Relative contributions of mitochondria and NADPH oxidase to deoxycorticosterone acetate-salt hypertension in mice

Abstract

We assessed the relative contribution of the mitochondrial respiratory chain and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase to deoxycorticosterone acetate (DOCA)-salt hypertension in mice. The daily mean arterial pressure was monitored by radiotelemetry in DOCA-salt-treated mice given vehicle or the mitochondrial respiratory chain complex I inhibitor rotenone. This treatment produced remarkable attenuation of DOCA-salt hypertension. Similar results were obtained with other inhibitors of mitochondrial function, including 5-hydroxydecanoate (specific for mitochondrial potassium-ATP channels), benzylguanidine (complexes I and III), and the cell-permeable manganese tetrakis (4-benzoic acid) porphyrin (a mimic of mitochondrial superoxide dismutase). In parallel with the blood pressure-lowering effect of rotenone, the DOCA-salt-induced increases in urinary 8-isoprostane excretion and in reactive oxygen species production of isolated kidney mitochondria were both significantly attenuated. Conversely, the DOCA-salt-induced reduction of urinary nitrate/nitrite excretion was significantly elevated. Following DOCA-salt treatment, mice deficient in NADPH oxidase subunits gp91(phox) or p47(phox) exhibited a partial attenuation of the hypertensive response at early but not later time points. Thus, the mitochondrial respiratory chain is a major source of oxidative stress in DOCA-salt hypertension, whereas NADPH oxidase may have a relatively minor role during the early stage of hypertension.

Nox2 as a potential target of mitochondrial superoxide and its role in endothelial oxidative stress

“…These data highlight the potential utility of rotenone in the studies of mitochondrial O 2 ·Ϫ . Indeed, rotenone has been shown to inhibit flow-induced dilation in human coronary resistance arteries (27) and attenuated DOCAsalt induced hypertension (56). Since rotenone supplementation causes neurodegeneration (38), in our work we used malate, the citric acid-cycle substrate, which regulates complex II activity and attenuates RET.…”

The Nox Family of NADPH Oxidases: Friend or Foe of the Vascular System?

“…Induction of hypertension by deoxycorticosterone acetate (DOCA) salt was impaired in Nox-deficient mice [75,76]. Physiologically, Nox proteins are expressed in the macula densa [77] and may contribute to tubuloglomerular feedback.…”

Nox2-Induced Production of Mitochondrial Superoxide in Angiotensin II-Mediated Endothelial Oxidative Stress and Hypertension

“…11). Indeed, it has been recently shown that rotenone attenuates DOCA-salt hypertension (53). Rotenone treatment, however, increases oxidative stress in healthy tissue and particularly in the brain, and can lead to the development of Parkinson's disease (41).…”