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Biomedical subjects

Ascan Warnholtz

Publications and source records attributed to Ascan Warnholtz.

13 recordsLinked to original sources
PubMed2007

A single loading dose of clopidogrel causes dose-dependent improvement of endothelial dysfunction in patients with stable coronary artery disease: results of a double-blind, randomized study.

Clinical studies have demonstrated beneficial effects for clopidogrel in patients with atherothrombotic disease. Recent in vitro studies identified stimulating effects of clopidogrel on endothelial cells, pointing towards mechanisms of action beyond the inhibition of platelet aggregation. We hypothesized that in vivo use of clopidogrel improves endothelial dysfunction in patients with coronary artery disease (CAD). Fifty-eight patients with CAD were randomly assigned to double-blinded oral administration of one single dose of clopidogrel 300 mg (C300) or 600 mg (C600), respectively. Endothelial function was assessed by measurement of flow-mediated dilation (FMD) of the brachial artery before and 2, 4 and 22 h after dose administration, respectively. Inhibition of the platelet ADP P2Y12 receptor by clopidogrel was monitored by the ex vivo analysis of ADP effects on prostaglandin-induced platelet VASP phosphorylation. C600 significantly improved FMD at 2, 4 and 22 h, while C300 significantly improved FMD at 4 and 22 h. Clopidogrel dose- and time-dependently inhibited the platelet ADP P2Y12 receptor without correlation with its stimulatory effects on FMD. Our study demonstrates for the first time in vivo that clopidogrel dose-dependently improves endothelial dysfunction. These results may indicate a new and potentially important aspect of the effect of clopidogrel treatment in patients with CAD.

Aged↗
PubMed2006

AT1-receptor blockade with irbesartan improves peripheral but not coronary endothelial dysfunction in patients with stable coronary artery disease.

Activation of the renin-angiotensin-aldosterone system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis. Studies evaluating the effect of AT1-receptor blockers on endothelial dysfunction in patients with coronary artery disease (CAD) revealed mixed results. Studies addressing the effects of AT1-receptor blockers on the coronary and peripheral function in the same study population, are still lacking. We therefore aimed to test the effects of long-term therapy with the AT1-receptor blocker irbesartan (IRB) on both, the coronary and peripheral endothelial function in patients with CAD. Seventy-two patients with CAD were randomly assigned to double-blinded treatment for 6 months with IRB 300 mg per day or placebo, respectively. Coronary and peripheral endothelial function were measured by intracoronary infusion of acetylcholine (final intracoronary concentration 10(-7.3) to 10(-5.6)M) and by determining flow-dependent dilation (FMD) of the brachial artery, respectively. IRB significantly improved FMD, while no change of coronary endothelial function was observed. Interestingly, plasma levels of N(G),N(G)-dimethyl-arginine, and the isoprostane excretion rate were not modified. IRB treatment improves peripheral but not coronary endothelial dysfunction in patients with CAD. Since reduced FMD of the brachial artery has been shown to be associated with a high-cardiovascular event rate, improvement of FMD by IRB may lead to better prognosis of patients with CAD.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

NADPH oxidase accounts for enhanced superoxide production and impaired endothelium-dependent smooth muscle relaxation in BKbeta1-/- mice.

OBJECTIVE: Nitric oxide (NO)-induced vasorelaxation involves activation of large conductance Ca2+-activated K+ channels (BK). A regulatory BKbeta1 subunit confers Ca2+, voltage, and NO/cGMP sensitivity to the BK channel. We investigated whether endothelial function and NO/cGMP signaling is affected by a deletion of the beta1-subunit. METHODS AND RESULTS: Vascular superoxide in BKbeta1-/- was measured using the fluorescent dye hydroethidine and lucigenin-enhanced chemiluminescence. Vascular NO formation was analyzed using electron paramagnetic resonance (EPR), expression of NADPH oxidase subunits, the endothelial NO synthase (eNOS), the soluble guanylyl cyclase (sGC), as well as the activity and expression of the cyclic GMP-dependent kinase I (cGK-I) were assessed by Western blotting technique. eNOS, sGC, cGK-I expression and acetylcholine-induced NO production were unaltered in Bkbeta1-/- animals, whereas endothelial function was impaired and the activity of the cGK-I was reduced. Vascular O2- and expression of the NADPH oxidase subunits p67phox and Nox1 were increased. Endothelial dysfunction was normalized by the NADPH oxidase inhibitor apocynin. Potassium chloride- and iberiotoxin-induced depolarization mimicked the effect of BKbeta1-deletion by increasing vascular O2- in an NADPH-dependent fashion. CONCLUSIONS: The deletion of BKbeta1 causes endothelial dysfunction by increasing O2- formation via increasing activity and expression of the vascular NADPH oxidase.

Animals↗
PubMed2005

Oxypurinol improves coronary and peripheral endothelial function in patients with coronary artery disease.

Coronary endothelial dysfunction is a powerful prognostic marker in patients with coronary artery disease (CAD) that is centrally related to oxidative inhibition of nitric oxide (NO)-dependent vascular cell signaling. Xanthine oxidase (XO), which both binds to and is expressed by endothelial cells, generates superoxide and hydrogen peroxide upon oxidation of purines. Whether inhibition of xanthine oxidase activity results in improved coronary vasomotor function in patients with CAD, however, remains unknown. We assessed coronary and peripheral (brachial artery) endothelial function in 18 patients (pts; 65+/-8 years, 86% male) with angiographically documented CAD, preserved left ventricular function, and non-elevated uric acid levels (233+/-10 microM). Patients received incremental doses of intracoronary acetylcholine (ACh; 10(-7) to 10(-5) microM), and minimal lumen diameter (MLD) and coronary blood flow (CBF) were assessed before and after intravenous administration of oxypurinol (200 mg). Oxypurinol inhibited plasma XO activity 63% (0.051+/- 0.001 vs 0.019+/- 0.005 microU/mg protein; p<0.01). In pts who displayed endothelial dysfunction as evidenced by coronary vasoconstriction in response to ACh (n=13), oxypurinol markedly attenuated ACh-induced vasoconstriction (-23+/- 4 vs -15+/- 4% at ACh 10(-5) microM, p<0.05) and significantly increased CBF (16+/-17 vs 62+/-18% at ACh 10(-5) microM, p<0.05), whereas in patients with preserved coronary endothelial function, oxypurinol had no effect on ACh-dependent changes in MLD (+2.8+/- 4.2 vs 5.2+/- 0.7%, p>0.05) or CBF (135+/-75 vs 154+/-61%, p>0.05). Flow-mediated dilation of the brachial artery, assessed in eight consecutive patients, increased from 5.1+/-1.5 before to 7.6+/-1.5% after oxypurinol administration (p < 0.05). Oxypurinol inhibition of XO improves coronary vascular endothelial dysfunction, a hallmark of patients with CAD. These observations reveal that XO-derived reactive oxygen species significantly contribute to impaired coronary NO bioavailability in CAD and that XO inhibition represents an additional treatment concept for inflammatory vascular diseases that deserves further investigation.

Aged↗
PubMed2005

The oxidative stress concept of nitrate tolerance and the antioxidant properties of hydralazine.

The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted as a result of the development of nitrate tolerance. With initiation of NTG therapy, it is possible to detect neurohormonal activation and intravascular volume expansion. These so-called pseudotolerance mechanisms may compromise the vasodilatory effects of NTG. Long-term nitrate treatment also is associated with decreased vascular responsiveness caused by changes in intrinsic mechanisms of the tolerant vasculature itself. According to the oxidative stress concept, increased vascular superoxide (O2-) production and an increased sensitivity to vasoconstrictors secondary to activation of protein kinase C contribute to the development of tolerance. Nicotinamide adenine dinucleotide phosphate oxidase and the uncoupled endothelial nitric oxide synthase may be O2- -producing enzymes. Nitric oxide (NO) and O2-, both derived from NTG and the vessel wall, form peroxynitrite in a diffusion-limited rapid reaction. Peroxynitrite, O2-, or both may be responsible for the development of nitrate tolerance and cross-tolerance to direct NO donors (eg, sodium nitroprusside, sydnonimines) and endothelium-dependent NO synthase-activating vasodilators. Hydralazine is an efficient reactive oxygen species (ROS) scavenger and an inhibitor of O2- generation. When given concomitantly with NTG, hydralazine prevents the development of nitrate tolerance and normalizes endogenous rates of vascular O2- production. Recent experimental work has defined new tolerance mechanisms, including inhibition of the enzyme that bioactivates NTG (ie, mitochondrial aldehyde dehydrogenase isoform 2 [ALDH2]) and mitochondria as potential sources of ROS. NTG-induced ROS inhibit the bioactivation of NTG by ALDH2. Both mechanisms increase oxidative stress and impair NTG bioactivation, and now converge at the level of ALDH2 to support a new theory for NTG tolerance and NTG-induced endothelial dysfunction. The consequences of these processes for NTG downstream targets (eg, soluble guanylyl cyclase, cyclic guanosine monophosphate-dependent protein kinase), toxic effects contributing to endothelial dysfunction (eg, prostacyclin synthase inhibition) and novel applications of the antioxidant properties of hydralazine are discussed.

Animals↗
PubMed2005

Effect of tirofiban on percutaneous coronary intervention-induced endothelial dysfunction in patients with stable coronary artery disease.

Recent studies demonstrated that glycoprotein (GP) IIb/IIIa receptor antagonists improve endothelial dysfunction of forearm resistance vessels in patients with stable coronary artery disease. However, it remains unclear whether these findings can be extended to the conductance vessel level. In this study, we aimed to evaluate the acute effect of tirofiban on endothelial function of arterial conductance vessels in patients undergoing percutaneous coronary intervention (PCI). Endothelial function was examined by ultrasonographic measurement of flow-mediated vasodilation (FMD) of the brachial artery. Endothelium-independent vasodilation was determined in response to nitroglycerin. Sixty-six patients who underwent PCI were included in the study. Thirty-three patients received a bolus of 10 microg/kg body weight of tirofiban, whereas 33 patients who did not receive tirofiban served as the control group. FMD was measured in all patients before and 30 minutes after PCI. Tirofiban significantly improved FMD (6.0 +/- 0.4% before vs 7.8 +/- 0.5% after PCI, p <0.0001), whereas FMD deteriorated in patients in the control group (6.1 +/- 0.6% before vs 4.7 +/- 0.7% after PCI, p = 0.006). Nitroglycerin-induced dilation remained unaltered in response to PCI. In another group of 11 patients with coronary artery disease, FMD did not change after coronary angiography without coronary intervention. In conclusion, PCI induces endothelial dysfunction in forearm conductance vessels that can be reversed with tirofiban.

Aged↗
PubMed2004

Clinical aspects of reactive oxygen and nitrogen species.

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.

Cardiovascular Diseases↗
PubMed2002

Adverse effects of nitroglycerin treatment on endothelial function, vascular nitrotyrosine levels and cGMP-dependent protein kinase activity in hyperlipidemic Watanabe rabbits.

OBJECTIVE: With the present studies we sought to determine how treatment with nitroglycerin (NTG) affects endothelial function, oxidative stress and nitric oxide (NO)-downstream signaling in Watanabe heritable hyperlipidemic rabbits (WHHL). BACKGROUND: In vitro experiments have demonstrated potent antiatherosclerotic effects of NO suggesting that treatment with NO-donors such as NTG could compensate for the diminished availability of endothelial NO. Nitric oxide may, however, not only be scavenged by reaction with endothelium-derived superoxide but also form the potent oxidant and inhibitor of vascular function, peroxynitrite (ONOO(-)). METHODS: Watanabe heritable hyperlipidemic rabbits were treated for three days with NTG patches. Normolipidemic New Zealand White rabbits (NZWR) served as controls. Endothelial function was assessed ex vivo with organ chamber experiments and vascular superoxide was quantified using lucigenin (5 and 250 microM) and CLA-enhanced chemiluminescence. Vascular ONOO(-) formation was determined using nitrotyrosine antibodies. The activity of the cGMP-dependent kinase (cGK-I) was assessed by determining the phosphorylation of vasodilator-stimulated phosphoprotein VASP (P-VASP). RESULTS: Nitroglycerin treatment caused endothelial dysfunction in NZWR and WHHL, associated with an increase in superoxide and ONOO(-) production and a substantial drop in cGK-I activity. In vivo NTG-treatment decreased lipophilic antioxidants (alpha- and beta-carotene) in NZWR and WHHL. Treatment of NZWR with NTG also decreased plasma extracellular superoxide dismutase (EC-SOD)-activity. CONCLUSIONS: Nitroglycerin treatment of WHHL with exogenous NO worsens rather than improves endothelial dysfunction secondary to increased formation of superoxide and/or peroxynitrite leading to decreased cGK-I activity. The decrease in plasma levels of alpha- and beta-carotene may be at least in part due to a decrease in EC-SOD activity.

Animals↗
PubMed2002

Mechanisms underlying nitrate-induced endothelial dysfunction: insight from experimental and clinical studies.

The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted due to the development of nitrate tolerance. With initiation of nitroglycerin therapy one can detect neurohormonal activation and signs for intravascular volume expansion. These so called pseudotolerance mechanisms may compromise nitroglycerin's vasodilatory effects. Long-term treatment with nitroglycerin is also associated with a decreased responsiveness of the vasculature to nitroglycerin's vasorelaxant potency suggesting changes in intrinsic mechanisms of the tolerant vasculature itself may also contribute to tolerance. More recent experimental work defined new mechanisms of tolerance such as increased vascular superoxide production and increased sensitivity to vasoconstrictors secondary to an activation of the intracellular second messenger protein kinase C. As potential superoxide producing enzymes, the NADPH oxidase and the nitric oxide synthase have been identified. Nitroglycerin-induced stimulation of oxygen-derived free radicals together with NO derived from nitroglycerin may lead to the formation of peroxynitrite, which may be responsible for the development of tolerance as well as for the development of cross tolerance to endothelium-dependent vasodilators. The oxidative stress concept of tolerance and cross tolerance may explain why radical scavengers such as vitamin C or substances which reduce oxidative stress, such as ACE-inhibitors, AT1 receptor blockers or folic acid, are able to beneficially influence both tolerance and nitroglycerin-induced endothelial dysfunction. New aspects concerning the role of oxidative stress in nitrate tolerance and nitrate induced endothelial dysfunction and the consequences for the NO/cyclicGMP downstream target, the cGMP-dependent protein kinase will be discussed.

Animals↗
PubMed2000

Why do antioxidants fail to provide clinical benefit?

The results of recent randomized trials to test the influence of antioxidants on coronary-event rates and prognosis in patients with coronary-artery disease were disappointing. In none of these studies did the use of vitamin E improve prognosis. In contrast, treatment of coronary-artery disease with angiotensin-converting-enzyme (ACE) inhibitors reduced coronary-event rates and improved prognosis. ACE inhibition prevents the formation of angiotensin II, which has been shown to be a potent stimulus of superoxide-producing enzymes in atherosclerosis. The findings suggest that inhibition of superoxide production at enzymatic levels, rather than symptomatic superoxide scavenging, may be the better choice of treatment.

Journal Article↗