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Biomedical subjects

Malte Kelm

Publications and source records attributed to Malte Kelm.

At least 37 records · Page 2Linked to original sources
PubMed2005

Desferoxamine and ethyl-3,4-dihydroxybenzoate protect myocardium by activating NOS and generating mitochondrial ROS.

Protection from a prolyl hydroxylase domain-containing enzyme (PHD) inhibitor, desferoxamine (DFO), was recently reported to be dependent on production of reactive oxygen species (ROS). Ischemic preconditioning triggers the protected state by stimulating nitric oxide (NO) production to open mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels, generating ROS required for protection. We tested whether DFO and a second PHD inhibitor, ethyl-3,4-dihydroxybenzoate (EDHB), might have similar mechanisms. EDHB and DFO increased ROS generation by 50-75% (P < 0.001) in isolated rabbit cardiomyocytes. This increase after EDHB exposure was blocked by N(omega)-nitro-L-arginine methyl ester (L-NAME), an NO synthase (NOS) inhibitor; ODQ, a guanylyl cyclase antagonist; and Rp-8-bromoguanosine-3',5'-cyclic monophosphorothioate Rp isomer, a PKG blocker, thus implicating the NO pathway in EDHB's signaling. Glibenclamide, a nonselective K(ATP) channel blocker, or 5-hydroxydecanoate, a selective mitoK(ATP) channel antagonist, also prevented EDHB's ROS production, as did blockade of mitochondrial electron transport with myxothiazol. NOS is activated by Akt. However, neither wortmannin, an inhibitor of phosphatidylinositol-3-kinase, nor Akt inhibitor blocked EDHB-induced ROS generation, indicating that EDHB initiates signaling downstream of Akt. DFO also increased ROS production, and this effect was blocked by ODQ, 5-hydroxydecanoate, and N-(2-mercaptopropionyl)glycine, an ROS scavenger. DFO increased cardiomyocyte production of nitrite, a metabolite of NO, and this effect was blocked by an inhibitor of NOS. DFO also spared ischemic myocardium in intact hearts. This infarct-sparing effect was blocked by ODQ, L-NAME, and N-(2-mercaptopropionyl)glycine. Hence, DFO and EDHB stimulate NO-dependent activation of PKG to open mitoK(ATP) channels and produce ROS, which act as second messengers to trigger entrance into the preconditioned state.

ATP-Binding Cassette Transporters↗
PubMed2005

Hypoxia impairs systemic endothelial function in individuals prone to high-altitude pulmonary edema.

RATIONALE: High-altitude pulmonary edema (HAPE) is characterized by excessive pulmonary vasoconstriction and is associated with decreased concentrations of nitric oxide (NO) in the lung. OBJECTIVES: We hypothesized that individuals susceptible to HAPE (HAPE-S) would also have dysfunction of the vascular NO vasodilator pathway during hypoxia in the systemic vasculature. METHODS: During normoxia (FI(O(2)) = 0.21) and 4 hours of normobaric hypoxia (FI(O(2)) = 0.12, corresponding to an altitude of 4,500 m above sea level) endothelium-dependent and endothelium-independent vasodilator responses to intraarterial infusion of acetylcholine (ACh) and sodium nitroprusside, respectively, were measured by forearm venous occlusion plethysmography in nine HAPE-S subjects and in nine HAPE-resistant control subjects. MAIN RESULTS: Pulmonary artery systolic pressure increased from 22 +/- 3 to 33 +/- 6 mm Hg (p < 0.001) during hypoxia in control subjects, and from 25 +/- 4 to 50 +/- 9 mm Hg in HAPE-S subjects (p < 0.001). Despite similar responses during normoxia in both groups, ACh-induced changes in forearm blood flow markedly decreased during hypoxia in HAPE-S subjects (p = 0.01) but not in control subjects. The attenuated vascular response to ACh infusion during hypoxia inversely correlated with increased pulmonary artery systolic pressure (p = 0.04) and decreased plasma nitrite correlated with attenuated ACh-induced vasodilation in HAPE-S subjects (p = 0.02). CONCLUSIONS: Hypoxia markedly impairs vascular endothelial function in the systemic circulation in HAPE-S subjects due to a decreased bioavailability of NO. Impairment of the NO pathway could contribute to the enhanced hypoxic pulmonary vasoconstriction that is central to the pathogenesis of HAPE.

Acetylcholine↗
PubMed2005

Incidence and predictors of target vessel revascularization and clinical event rates of the sirolimus-eluting coronary stent (results from the prospective multicenter German Cypher Stent Registry).

Randomized trials have demonstrated the ability of drug-eluting stents to decrease the risk of restenosis after coronary stent implantation. However, the incidences of major cardiovascular/cerebral adverse events (MACCEs) and target vessel revascularization (TVR) during follow-up in a routine clinical setting remain to be determined. We analyzed data of the multicenter German Cypher Stent Registry. From April 2002 to March 2003, 1,726 patients at 93 hospitals who received >/=1 sirolimus-eluting coronary stent were included. Median follow-up was 6.7 months. During follow-up, death occurred in 1.2% of patients (20 of 1,726), nonfatal myocardial infarction in 2.5% (43 of 1,706), and nonfatal stroke in 0.5% (7 of 1,469). TVR was performed in 8.6% of patients, with percutaneous coronary intervention in 7.3% and coronary artery bypass grafting in 1.5%. The overall rate of MACCEs or TVR was 10.8% (186 of 1,726). Independent predictors of TVR were the target vessel being a bypass graft (odds ratio [OR] 2.43, 95% confidence interval [CI] 1.41 to 4.18, p = 0.001), management of >1 lesion during the same intervention (OR 1.75, 95% CI 1.04 to 2.96, p = 0.035), 2- or 3-vessel disease (OR 1.69, 95% CI 1.05 to 2.72, p = 0.030), and age (per decade; OR 0.82, 95% CI 0.69 to 0.98, p = 0.025). These data confirm the safety and effectiveness of using the sirolimus-eluting stent in daily clinical practice. The management of bypass grafts and multiple lesions in 1 session and the presence of multivessel disease were predictors of MACCEs or TVR.

Angioplasty, Balloon, Coronary↗
PubMed2005

Impaired progenitor cell activity in age-related endothelial dysfunction.

OBJECTIVES: We investigated whether human age-related endothelial dysfunction is accompanied by quantitative and qualitative alterations of the endothelial progenitor cell (EPC) pool. BACKGROUND: Circulating progenitor cells with an endothelial phenotype contribute to the regeneration and repair of the vessel wall. An association between the loss of endothelial integrity and EPC modification may provide a background to study the mechanistic nature of such age-related vascular changes. METHODS: In 20 old and young healthy individuals (61 +/- 2 years and 25 +/- 1 year, respectively) without major cardiovascular risk factors, endothelial function, defined by flow-mediated dilation of the brachial artery via ultrasound, as well as the number and function of EPCs isolated from peripheral blood, were determined. RESULTS: Older subjects had significantly impaired endothelium-dependent dilation of brachial artery (flow-mediated dilation [FMD] 5.2 +/- 0.5% vs. 7.1 +/- 0.6%; p < 0.05). Endothelium-independent dilation after glycerol trinitrate (GTN) was not different, but the FMD/GTN ratio was significantly lower in old subjects (49 +/- 4% vs. 37 +/- 3%; p < 0.05), suggesting endothelial dysfunction. There were no differences in the numbers of circulating EPCs, defined as CD34/KDR or CD133/KDR double-positive cells in peripheral blood. In contrast, lower survival (39 +/- 6 cells/mm(2) vs. 65 +/- 11 cells/mm(2); p < 0.05), migration (80 +/- 12 vs. 157 +/- 16 cells/mm(2); p < 0.01), and proliferation (0.20 +/- 0.04 cpm vs. 0.44 +/- 0.07 cpm; p < 0.05) implicate functional impairment of EPCs from old subjects. The FMD correlated univariately with EPC migration (r = 0.52, p < 0.05) and EPC proliferation (r = 0.49, p < 0.05). Multivariate analysis showed that both functional features represent independent predictors of endothelial function. CONCLUSIONS: Maintenance of vascular homeostasis by EPCs may be attenuated with age based on functional deficits rather than depletion of CD34/KDR or CD133/KDR cells.

AC133 Antigen↗
PubMed2005

Erythrocytes are the major intravascular storage sites of nitrite in human blood.

Plasma levels of nitrite ions have been used as an index of nitric oxide synthase (NOS) activity in vivo. Recent data suggest that nitrite is a potential intravascular repository for nitric oxide (NO), bioactivated by a nitrite reductase activity of deoxyhemoglobin. The precise levels and compartmentalization of nitrite within blood and erythrocytes have not been determined. Nitrite levels in whole blood and erythrocytes were determined using reductive chemiluminescence in conjunction with a ferricyanide-based hemoglobin oxidation assay to prevent nitrite destruction. This method yields sensitive and linear measurements of whole blood nitrite over 24 hours at room temperature. Nitrite levels measured in plasma, erythrocytes, and whole blood from 15 healthy volunteers were 121 plus or minus 9, 288 plus or minus 47, and 176 plus or minus 17 nM, indicating a surprisingly high concentration of nitrite within erythrocytes. The majority of nitrite in erythrocytes is located in the cytosol unbound to proteins. In humans, we found a significant artery-to-vein gradient of nitrite in whole blood and erythrocytes. Shear stress and acetylcholine-mediated stimulation of endothelial NOS significantly increased venous nitrite levels. These studies suggest a dynamic intravascular NO metabolism in which endothelial NOS-derived NO is stabilized as nitrite, transported by erythrocytes, and consumed during arterial-to-venous transit.

Adult↗
PubMed2005

Enzyme-independent nitric oxide formation during UVA challenge of human skin: characterization, molecular sources, and mechanisms.

Many of the local UV-induced responses including erythema and edema formation, inflammation, premature aging, and immune suppression can be influenced by nitric oxide synthase (NOS)-produced NO which is known to play a pivotal role in cutaneous physiology. Besides NOS-mediated NO production, UV radiation might trigger an enzyme-independent NO formation in human skin by a mechanism comprising the decomposition of photo-reactive nitrogen oxides. Therefore, we have examined the chemical-storage forms of potential NO-generating agents, the mechanisms and kinetics of their decomposition, and their biological relevance. In normal human skin specimens we find nitrite and S-nitrosothiols (RSNO) at concentrations 25- or 360-fold higher than those found in plasma of healthy volunteers. UVA irradiation of human skin leads to high-output formation of bioactive NO due to photo-decomposition of RSNO and nitrite which represents the primary basis for NO formation during UVA exposure. Interestingly, reduced thiols strongly augment photo-decomposition of nitrite and are essential for maximal NO release. The enzyme-independent NO formation found in human skin opens a completely new field in cutaneous physiology and will extend our understanding of mechanisms contributing to skin aging, inflammation, and cancerogenesis.

Animals↗
PubMed2005

The emerging biology of the nitrite anion.

Nitrite has now been proposed to play an important physiological role in signaling, blood flow regulation and hypoxic nitric oxide homeostasis. A recent two-day symposium at the US National Institutes of Health highlighted recent advances in the understanding of nitrite biochemistry, physiology and therapeutics.

Animals↗
PubMed2005

Cocoa polyphenols and inflammatory mediators.

Cocoa products are sources of flavan-3-ols, which have attracted interest regarding cardiovascular health. This review provides a survey of our research on the effects of cocoa polyphenols on leukotriene and nitric oxide (NO) metabolism and on myeloperoxidase-induced modification of LDL. Because intake of flavonoid-rich chocolate by human subjects was reported to decrease the plasma concentrations of proinflammatory cysteinyl leukotrienes, we assessed whether cocoa polyphenols inhibited human 5-lipoxygenase, the key enzyme of leukotriene synthesis. (-)-Epicatechin and other cocoa flavan-3-ols proved to be inhibitory at the enzyme level. This action may confer antileukotriene action in vivo. In a double-blind crossover study, 20 individuals at risk for cardiovascular diseases received cocoa beverages with high or low contents of flavan-3-ols. NO-dependent, flow-mediated dilation of the brachial artery and concentrations of nitroso compounds in plasma were measured, and it was shown that ingestion of the high-flavanol coca drink but not the low-flavanol cocoa drink significantly increased plasma concentrations of nitroso compounds and flow-mediated dilation of the brachial artery. Therefore, ingested flavonoids may reverse endothelial dysfunction through enhancement of NO bioactivity. Oxidative modification of LDL appears to be crucial for atherogenesis, and one of the mediators is the proinflammatory proatherogenic enzyme myeloperoxidase. Micromolar concentrations of (-)-epicatechin or other flavonoids were found to suppress lipid peroxidation in LDL induced by myeloperoxidase in the presence of physiologically relevant concentrations of nitrite, an NO metabolite. Adverse effects of NO metabolites, such as nitrite and peroxynitrite, were thus attenuated.

Animals↗
PubMed2005

Reduction of peripheral flow reserve impairs endothelial function in conduit arteries of patients with essential hypertension.

BACKGROUND: A diminished flow reserve in resistance vessels is a hallmark of hypertensive microvascular disease. Hypertension is associated with structural alterations in the microcirculation and a reduced endothelium-dependent dilation in conduit arteries. Both have been demonstrated to predict future cardiovascular events. OBJECTIVE: We hypothesized that a reduced peripheral flow reserve impairs endothelial function in upstream conduit arteries in patients with arterial hypertension. DESIGN: In 43 hypertensive patients (HT) and 38 normotensive controls (NT) endothelial function of the brachial artery was assessed by measurement of flow-mediated dilatation (FMD), using high-resolution ultrasound. Peripheral flow reserve (FR) was determined via measurements of forearm blood flow at rest and during increments of reactive hyperaemia, using venous occlusion plethysmography. RESULTS: FMD was markedly impaired in HT (3.6 +/- 0.3%) as compared with NT (10.2 +/- 0.3%), whereas maximum brachial artery diameter following endothelium-independent dilatation was similar in both groups. In hypertensive patients FR was significantly reduced (HT, 3.2 versus NT, 6.0) during reactive hyperaemia after 5 min of ischaemia. FR was associated with FMD (r = 0.68, P < 0.01). Multiple stepwise regression analysis identified FR as a strong independent variable determining the extent of FMD (r2 = 0.46, P < 0.01). In HT the dose-response curve of FMD upon stepwise increases of FR was shifted significantly to the right. Normalization of FR improved FMD in HT by more than 60%. CONCLUSIONS: In essential hypertension a reduced FR contributes to the endothelial dysfunction of upstream conduit arteries. These findings may have therapeutic and prognostic implications in patients with arterial hypertension.

Adult↗
PubMed2005

Nitric oxide differentially regulates proliferation and mobilization of endothelial progenitor cells but not of hematopoietic stem cells.

To investigate the role of nitric oxide in controlling endothelial progenitor (EPC) and hematopoietic stem cell (HSC) mobilization, wild-type mice, L-NAME treated WT and eNOS-/- mice received either PBS or G-CSF for 5 days. Under unstimulated conditions bone marrow of either L-NAME treated WT and eNOS-/- mice, representing acute and chronic NO-deficiency, showed higher CD34(+)Flk-I+ EPC numbers compared to their WT littermates. Furthermore, CD34(+)Flk-I+ progenitors under NO-deficient conditions showed a higher cell turn over since the proliferation and apoptosis activity under in vivo as well as in vitro conditions were enhanced. In line with this finding bone marrow derived EPC differentiation towards endothelial cells was modulated in an NO-dependent manner. Administration of G-CSF resulted in an increase of EPC within the bone marrow of WT animals with a consecutive release of these cells into the peripheral circulation. Under NO-deficient conditions G-CSF failed to increase EPC numbers. In contrast, the HSC population c-kit(+)Lin- was not influenced by nitric oxide. Thus, NO differentially supports the mobilization of the endothelial committed progenitor subpopulation in bone marrow but does not have an effect on HSC in vivo.

Animals↗
PubMed2004

Nitric oxide in myocardial ischemia/reperfusion injury.

Administration of nitric oxide (NO), NO donors or drugs that enhance NO release (statins, calcium antagonists, ACE-inhibitors, dexamethasone) prior to ischemia protects the myocardium against ischemia/reperfusion injury. While this exogenous administration of NO prior to ischemia can initiate a preconditioning-like phenomenon, endogenous NO-synthase (NOS)-derived NO is not involved in triggering or mediating the early phase of ischemic preconditioning's protection, but does play a pivotal role for initiating and mediating the delayed phase of ischemic preconditioning's protection. The present review now summarizes the importance of endogenous and exogenous NO when given at the time of reperfusion for vascular and myocardial function and morphological outcome following ischemia/reperfusion. Given the inconsistency of the published data, potential confounding factors that might affect experimental results on the role of NO in myocardial ischemia/reperfusion were identified, such as (1) the lack of characterization of the involved NOS isoforms in myocardial ischemia/reperfusion injury in different animal species, (2) the lack of direct measurements of myocardial NO concentration and/or NOS activity to assure sufficient NOS inhibition, (3) the lack of consideration of nonenzymatic NO production as a potential source of NO, and (4) the absence of plasma or blood components in in vitro studies influencing NO delivery and metabolism. Future research on the importance of NO in ischemia/reperfusion injury will have to focus more precisely on the identification and standardization of potential confounding experimental factors that influence synthesis, transport, and interaction of NO with various targets in blood and tissue.

Animals↗
PubMed2004

Circulating NO pool: assessment of nitrite and nitroso species in blood and tissues.

The formation of nitric oxide (NO) has been linked to many regulatory functions in mammalian cells. With the appreciation that NO-mediated nitrosation reactions are involved in cell signaling and pathology there is a need to elucidate and better characterize the different biochemical pathways of NO in vivo. Despite significant methodological advances over the years one major obstacle in assessing the significance of nitrosated species and other NO-related metabolites remains: their reliable measurement in complex biological matrices. In this review we briefly discuss the major routes of NO metabolism and transport in the mammalian circulation, considering plasma, red blood cell, and tissue compartments separately. In addition, we attempt to give a recommendation as to the most appropriate analytical technique and sample processing procedures for the reliable quantification of either species.

Biological Transport↗
PubMed2004

[Safety and current indications during "real life" use of sirolimus-eluting coronary stents in Germany. Results from the prospective multicenter German Cypher Registry].

BACKGROUND: Although randomized, controlled clinical trials (RCTs) showed a reduced target vessel revascularization rate and a good safety profile for the sirolimus-eluting coronary Cypher stent, at least the safety data need to be confirmed by larger data in clinical practice. Under the circumstances of frozen medical budgets in Germany, there may also be a shift toward implantation of a drug-eluting stent (DES) for indications not yet evaluated by RCTs. METHODS: The authors analyzed the data of the German Cypher Registry a nationwide registry which was initiated in parallel to the launch of the first DES, the Cypher stent, in April 2002. RESULTS: From April 2002 until December 2003, 3,579 interventions using a Cypher stent at 102 centers were included in the German Cypher Registry. This reflects a proportion of this DES compared to all stents implanted at the participating centers of < 10%. Patients' median age was 63.4 years (quartiles: 55-70 years) with 75% men. Renal insufficiency was seen in 10.1%, previous myocardial infarction in 37%, prior percutaneous coronary intervention (PCI) in 54.6%, and prior coronary artery bypass grafting (CABG) in 18.7%. In a large proportion of interventions, Cypher stents were implanted in lesions or in clinical situations not yet evaluated by RCTs: 10.1% ST elevation myocardial infarction, 1.8% cardiogenic shock, 2.1% left main stenoses, 5.5% CABG lesions, 23.2% in-stent stenosis, and 6% chronic total occlusions. PCI before DES implantation was performed in 65.5% of cases, a mean of 1.02 +/- 0.43 Cypher stents per lesion were implanted with a median sum length of all Cypher stents per lesion of 18 mm (quartiles: 13-21 mm). Maximum median balloon diameter during stent implantation was 3.00 mm (quartiles: 2.75-3.00 mm). Acute complication rate was low, with 0.2% deaths, 0.3% subacute stent thromboses, 1.3% myocardial infarctions, 2.1% urgent PCIs, and 0.2% CABGs. CONCLUSION: In about one half of the patients included into the German Cypher Registry, the DES were implanted in lesions that were excluded from RCTs. The use of this sirolimus-eluting coronary stent in "real life" conditions was found to be safe concerning acute complications.

Administration, Topical↗
PubMed2004

Coronary flow reserve measurements in hypertension.

Taken together, the diagnostic algorithm is leaded by a simple ECG stress test. In case of ST-segment depression the preferred image test should be stress ECG to bring patients at high risk for significant epicardial coronary artery stenosis to coronary angiography (and revascularization). In case of the lack of wall motion abnormalities (during stress-echo test) or absence of epicardial stenosis one may further assess coronary flow reserve with noninvasive Doppler harmonic echocardiography. For ultimate quantitative assessment invasive procedures, such as argon dilution or intracoronary Doppler techniques, represent the appropriate approach. Treatment of microvascular disease may be followed-up by these new noninvasive diagnostic approaches in future and also, at present, by monitoring ST-segment depression.

Angiography↗
PubMed2004

Chronic treatment with fluvastatin improves smooth muscle dilatory function in genetically determined hyperlipoproteinemia.

We hypothesized that the HMG-CoA reductase inhibitor fluvastatin, does not only improve endothelium-dependent vasorelaxation, but that it also increases vascular smooth muscle reactivity in hyperlipoproteinemia. New Zealand White (NZW) rabbits aged 37 weeks (control), Watanabe Heritable Hyperlipidemic rabbits (WHHL) aged 37 weeks, and WHHL aged 35 weeks with fluvastatin treatment of 17 weeks (10 mg/kg/d) were examined. Aortas were isolated for isometric tension recording. Both endothelium-dependent and independent relaxation were impaired in WHHL. Fluvastatin significantly restored impaired endothelium-independent relaxation (WHHL: 57 +/- 12 versus WHHL+ fluvastatin: 150 +/- 22%; P < 0.05) and in tendency endothelium-dependent relaxation (WHHL: 26 +/- 5 versus WHHL+ fluvastatin: 83 +/- 29%; (P = 0.07)). In parallel, fluvastatin restored nitrite plasma level in hyperlipoproteinemic animals (WHHL: 480 (13-3821) versus WHHL+ fluvastatin: 808 (467-1595) nmol; P < 0.05). Thus, chronic treatment with fluvastatin not only improves endothelial but also vascular smooth muscle function in hyperlipoproteinemia, which may contribute to the beneficial clinical effects of statins.

Animals↗
PubMed2003

Thiols enhance NO formation from nitrate photolysis.

Nitrate is generally considered an inert oxidative breakdown product of nitric oxide (NO). Whereas it has been shown that limited amounts of NO are produced during the photolysis of nitrate in aqueous solution, the photochemistry of nitrate in biological matrices such as plasma is unknown. We hypothesized that thiols, which are ubiquitously present in biological systems, may significantly enhance NO-quantum yields from nitrate photolysis. Exposure of fresh human plasma to high-intensity UV-light resulted in NO-formation (19 +/- 3 nmol/l/min) as measured by gas phase chemiluminescence, and this signal was almost completely abolished by the removal of plasma N-oxides (2 +/- 1 nmol/l/min). Reconstitution of NOx-depleted plasma samples with a physiological concentration of nitrate, but not nitrite, restored photolytic NO-generation to values comparable to naïve plasma. Addition of the thiol-reducing agent, dithiothreitol or the sulfhydryl-bearing amino acid, L-cysteine increased NO-formation above control levels. Thiol-blockade by either N-ethylmaleimide (NEM) or mercuric chloride (HgCl2) reduced basal NO formation from 19 +/- 3 to 7 +/- 2 and 4 +/- 1 nmol/l/min, respectively. Exposure of plasma to UV-light increased NO-adduct concentrations from 18 +/- 5 to 1662 +/- 658 nmol/l. Collectively, our results show that thiols facilitate photolytic conversion of nitrate to NO and NO-adducts such as S-nitrosothiols. This may lead to substantial overestimation of the latter when photolysis-based methodologies are used for their determination. Whether this novel reaction channel also has in vivo relevance remains to be investigated.

Nitrates↗