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Biomedical subjects

Rainer H Böger

Publications and source records attributed to Rainer H Böger.

At least 19 recordsLinked to original sources
PubMed2007

Impact of atorvastatin treatment on platelet-activating factor acetylhydrolase and 15-F(2trans)-isoprostane in hypercholesterolaemic patients.

AIMS: Isoprostanes are the product of free radical oxidation of arachidonic acid, whose hydrolysis from phospholipids is presumably catalysed by phospholipases A(2) (PLA(2)s) such as group IIA or V PLA(2)s, or group VII PLA(2)[platelet-activating factor acetylhydrolase (PAF-AH), lipoprotein-associated phospholipase]. Atorvastatin reduces concentrations of low-density lipoprotein (LDL), with which PAF-AH is associated, and PLA(2)s' protein concentrations. We investigated the effect of atorvastatin on PLA(2)s and PAF-AH activity and the urinary excretion of 15-F(2trans)-isoprostane (15-F(2t)-IsoP, 8-iso-PGF(2alpha), iPF(2alpha)-III). METHODS: Twenty-four hypercholesterolaemic individuals naive to lipid-lowering therapy were randomized to atorvastatin 40 mg or placebo for 6 weeks. The 15-F(2t)-isoP urinary excretion (gas chromatography/mass spectrometry), PAF-AH and group IIA and V PLA(2) activities (photometry) were assessed at baseline and end-point. RESULTS: At end-point, 15-F(2t)-isoP urinary excretion concentrations as well as PLA(2)s' activity were unchanged under atorvastatin (mean change 0.21 +/- 1.79 ng h(-1), 95% confidence interval -0.92, 1.35 and 0.33 +/- 0.94 nmol min(-1) ml(-1), -0.27, 0.93) and under placebo (mean change 0.69 +/- 1.69 ng h(-1), -0.52, 1.90 and 1.29 +/- 2.16 nmol min(-1) ml(-1), -0.25, 2.84). Atorvastatin treatment decreased total (P < 0.001) and LDL-cholesterol (P < 0.001) but had no effect on high-density lipoprotein. PAF-AH activity was lowered in the atorvastatin group (mean change - 5.27+/- 1.96 nmol min(-1) ml(-1), -6.51, -4.03, P < 0.001) but not in the placebo group (mean change 1.02 +/- 1.64 nmol min(-1) ml(-1), 0.15, 2.20), and the change in PAF-AH activity was correlated with that in total (P = 0.03) and LDL-cholesterol (P = 0.03). CONCLUSION: Our results show a lowering effect of atorvastatin on PAF-AH activity associated with its lipid-lowering effect and exclude a key role of PAF-AH in the liberation of 15-F(2t)-isoP from phospholipids.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2006

High-throughput liquid chromatographic-tandem mass spectrometric determination of arginine and dimethylated arginine derivatives in human and mouse plasma.

The balance between nitric oxide (NO) and vasoconstrictors like endothelin is essential for vascular tone and endothelial function. L-Arginine is converted to NO and L-citrulline by NO synthase (NOS). Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of NO formation. ADMA is degraded by dimethylamino dimethylhydrolases (DDAHs), while SDMA is exclusively eliminated by the kidney. In the present article we report a LC-tandem MS method for the simultaneous determination of arginine, ADMA, and SDMA in plasma. This method is designed for high sample throughput of only 20-mul aliquots of human or mouse plasma. The analysis time is reduced to 1.6 min by LC-tandem MS electrospray ionisation (ESI) in the positive mode. The mean plasma levels of l-arginine, ADMA, and SDMA were 74+/-19 (SD), 0.46+/-0.09, and 0.37+/-0.07 microM in healthy humans (n=85), respectively, and 44+/-14, 0.72+/-0.23, and 0.19+/-0.06 microM in C57BL/6 mice. Also, the molar ratios of arginine to ADMA were different in man and mice, i.e. 166+/-50 and 85+/-22, respectively.

Analytic Sample Preparation Methods↗
PubMed2006

Asymmetrical dimethylarginine (ADMA) and coronary endothelial function in patients with coronary artery disease and mild hypercholesterolemia.

OBJECTIVE: To investigate the association of the endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) and coronary endothelial function. METHODS AND RESULTS: In 289 patients with coronary artery disease we assessed coronary endothelium-dependent and -independent vascular responses to intracoronary infusion of acetylcholine, adenosine, and nitroglycerin, respectively, and determined plasma ADMA and l-arginine concentrations by HPLC. After 6 months of treatment with either cerivastatin, nifedipine, cerivastatin+nifedipine, or placebo, coronary vascular function testing as well as ADMA and l-arginine determinations were repeated. We observed no correlation of plasma ADMA or l-arginine concentration and coronary response to acetylcholine, adenosine or nitroglycerin baseline, and no correlation of changes of ADMA or l-arginine plasma concentration with changes in coronary function (all r and rho<0.3, all p>0.05). CONCLUSION: At physiological plasma concentrations ADMA appears to have only little impact on coronary endothelial function.

Acetylcholine↗
PubMed2006

Asymmetric dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter Coronary Artery Risk Determination investigating the Influence of ADMA Concentration (CARDIAC) study.

BACKGROUND: Asymmetric dimethylarginine (ADMA) plasma levels have been shown to be elevated in diseases related to endothelial dysfunction such as hypertension, hyperlipidemia, diabetes mellitus, and others. It has been shown that ADMA predicts cardiovascular mortality in patients who have coronary heart disease (CHD). However, the question whether ADMA is an independent risk factor for CHD still remains unresolved. METHODS: The CARDIAC study is a multicenter case-control study, designed to detect differences in ADMA plasma levels between patients with CHD and controls from the general population. We included in our analysis 131 cases and 131 controls, matched for age, sex, and body mass index. RESULTS: We found that cases had higher ADMA plasma levels than controls (0.70 micromol/L [0.59-0.87 micromol/L] vs 0.60 micromol/L [0.54-0.69 micromol/L], P < .001). To evaluate the predictive power of ADMA regarding CHD, we calculated 2 multivariate logistic regression models including laboratory parameters and traditional risk factors. The odds ratio for ADMA in the multivariate model including the laboratory characteristics was 2.59 (1.61-4.17; P < .001); the odds ratio for the multivariate model including other risk factors was 6.04 (2.56-14.25; P < .001) for the third tertile (>0.72 micromol/L) versus the first (<0.58 micromol/L). CONCLUSIONS: We conclude from the results of our study that ADMA is an independent risk factor for CHD.

Aged↗
PubMed2006

Telmisartan improves insulin sensitivity in nondiabetic patients with essential hypertension.

Hypertension is a cardiovascular risk factor commonly associated with insulin resistance, the metabolic syndrome, and type 2 diabetes mellitus. Recent in vitro data indicate that certain angiotensin receptor antagonists, for example, telmisartan, activate peroxisome proliferator-activated receptor gamma (PPAR-gamma) and increase adiponectin protein content in adipocytes. By this means, they may improve insulin sensitivity in vivo. To investigate the effect of antihypertensive treatment on insulin sensitivity and fasting adiponectin serum levels, 37 nondiabetic patients with essential hypertension were randomized to receive telmisartan, the calcium channel blocker nisoldipine, or their combination for 6 weeks in a prospective, parallel group study. Fasting serum glucose, insulin, and adiponectin were evaluated before, 3 weeks (low dose), and 6 weeks (high dose) after initiation of treatment. Furthermore, the effect of telmisartan on PPAR-gamma receptor activity was investigated in vitro using a PPAR-gamma reporter gene assay. As reported previously, telmisartan significantly enhanced PPAR-gamma receptor activity in vitro. At baseline, a positive correlation between insulin serum levels and body mass index of investigated subjects was observed, whereas body mass index and serum adiponectin levels were negatively associated. High-dose treatment with telmisartan but not with nisoldipine reduced serum insulin levels as well as the homeostasis model assessment of insulin resistance, but did not affect serum adiponectin levels. In conclusion, in our study cohort of nondiabetic patients with essential hypertension, telmisartan improved insulin sensitivity by mechanisms apparently not involving adiponectin induction. Future studies will demonstrate whether these telmisartan-induced effects may contribute to a blood pressure-independent reduction in cardiovascular morbidity.

Adiponectin↗
PubMed2006

Asymmetric dimethylarginine (ADMA): a novel risk marker in cardiovascular medicine and beyond.

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), an endogenous messenger molecule formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA)--an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Supplementation with L-arginine has been shown to restore vascular function and to improve the clinical symptoms of various diseases associated with vascular dysfunction.

Arginine↗
PubMed2006

Live and let die: asymmetric dimethylarginine and septic shock.

Nitric oxide (NO) is an important mediator of host defence and of vascular tone. In septic shock, upregulation of inducible NO synthase leads to the production of vast amounts of NO, which contribute to pathogen elimination but also to inappropriate vasodilation and to loss of vascular resistance. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthases shown to contribute to the regulation of vascular tone. ADMA was recently identified as a marker of organ dysfunction and mortality in intensive care patients and as a novel cardiovascular risk factor. In the present issue of Critical Care, a study by O'Dwyer and colleagues identifies ADMA as a potential regulator of NO production in septic shock. Being an inhibitor of NO production, ADMA may at least partly counteract pathological hypotension, but at the same time may impair the NO-dependent host defence. A mechanism is proposed by which the interplay between ADMA and inducible NO synthase activity is mediated. ADMA levels should be determined in future studies evaluating the regulation of NO in the intensive care setting.

Arginine↗
PubMed2006

Renal impairment: a challenge for opioid treatment? The role of buprenorphine.

Impairment of renal function is common among elderly patients due to an age-related decline in renal excretory function. In addition, many diseases such as hypertension and diabetes mellitus are associated with an accelerated decline in renal function. Renal dysfunction affects the metabolism of compounds and thus has important therapeutic consequences for drug safety. For pain patients who have reduced renal function such as those in palliative care, most opioids used for chronic pain treatment should be administered at reduced dosages, with increased dosage intervals, or not at all because of the risk of accumulation of the parent compound or its metabolites. For instance, for morphine or codeine, active metabolites are formed in the liver and cleared by the kidney and may therefore accumulate in cases of renal dysfunction. In contrast, buprenorphine can be administered at normal doses in patients with renal dysfunction because it is mainly excreted through the liver. In patients undergoing regular haemodialysis treatment, removal of an opioid during dialysis varies between individuals based upon a number of factors including the dialysis technique used. Morphine appears to be difficult to process in haemodialysis patients due to possible 'rebound' of metabolites between dialysis sessions. By contrast, the pharmacokinetics of buprenorphine are unchanged in haemodialysis patients, which means that there is no need for dose-reduction with this drug. Thus, in patients with reduced renal function, chronic renal insufficiency and haemodialysis, buprenorphine appears to be a safe choice when opioid treatment is initiated.

Adult↗
PubMed2005

Elevation of asymmetrical dimethylarginine (ADMA) and coronary artery disease in men with erectile dysfunction.

BACKGROUND: Coronary artery disease (CAD) and erectile dysfunction (ED) of vascular origin are closely related and share common risk factors. The endogenous NO synthase inhibitor asymmetrical dimethylarginine (ADMA) has recently been identified as an independent risk marker for cardiovascular disease and it was the purpose of the present study to investigate the role ADMA in ED with and without underlying CAD. METHODS AND RESULTS: We determined plasma ADMA levels in 132 men with ED. Patients were divided into a group of 56 men with underlying CAD (ED-CAD) and a group of 76 men without clinical evidence for underlying CAD (ED-No-CAD). Diagnosis of ED was based on the International Index of Erectile Function Score (IIEF-5). Plasma ADMA concentrations in the ED-CAD group were elevated as compared to the ED-No-CAD group, median (IQR): 0.76 (0.65-0.91) micromol/l ADMA vs. 0.49 (0.36-0.71) micromol/l, p < 0.001. In a multiple logistic regression analysis adjusting for hypertension, hypercholesterolemia, low HDL cholesterol and diabetes or fasting glucose > or =6.1 mmol/l, ADMA remained a strong and independent predictor for presence of CAD. Odds ratios for second and third tertiles as compared to lowest tertile of plasma ADMA were 3.3 (95%CI, 1.1-10.3; p = 0.041) and 8.7 (95%CI, 2.8-27.2; p < 0.001), respectively. CONCLUSION: As elevation of ADMA has been found to be associated with many risk factors for both CAD and ED, our data provide further strong evidence for the close interrelation of CAD and ED. Determination of ADMA may help to identify underlying cardiovascular disease in men with ED.

Age Distribution↗
PubMed2005

Elevation of asymmetric dimethylarginine in patients with unstable angina and recurrent cardiovascular events.

AIMS: We investigated the role of asymmetric dimethylarginine (ADMA) for clinical outcome of patients with unstable angina. METHODS AND RESULTS: Forty-five patients with stable angina, 36 patients with unstable angina, and 40 healthy controls were included in this study. Coronary artery disease (CAD) patients were prospectively followed for 1 year. ADMA levels were measured at baseline and after 6 weeks using a validated ELISA. Baseline ADMA concentration in controls was significantly lower than in patients with CAD (0.59+/-0.23 vs. 0.76+/-0.17 micromol/L; P<0.001). Patients with unstable angina had significantly higher baseline ADMA levels than patients with stable angina (0.82+/-0.18 vs. 0.73+/-0.15 micromol/L; P=0.01). There was a significant reduction of ADMA levels at 6 weeks after percutaneous coronary intervention (PCI) in patients with unstable angina who experienced no recurrent cardiovascular event (from 0.81+/-0.14 to 0.73+/-0.19 micromol/L; P<0.05). In contrast, patients with unstable angina who had an event showed no significant decrease in ADMA at 6 weeks. Actuarial survival analysis showed a significantly higher event rate in patients with persistently elevated ADMA plasma concentrations. CONCLUSION: ADMA is significantly elevated in patients with unstable angina. A reduced ADMA level at 6 weeks after PCI may indicate a decreased risk of recurrent cardiovascular events.

Adult↗
PubMed2005

Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials.

Evidence has accumulated that asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. ADMA inhibits vascular NO production at concentrations found in pathophysiological conditions; it also causes local vasoconstriction when infused intra-arterially. ADMA is increased in the plasma of humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, chronic heart failure, and other clinical conditions. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation or reduced NO metabolite levels. In several prospective and cross-sectional studies, ADMA has evolved as a marker of cardiovascular risk. Moreover, prospective clinical studies have suggested that it may play a role as a novel cardiovascular risk factor. Zoccali and coworkers were the first to show that elevated ADMA is associated with a three-fold increased risk of future severe cardiovascular events and mortality in patients undergoing hemodialysis. Valkonen and coworkers demonstrated in a nested case-control study that elevated ADMA was associated with a four-fold increased risk for acute coronary events in clinically healthy, nonsmoking men. In patients with stable angina pectoris, preinterventional ADMA indicates the risk of developing restenosis or severe clinical events after coronary intervention. Furthermore, in humans with no underlying cardiovascular disease who are undergoing intensive care unit treatment, ADMA is a marker of the mortality risk. A number of additional prospective clinical trials are currently under way in diverse patient populations, among them individuals with congestive heart failure, cardiac transplantation patients, and patients with pulmonary hypertension. In summary, an increasing number of prospective clinical trials have shown that the association between elevated ADMA levels and major cardiovascular events and total mortality is robust and extends to diverse patient populations. However, we need to define more clearly in the future who will profit from ADMA determination, in order to use this novel risk marker as a more specific diagnostic tool.

Arginine↗
PubMed2005

ADMA and oxidative stress may relate to the progression of renal disease: rationale and design of the VIVALDI study.

The renin angiotensin system has been shown to be involved in the pathogenesis of vascular and renal sequelae of diabetes mellitus. In type 2 diabetes mellitus, angiotensin receptor blockers have been shown to exert clinical benefit by reducing the progression of diabetic nephropathy. They also improve endothelium-mediated vascular function. The latter effect is partly due to the reduction of angiotensin II-associated oxidative stress. Moreover, small clinical studies have shown that treatment with angiotensin receptor blockers also reduces the circulating levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. In the VIVALDI trial, the ability of the angiotensin receptor blocker telmisartan to reduce the progression of diabetic nephropathy (associated with proteinuria) in comparison with valsartan in more than 800 patients with type 2 diabetes during 1 year of treatment is being studied. In order to gain more detailed insight into the potential pathomechanisms associated with this effect, further end-points have been defined. Among these are the circulating levels of ADMA and the urinary excretion rate of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha). The former is an endogenous inhibitor of NO-mediated vascular function(s) and a prospectively determined marker of major cardiovascular events and mortality; the latter is a lipid peroxidation product resulting from the nonenzymatic peroxidation of arachidonic acid, which exerts detrimental vascular effects similar to those of thromboxane A2. Urinary 8-iso-PGF2alpha has been shown in clinical studies to be an independent marker of cardiovascular disease. Highlighting the effects of telmisartan on ADMA and 8-iso-PGF levels in such a large cohort of diabetic patients will enhance our understanding of the roles of dysfunctional NO metabolism and redox mechanisms in the pathogenesis of end-organ damage and its prevention by pharmacotherapy with angiotensin receptor blockers.

Adult↗
PubMed2005

Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality.

The endothelium plays a crucial role in the maintenance of vascular tone and structure by releasing the endothelium-derived vasoactive mediator, nitric oxide (NO). NO is formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA) - an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Accumulating evidence from prospective clinical studies suggests that elevated plasma or serum levels of ADMA are associated with an increased risk of major adverse cardiovascular events. This article gives an updated overview of the currently available literature on ADMA and cardiovascular disease from prospective clinical trials. Recently, advances have been made in the development of analytical methods that are reliable and fast enough to allow determination of ADMA in clinical routine.

Animals↗
PubMed2005

L-Arginine improves vascular function by overcoming deleterious effects of ADMA, a novel cardiovascular risk factor.

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), an endogenous messenger molecule formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA)--an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Supplementation with L-arginine has been shown to restore vascular function and to improve the clinical symptoms of various diseases associated with vascular dysfunction.

Arginine↗
PubMed2004

Determination of NG,NG-dimethyl-L-arginine, an endogenous NO synthase inhibitor, by gas chromatography-mass spectrometry.

A fully validated gas chromatographic-mass spectrometric (GC-MS) method for the accurate and precise quantification of NG,NG-dimethyl-L-arginine (asymmetric dimethylarginine, ADMA), an endogenous inhibitor of the NO synthase, in cell culture supernatants and in small volumes of plasma is described. ADMA was concentrated by solid phase extraction and converted to its methyl ester pentafluoropropionic amide derivative. The derivatives were analyzed without any further purification. Using gas chromatography-chemical ionization mass spectrometry, fragment ions at m/z 634 and m/z 640 were obtained for ADMA and for NG,NG-[2H6]-dimethyl-L-arginine ([2H6]-ADMA) as internal standard, respectively. [2H6]-ADMA was synthesized by reaction of L-ornithine fastened at bromcyan-agarose with dimethylamine. The limit of detection of the method was 2 fmol, while the limit of quantitation for cell culture supernatants was 0.05 microM. The method was validated in a concentration range of 0-1.2 microM in cell culture medium and 0-2 microM in 50 microl aliquots of human plasma. The precision was > or =97% and the accuracy was determined to be > or =94%. This method is fast, rugged and an alternative to high performance liquid chromatography (HPLC) analysis of ADMA in cell culture supernatants and small volumes of human plasma.

Arginine↗