PubMed Health⌕ Search

Biomedical subjects

Andreas Schäfer

Publications and source records attributed to Andreas Schäfer.

At least 19 recordsLinked to original sources
PubMed2006

The CX3C chemokine fractalkine induces vascular dysfunction by generation of superoxide anions.

OBJECTIVE: The chemokine fractalkine activates platelets and induces leukocyte adhesion to the endothelium. Expression of fractalkine and its receptor, CX3CR1, is elevated in coronary artery disease. We assessed the effects of fractalkine on vascular function in isolated rat aorta. METHODS AND RESULTS: CX3CR1 expression was demonstrated in rat aortic endothelial and smooth muscle cells by immunohistochemistry, Western blot, and polymerase chain reaction (PCR). Fractalkine (up to 1 microg/mL) did not directly induce contractile or relaxant responses when applied to rat aortic rings in organ baths. Short-term incubation with fractalkine (1 microg/mL) for 5 minutes did not affect vascular reactivity. Pretreatment of isolated rat aortic rings with fractalkine for 2 hours impaired acetylcholine-induced nitric oxide (NO)-mediated relaxation after preconstriction with phenylephrine in a concentration-dependent manner. The concentration response to the NO donor DEA-NONOate was significantly shifted to the right. The radical scavenger tiron normalized the attenuated acetylcholine-induced relaxation after fractalkine incubation. Aortic superoxide formation was enhanced by fractalkine, which was inhibited by diphenyleneiodonium but not by inhibitors of xanthine oxidase or NO synthase. CONCLUSIONS: In addition to its role as a chemokine and adhesion molecule, fractalkine induces vascular dysfunction by stimulating vascular reactive oxygen species resulting in reduced NO bioavailability.

Acetylcholine↗
PubMed2006

Soluble guanylyl cyclase activation with HMR1766 attenuates platelet activation in diabetic rats.

OBJECTIVE: Platelet activation significantly contributes to cardiovascular morbidity and mortality in diabetes. An association between impaired NO-mediated platelet inhibition and platelet activation has recently been demonstrated in experimental diabetes. Guanylyl cyclase activation enhances the reduced signaling via the NO/cGMP pathway. We investigated whether chronic guanylyl cyclase activation would beneficially modulate platelet activation in experimental diabetes mellitus. METHODS AND RESULTS: Diabetes was induced by streptozotocin-injection in male Wistar rats. After 2 weeks, treatment with either placebo or the guanylyl cyclase activator HMR1766 (10 mg/kg twice daily by gavage) was initiated. Two weeks later, in vivo platelet activation and in vitro platelet reactivity were assessed. Chronic treatment with HMR1766 enhanced NO/cGMP-mediated signaling in platelets from diabetic rats determined by in vivo phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) at Ser157 and Ser239. In parallel, platelet-binding of fibrinogen, surface-expression of P-selectin, appearance of platelet-derived microparticles, and platelet-aggregates with other blood cells were significantly reduced by chronic treatment with HMR1766. CONCLUSIONS: Chronic activation of soluble guanylyl cyclase in diabetic rats improved markers of platelet activation and is a rationale approach for prevention of adverse cardiovascular events in diabetes.

Animals↗
PubMed2006

Medroxyprogesterone acetate but not drospirenone ablates the protective function of 17 beta-estradiol in aldosterone salt-treated rats.

Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction. To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17beta-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity. The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17beta-estradiol in ovariectomized animals after 8 weeks of continuous treatment. The beneficial role of 17beta-estradiol on blood pressure, cardiac hypertrophy, vascular osteopontin expression, perivascular fibrosis, and impaired NO-dependent relaxation of isolated aortic rings was completely abrogated by coadministration of medroxyprogesterone acetate. In contrast, drospirenone was either neutral or additive to 17beta-estradiol in protecting against aldosterone salt-induced cardiovascular injury and inflammation. The current results support the hypothesis of complex interactions among estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptor signaling in cardiovascular injury and inflammation. Novel progestins, such as drospirenone, confer superior effects compared with medroxyprogesterone acetate in a model of aldosterone-induced heart disease because of its antimineralocorticoid properties.

Aldosterone↗
PubMed2006

Efficient simulation of magnetic resonance imaging with Bloch-Torrey equations using intra-voxel magnetization gradients.

The process of image formation in magnetic resonance imaging (MRI) can be simulated by means of an iterative solution of Bloch-Torrey equations. This is a useful accessory to analyze the influence of sample properties, sequence parameters and hardware specifications on the MRI signal. In this paper, a computer algorithm is presented which is based on calculating partial derivatives of the magnetization vector. This technique allows more efficient simulation than summation of isochromats (the latter being commonly employed for this purpose) and, as a result, the effect of diffusion on the MRI signal can be calculated iteratively. A detailed description of the algorithm is given, and its feasibility for different applications is studied. It is shown that the algorithm is most applicable to simulating the effect of field perturbations, i.e. intra-voxel dephasing, but is also useful for other typical imaging experiments and the simulation of diffusion weighting.

Algorithms↗
PubMed2005

Rosuvastatin reduces platelet activation in heart failure: role of NO bioavailability.

OBJECTIVES: Endothelial dysfunction and platelet activation are part of the cardiovascular phenotype in congestive heart failure (CHF). We investigated whether 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibition would beneficially modulate vascular NO bioavailability and platelet activation in experimental CHF. METHODS AND RESULTS: Chronic myocardial infarction was induced by coronary ligation in male Wistar rats. Animals were either treated with placebo or the HMG-CoA reductase inhibitor rosuvastatin. After 10 weeks, hemodynamic assessment was performed and endothelial function was determined in organ bath studies. NO bioavailability was assessed by in vivo platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Markers of platelet degranulation (surface expression of P-selectin and glycoprotein 53) were determined as well as the amount of circulating platelet-leukocyte aggregates. Endothelium-dependent, acetylcholine-induced vasorelaxation was significantly impaired in aortic rings from CHF rats and improved by rosuvastatin. In parallel, in vivo VASP phosphorylation reflecting NO bioavailability was significantly attenuated in platelets from CHF rats and normalized by rosuvastatin. Platelet activation, which was increased in CHF, was reduced by treatment with rosuvastatin. CONCLUSIONS: HMG-CoA reductase inhibition improved endothelial function, increased systemic NO bioavailability and inhibited exaggerated platelet activation in CHF rats. These mechanisms may contribute to the beneficial effects of statin treatment in CHF.

Animals↗
PubMed2005

Functional magnetic resonance imaging with intermolecular double-quantum coherences at 3 T.

Functional magnetic resonance imaging (fMRI) based on the selection of intermolecular double-quantum coherences (iDQC) was performed with a standard birdcage coil at 3 T in a group of normal human volunteers. Suppression of spurious signal contributions from unwanted coherence-transfer pathways was achieved by combining a two-step phase cycle and a long repetition time of 5 s. A gradient-recalled echo iDQC sequence (echo time, T(E) = 80 ms) yielded robust activation with a visual paradigm. Maximum z-scores were about half of those observed with conventional blood-oxygen level dependent fMRI, whereas the functional signal change increased by more than a factor of 5. No activation was obtained with a spin-echo iDQC sequence (T(E) = 160 ms), in which dephasing accumulated during the evolution period was fully rephased by an appropriate delay time. It is hypothesized that substantial inherent diffusion weighting of the iDQC technique efficiently suppresses intravascular contributions to the functional contrast. A consistent quantitative explanation of the observed amount of signal change currently remains speculative.

Adult↗
PubMed2004

Reduced vascular NO bioavailability in diabetes increases platelet activation in vivo.

OBJECTIVE: Platelet activation is a feature of cardiovascular disease that is also characterized by endothelial dysfunction. The direct relationship between impaired endothelium-derived NO bioavailability and platelet activation remains unclear. We investigated whether acute inhibition of NO production modulates platelet activation in mice and whether specific rescue of endothelial function in diabetes modifies platelet activation. METHODS AND RESULTS: Intravenous injection of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester in wild-type (WT) mice significantly reduced platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation and increased platelet surface expression of P-selectin, CD40 ligand, and fibrinogen platelet binding, demonstrating that NO production exerts tonic inhibition of platelet activation in mice. Diabetes was induced by streptozotocin injection in WT or endothelial-targeted guanosine 5'-triphosphate cyclohydrolase I (GCH)-transgenic (GCH-Tg) mice protected from endothelial dysfunction in diabetes by sustained levels of tetrahydrobiopterin in vascular endothelium. Platelet VASP phosphorylation was significantly reduced in diabetic WT but not in diabetic GCH-Tg mice. P-selectin, CD40 ligand expression, and fibrinogen binding were increased in diabetic WT mice but remained unchanged compared with controls in endothelial-targeted GCH-Tg mice. CONCLUSIONS: Platelet activation results from acute and chronic reduction in NO bioactivity. Rescue of platelet activation in diabetes by endothelial-specific restoration of NO production demonstrates that platelet function in vivo is principally regulated by endothelium-derived NO. Endothelial dysfunction caused by uncoupling of endothelial NO synthase is well described in diabetes mellitus and may lead to platelet activation. Acute loss of systemic NO bioavailability causes platelet activation. eNOS uncoupling prevention in diabetes preserved systemic NO bioavailability and maintained a physiological platelet state without activation in vivo.

Animals↗
PubMed2004

Reduced basal nitric oxide bioavailability and platelet activation in young spontaneously hypertensive rats.

OBJECTIVE: To investigate the role of basal nitric oxide (NO) bioavailability for platelet activation in young spontaneously hypertensive rats before onset of hypertension. Phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) in platelets was used as a sensitive monitor of in vivo NO bioavailability. METHODS AND RESULTS: Whole blood samples were taken from 10-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In vivo surface-expression of P-selectin and platelet-binding of fibrinogen were assessed by flow cytometry. Platelet VASP-phosphorylation at its serine 239 (Ser239) and serine 157 (Ser157) residues was assessed using specific antibodies to determine NO bioavailability in vivo, and compared with endothelial vasomotor function. The increment in vascular tone following inhibition of NO-synthase in slightly preconstricted aortic rings was reduced indicating less NO formation under physiological stimulation (WKY 71.1+/-4.1%; SHR 57.8+/-2.4%, P<0.05). In vivo platelet VASP-phosphorylation was significantly reduced at both phosphorylation sites in SHR (mean fluorescence for Ser239: WKY: 15.2+/-0.6; SHR: 11.7+/-0.5, P<0.01; Ser157: WKY: 53.0+/-3.0; SHR: 35.0+/-3.5, P<0.05). Surface-expression of P-selectin and membrane-bound fibrinogen were significantly enhanced in SHR compared with WKY (P-selectin: WKY: 23.2+/-3.4; SHR 58.3+/-7.9, P<0.001; platelet-bound fibrinogen: WKY: 8.6+/-0.5; SHR: 13.5+/-1.1, P<0.001). In vitro preincubation of platelets with the NO donor sodium nitroprusside normalized platelet surface-expression of P-selectin in SHR. CONCLUSION: Using VASP-phosphorylation as a sensitive monitor of in vivo NO bioavailability, these data provide evidence that reduced vascular NO formation in vivo contributes to increased platelet activation in young SHR.

Animals↗
PubMed2004

Rapid regulation of platelet activation in vivo by nitric oxide.

BACKGROUND: Platelet activation is a feature of many cardiovascular diseases characterized by endothelial dysfunction. The mechanistic relationship between impaired systemic nitric oxide (NO) bioavailability and platelet activation in vivo remains unclear. We investigated whether acute inhibition of NO production in humans modulates platelet activation in vivo and whether exogenous NO would counteract such an effect. METHODS AND RESULTS: Intravenous injection of the NO synthase inhibitor N(G)-monomethyl-l-arginine in healthy volunteers resulted in NO synthase inhibition as detected by increased blood pressure and by significantly reduced phosphorylation of platelet vasodilator-stimulated phosphoprotein, an indicator of NO signaling. NO synthase inhibition increased platelet activation as determined by enhanced platelet binding of fibrinogen and surface expression of P-selectin, glycoprotein 53, and CD40 ligand, demonstrating tonic inhibition of platelet activation by NO production in vivo. Sublingual administration of the NO donor glyceryl trinitrate normalized platelet VASP phosphorylation and restored markers of platelet activation to baseline levels. CONCLUSIONS: Acute inhibition of endogenous NO production in humans causes rapid platelet activation in vivo, which is reversed by exogenous NO, demonstrating that platelet function in vivo is rapidly regulated by NO bioavailability.

Adult↗
PubMed2004

Endothelial dysfunction in congestive heart failure: ACE inhibition vs. angiotensin II antagonism.

BACKGROUND: Endothelial dysfunction of the vasculature contributes to the elevated peripheral resistance and reduced myocardial perfusion in congestive heart failure (CHF). The present study systematically investigated the effect of angiotensin II (AT(1))- receptor blockade on vascular superoxide (O(2)(-)) production and endothelial dysfunction. METHODS AND RESULTS: Vasodilator responses and O(2)(-) production were determined in aortic rings from Wistar rats with experimental CHF 10 weeks after extensive myocardial infarction and compared with sham-operated animals (Sham). Rats were either treated with placebo (P), with the AT(1)-receptor antagonist Irbesartan (50 mg kg(-1) day(-1)) or with the ACE inhibitor Trandolapril (0.3 mg kg(-1) day(-1)). In CHF-P, endothelium-dependent, acetylcholine-induced relaxation was significantly attenuated compared with Sham-P. Chronic treatment with Trandolapril or Irbesartan significantly improved endothelium-dependent relaxation. Aortic O(2)(-) formation was markedly increased in CHF, and was not significantly affected by Trandolapril treatment, while it was reduced by Irbesartan. eNOS expression was reduced in CHF and normalised by both treatments. CONCLUSION: Endothelial vasomotor function in CHF rats was normalised by long-term treatment with an ACE inhibitor or an AT(1)-antagonist. Reduced aortic eNOS expression was normalised by both treatments, whereas aortic superoxide formation was only reduced by the AT(1)-antagonist Irbesartan.

Analysis of Variance↗
PubMed2004

Novel O-glycosyl amino acid mimetics as building blocks for O-glycopeptides act as inhibitors of galactosidases.

As potential lead structures for a new class of glycosidase inhibitors the novel O-glycosyl amino acid mimetics 3'-O-[2,6-anhydro-D-glycero-L-gluco-heptitol-1-yl]-L-serine 3 and-L-threonine 4 were synthesized, employing regio- and stereoselective aziridine ring opening methodology. They proved to be stable in the presence of glycosidases and showed competitive inhibition of alpha-galactosidase from Aspergillus niger.

Amino Acids↗
PubMed2004

Increased platelet activation in young Zucker rats with impaired glucose tolerance is improved by acarbose.

Patients with diabetes display increased platelet activation. Recent data show a markedly increased risk for cardiovascular events already in pre-diabetic individuals with impaired glucose tolerance (IGT). We investigated whether IGT is associated with platelet activation. Blood samples were collected from young lean (control) and obese Zucker rats, an established model of IGT, after single oral application of sucrose (4 g.kg-1). Platelet-bound fibrinogen and platelet surface-expression of P-selectin were assessed as indices of platelet activation using flow cytometry. In lean Zucker rats, acute sucrose application induced fibrinogen-binding and P-selectin surface-expression, which was prevented by co-administration of acarbose (10 mg.kg-1). In obese Zucker rats, platelet activation was already maximally increased under baseline conditions with no significant increase after sucrose application. Chronic treatment with acarbose (15 mg.kg-1.day-1) significantly reduced platelet activation in these animals. Acute ingestion of sucrose induces platelet activation which is prevented by acarbose. IGT is associated with marked platelet activation that can be reduced by chronic administration of acarbose. The positive modulation of platelet activation by acarbose may contribute to the reduction of cardiovascular events in patients with IGT.

Acarbose↗
PubMed2004

Endothelial dysfunction in heart failure: mechanisms and therapeutic approaches.

Endothelial dysfunction contributes to the development of impaired coronary and systemic perfusion as well as reduced exercise capacity in patients with congestive heart failure (CHF). Thereby endothelial dysfunction is assumed to have a fundamental impact on morbidity and potential mortality in this disease. Reduced bioavailability of nitric oxide (NO) and abundant formation of reactive oxygen species (ROS) within the vascular wall are the key determinants in endothelial dysfunction. The resulting imbalance between NO and ROS mainly results from neurohumoral activation associated with CHF. The excessive activation of the renin-angiotensin-aldosterone and endothelin systems plays a pivotal role. Treatment with ACE inhibitors, angiotensin-, aldosterone-, and endothelin-antagonists has been shown to beneficially modulate endothelial dysfunction in CHF. Furthermore, antioxidants, L-arginine, cofactors of endothelial NO-synthase, and exercise training positively modulate endothelial function. This article reviews the current knowledge of the pathophysiological events contributing to endothelial dysfunction in CHF as well as several treatment options to reverse those changes.

Animals↗
PubMed2004

Platelet activation in heart failure.

Heart failure is a common disease in aging western populations. Not only severe but even mild to moderate heart failure is associated with increasing risk for stroke. This can partly be attributed to concomitant atrial fibrillation, a well-known risk factor for stroke. Furthermore, the increased risk for thromboembolic events in congestive heart failure has been attributed to a hypercoagulable state including formation of intraventricular thrombi. However, more recently, enhanced platelet activation has been described in patients with heart failure in sinus rhythm. Vascular endothelial dysfunction and reduced formation of the platelet inhibitor nitric oxide appear to contribute to platelet activation in heart failure. This review article summarizes the historical knowledge of abnormal platelet function in heart failure, focuses on pathophysiological changes in heart failure which could influence platelet activation, and discusses drug regimens investigated in heart failure to reduce platelet activation either by direct anti-platelet effects or by modulating the release of platelet inhibiting substances.

Anticoagulants↗
PubMed2003

Novel role of the membrane-bound chemokine fractalkine in platelet activation and adhesion.

Chemokines released by the endothelium have proaggregatory properties on platelets. Fractalkine, a recently discovered membrane-bound chemokine with a transmembrane domain, is expressed in vascular injury; however, the effects of fractalkine on platelets have not yet been investigated. Blood was taken from healthy Wistar-Kyoto rats and the expression of the fractalkine receptor on platelets was demonstrated. The modulation of surface expression of P-selectin was assessed by flow cytometry. P-selectin expression was significantly enhanced by in vitro stimulation with recombinant rat fractalkine compared with baseline levels. Selectively inhibiting the function of recombinant fractalkine by an antagonizing antibody or the disruption of the G-protein-coupled intracellular signaling cascade of the fractalkine receptor by pertussis toxin (PTX) completely prevented fractalkine-mediated platelet activation. Preincubation with apyrase significantly attenuated the fractalkine-induced degranulation. In a flow chamber model of platelet adhesion, stimulation with fractalkine significantly enhanced platelet adhesion to collagen and fibrinogen. Similar to P-selectin expression, enhanced adhesion could be prevented by the antagonizing antibody or preincubation of platelets with PTX. Fractalkine, which is overexpressed in atherosclerosis and vascular injury, contributes to platelet activation and adhesion and hence is likely to play a pathophysiologically important role for increased thrombogenesis in vascular diseases.

Analysis of Variance↗
PubMed2003

Shape-persistant macrocycles with terpyridine units: synthesis, characterization, and structure in the crystal.

The synthesis of a variety of shape-persistent macrocycles with either one (1a-d, 2) or two (opposing) terpyridine units (3, 4, 5a-c) and inner diameters of up to 2 nm is described. The sequences are mainly based on transition metal cross-coupling reactions and, whenever appropriate, compared with one another regarding their respective efficiency. Typical overall yields and amounts prepared range from 8% (4) to 27% (3) and 25 mg (1a) to 290 mg (1b), respectively. For solubility and processing of the targeted cycles, all precursors have already been decorated with flexible side chains (hexyloxy or hexyloxymethyl). The cycles' characterization is based on MALDI-TOF mass spectrometry, 2D NMR spectroscopy, and/or low-temperature single-crystal X-ray diffraction. Their packing in the crystal is discussed in terms of both number and length of side chains. Cycle 1d was physisorbed into an ordered structure at the solution-HOPG interface and investigated by scanning tunneling microscopy (STM).

Journal Article↗
PubMed2003

Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction.

OBJECTIVES: To investigate the effects of adding the selective aldosterone receptor antagonist eplerenone to ACE inhibition on endothelium-dependent vasodilation in rats with chronic heart failure (CHF). BACKGROUND: Addition of the non-selective aldosterone antagonist spironolactone to ACE-inhibitors reduces mortality and morbidity in CHF and improves endothelial vasomotor dysfunction, but is associated with considerable side-effects. METHODS: Starting 10 days after extensive myocardial infarction (MI) or sham-operation, Wistar rats were treated either with placebo, the ACE inhibitor trandolapril (TR, 0.3 mg/kg body weight per day), the selective aldosterone receptor antagonist eplerenone (EPL, 100 mg/kg per day) or a combination of both for 9 weeks. RESULTS: Maximum acetylcholine-induced, nitric oxide-dependent relaxation was significantly attenuated in aortic rings from rats with CHF compared with sham-operated animals (R(max) 55% vs. 87%). EPL alone slightly and TR significantly improved NO-mediated relaxation (CHF-EPL 66%; CHF-TR: 78%), while treatment with both EPL and TR completely restored endothelium-dependent vasorelaxation (CHF-EPL-TR: 83%). Aortic superoxide formation was significantly increased in rats with CHF compared with sham-operated animals, but was normalised by treatment with EPL or TR-EPL. Expression of the endothelial nitric oxide synthase was decreased in CHF and normalised in all treatment groups. CONCLUSIONS: In experimental CHF, the selective aldosterone antagonist EPL reduced the increased vascular superoxide formation. Although a combination of TR and EPL normalised endothelium-dependent relaxation, ACE inhibition as a monotherapy was almost equally effective.

Angiotensin-Converting Enzyme Inhibitors↗