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Updated: Jun 30, 2026

Simultaneous Measurement of Superoxide/Hydrogen Peroxide and NADH Production by Flavin-containing Mitochondrial Dehydrogenases

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

Carolina D Garciarena¹, Claudia I Caldiz, María V Correa

¹Centro de Investigaciones Cardiovasces, Facultad de Ciencias Médicas, UNLP 60 y 120, 1900 La Plata, Argentina.

Journal of Applied Physiology (Bethesda, Md. : 1985)

|September 20, 2008

Summary

Na(+)/H(+) exchanger-1 (NHE-1) inhibitors directly act on mitochondria to reduce reactive oxygen species (ROS) production. This finding impacts understanding of cardiac disease treatments involving NHE-1 inhibition.

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Oxygen-Independent Assays to Measure Mitochondrial Function in Mammals

Oxygen-Independent Assays to Measure Mitochondrial Function in Mammals

Published on: May 19, 2023

Area of Science:

Cardiovascular Research
Mitochondrial Physiology
Pharmacology

Background:

Reactive oxygen species (ROS) play a role in cardiac dysfunction.
Na(+)/H(+) exchanger-1 (NHE-1) inhibitors are investigated for cardiovascular benefits.
The direct mitochondrial effects of NHE-1 inhibitors on ROS production remain unclear.

Purpose of the Study:

To investigate the direct mitochondrial action of NHE-1 inhibitors on ROS production in cat myocardium.
To determine if NHE-1 inhibitors can prevent NADPH oxidase (NOX)-dependent ROS generation.
To elucidate the role of mitochondria in NOX-dependent ROS release and the effect of NHE-1 inhibitors.

Main Methods:

Assessment of superoxide anion (O(2)(-)) production using chemiluminescence.
Administration of Angiotensin II and endothelin-1 to induce ROS.
Treatment with NHE-1 inhibitors (cariporide, BIIB-723, EMD-87580) and mitochondrial modulators.
Evaluation of mitochondrial swelling and protein phosphorylation (ERK1/2, p90 ribosomal S6 kinase).

Main Results:

Angiotensin II and endothelin-1 increased NOX-dependent O(2)(-) production.
NHE-1 inhibitors prevented this increase without scavenging ROS.
Mitochondria were identified as the source of NOX-dependent ROS via a ROS-induced ROS release mechanism.
NHE-1 inhibitors, particularly cariporide, directly inhibited mitochondrial swelling and O(2)(-) production, suggesting MPTP pore action.
Cariporide also prevented downstream signaling pathways (ERK1/2, p90 ribosomal S6 kinase phosphorylation).

Conclusions:

NHE-1 inhibitors exert a direct mitochondrial effect by reducing ROS production.
This action involves blunting the ROS-induced ROS release mechanism and potentially modulating the mitochondrial permeability transition pore (MPTP).
These findings necessitate a re-evaluation of the therapeutic mechanisms of NHE-1 inhibitors in cardiac diseases like ischemia-reperfusion injury and heart failure.