Dirk Stalleicken

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Anti-ischemic therapy with organic nitrates is complicated by tolerance. Induction of tolerance is incompletely understood and likely multifactorial. Recently, increased production of reactive oxygen species (ROS) has been investigated, but it has not been clear if this is a direct consequence of the organic nitrate on the vessel or an in vivo adaptation to(More)
Mitochondrial aldehyde dehydrogenase (ALDH-2) was recently identified to be essential for the bioactivation of glyceryl trinitrate (GTN). Here we assessed whether other organic nitrates are bioactivated by a similar mechanism. The ALDH-2 inhibitor benomyl reduced the vasodilator potency, but not the efficacy, of GTN, pentaerythritol tetranitrate (PETN), and(More)
Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl tetranitrate (PETN) is an(More)
The organic nitrate pentaerythrityl tetranitrate (PETN) is known to exert long-term antioxidant and antiatherogenic effects by as yet unidentified mechanisms. In cultured endothelial cells derived from human umbilical vein, the active PETN metabolite PETriN (0.01-1 mM) increased heme oxygenase (HO)-1 mRNA and protein levels in a concentration-dependent(More)
BACKGROUND Chronic therapy with nitroglycerin (GTN) results in a rapid development of nitrate tolerance which is associated with an increased production of reactive oxygen species (ROS). According to recent studies, mitochondrial ROS formation and oxidative inactivation of the organic nitrate bioactivating enzyme mitochondrial aldehyde dehydrogenase(More)
OBJECTIVE Nitrate tolerance is likely attributable to an increased production of reactive oxygen species (ROS) leading to an inhibition of the mitochondrial aldehyde dehydrogenase (ALDH-2), representing the nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN) bioactivating enzyme, and to impaired nitric oxide bioactivity and signaling. We tested(More)
Pentaerithrityl tetranitrate (PETN) is a long-acting donor of nitric oxide (NO) and has recently been characterized as an antianginal agent that, in contrast with other nitric acid esters, does not induce oxidative stress and is therefore free of tolerance. Moreover, animal experiments have revealed that PETN actively reduces oxygen radical formation in(More)
BACKGROUND The organic nitrate pentaerithrityl tetranitrate (PETN) has been shown to have ancillary properties that prevent the development of tolerance and endothelial dysfunction. This randomized, double-blind, placebo-controlled, multicentre study ('CLEOPATRA' study) was designed to investigate the anti-ischaemic efficacy of PETN 80 mg b.i.d. (morning(More)
Recent animal data suggest that reduced lipoic acid (LA) prevents oxidative inhibition of the nitrate bioactivating enzyme, the mitochondrial aldehyde dehydrogenase (ALDH-2), and that pentaerythritol tetranitrate (PETN) does not induce nitrate tolerance because of its intrinsic antioxidative properties, thereby preserving ALDH-2 activity. We sought to(More)
Neither therapeutic dosage of nitrovasodilators nor the development of tolerance correlates with nitrate groups in these molecules. Clinically, low dosages of glyceryl trinitrate (GTN) develop tolerance, but 100-fold higher dosages of pentaerythrityl tetranitrate (PETN) do not. Vasorelaxation was studied on prostaglandian F2alpha (PGF2alpha)-precontracted(More)