The organic
nitrate pentaerythritol tetranitrate is devoid of
nitrate tolerance, which has been attributed to the induction of the
antioxidant enzyme heme oxygenase (HO)-1. With the present study, we tested whether chronic treatment with
pentaerythritol tetranitrate can improve
angiotensin II-induced vascular oxidative stress and dysfunction. In contrast to isosorbide-5 mononitrate (75 mg/kg per day for 7 days), treatment with
pentaerythritol tetranitrate (15 mg/kg per day for 7 days) improved the impaired endothelial and smooth muscle function and normalized vascular and cardiac
reactive oxygen species production (mitochondria,
NADPH oxidase activity, and uncoupled endothelial
NO synthase), as assessed by
dihydroethidine staining,
lucigenin-enhanced chemiluminescence, and quantification of
dihydroethidine oxidation products in
angiotensin II (1 mg/kg per day for 7 days)-treated rats. The
antioxidant features of
pentaerythritol tetranitrate were recapitulated in spontaneously hypertensive rats. In addition to an increase in HO-1
protein expression,
pentaerythritol tetranitrate but not isosorbide-5 mononitrate normalized vascular
reactive oxygen species formation and augmented aortic
protein levels of the
tetrahydrobiopterin-synthesizing
enzymes GTP-cyclohydrolase I and
dihydrofolate reductase in
angiotensin II-treated rats, thereby preventing endothelial
NO synthase uncoupling. Haploinsufficiency of HO-1 completely abolished the beneficial effects of
pentaerythritol tetranitrate in
angiotensin II-treated mice, whereas HO-1 induction by
hemin (25 mg/kg) mimicked the effect of
pentaerythritol tetranitrate. Improvement of vascular function in this particular model of arterial
hypertension by
pentaerythritol tetranitrate largely depends on the induction of the
antioxidant enzyme HO-1 and identifies
pentaerythritol tetranitrate, in contrast to isosorbide-5 mononitrate, as an organic
nitrate able to improve rather than to worsen endothelial function.