Gp91phox-containing NAD(P)H oxidase mediates attenuation of nitric oxide-dependent control of myocardial oxygen consumption by ANG II.

We have previously reported that ANG II stimulation increased superoxide anion (O2-) through the activation of NAD(P)H oxidase and inhibited nitric oxide (NO)-dependent control of myocardial oxygen consumption (MVo2) by scavenging NO. Our objective was to investigate the role of NAD(P)H oxidase, especially the gp91phox subunit, in the NO-dependent control of MVo2. MVo2 in mice with defects in the expression of gp91phox [gp91Phox(-/-)] was measured with a Clark-type oxygen electrode. Baseline MVo2 was not significantly different between wildtype (WT) and gp91Phox(-/-) mice. Stimulation of NO production by bradykinin (BK) induced significant decreases in MVo2 in WT mice. BK-induced reduction in MVo2 was enhanced in gp91phox(-/-) mice. BK-induced reduction in MVo2 in WT mice was attenuated by 10 a mol/l ANG II, which was restored by coincubation with Tiron or apocynin. In contrast to WT mice, BK-induced reduction in MVo2 in gp91phox(-/-) mice was not altered by ANG II. There was a decrease in lucigenin (5 × 10-6 mol/l)-detectable O2- in gp91phox(--/-) mice compared with WT mice. ANG II resulted in significant increases in O2- production in WT mice, which was inhibited by coincubation with Tiron or apocynin. However, ANG II had no effect on O2- production in gp91phox(-/-) mice. Histological examination showed that the development of abscesses and/or the invasion of inflammatory cells occurred in lungs and livers but not in hearts and kidneys from gp91phox(-/-) mice. These results indicate that the gp91phox subunit of NAD(P)H oxidase mediates O2- production through the activation of NAD(P)H oxidase and attenuation of NO-dependent control of MVo2 by ANG II. [ABSTRACT FROM AUTHOR]