in cat myocardium. Angiotensin II and endothelin-1 induced an NADPH oxidase (NOX)-dependent increase in anion superoxide (O₂^–) production detected by chemiluminescence. Three different NHE-1 inhibitors [cariporide, BIIB-723, and EMD-87580] with no ROS scavenger activity prevented this increase. The mitochondria appeared to be the source of the NOX-dependent ROS released by the "ROS-induced ROS release mechanism" that was blunted by the mitochondrial ATP-sensitive potassium channel blockers 5-hydroxydecanoate and glibenclamide, inhibition of complex I of the electron transport chain with rotenone, and inhibition of the permeability transition pore (MPTP) by cyclosporin A. Cariporide also prevented O₂^– production induced by the opening of mK_ATP with diazoxide. Ca²⁺-induced swelling was evaluated in isolated mitochondria as an indicator of MPTP formation. Cariporide decreased mitochondrial swelling to the same extent as cyclosporin A and bongkrekic acid, confirming its direct 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 the existence of a direct mitochondrial action of NHE-1 inhibitors in preventing ROS release. In conclusion, we report a mitochondrial action of NHE-1 inhibitors that should lead us to revisit or reinterpret previous landmark observations about their beneficial effect in several cardiac diseases, such as ischemia-reperfusion injury and cardiac hypertrophy and failure. Further studies are needed to clarify the precise mechanism and site of action of these drugs in blunting MPTP formation and ROS release.

sodium/hydrogen exchanger-1; reactive oxygen species; mitochondria

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				C. D. Garciarena, C. I. Caldiz, E. L. Portiansky, G. E. Chiappe de Cingolani, and I. L. Ennis Chronic NHE-1 blockade induces an antiapoptotic effect in the hypertrophied heart J Appl Physiol, April 1, 2009; 106(4): 1325 - 1331. [Abstract] [Full Text] [PDF]