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Biomedical subjects

R H Böger

Publications and source records attributed to R H Böger.

At least 19 recordsLinked to original sources
PubMed2005

Increased urinary excretion of 8-iso-prostaglandin F2alpha in patients with HFE-related hemochromatosis: a case-control study.

The hypothesis according to which iron overload could be harmful has been extensively and controversially discussed in the literature. One underlying pathological mechanism may be elevated oxidative stress. Thus, we studied the correlation between hemochromatosis and an established marker of oxidative stress, 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha, iPF2alpha-III, 15-F2t-IsoP). We enrolled 21 patients with hemochromatosis, positive for the homozygous C282Y mutation in the HFE gene, and 21 healthy controls frequency-matched by age and gender in a case-control study design. The objective was to show that iron overload in HFE-related hemochromatosis is associated with increased oxidative stress assessed through 8-iso-PGF(2alpha) urinary excretion, and that oxidative stress is impacted by iron-removal treatment (phlebotomy). Study parameters were transferrin saturation, 8-iso-PGF(2alpha) urine excretion, transferrin, ferritin, serum iron, and vitamins A and E for all participants. Iron concentration in the liver and non-transferrin-bound iron were measured in patients only. We found a significant difference in 8-iso-PGF2alpha in patients (245 [interquartile range 157-348] pg/mg creatinine) compared with controls (128 [106-191] pg/mg creatinine, P = 0.002). Vitamin A was significantly reduced in cases (0.34 [0.25-1.83] microg/ml compared to 3.00 [2.11-3.39] microg/ml, P < 0.001), while vitamin E did not show a significant difference in cases (14.7 [11.5-18.1] microg/ml) compared with controls (14.9 [13.1-19.2] microg/ml, P = 0.52). After phlebotomy treatment and normalization of the iron parameters in the hemochromatosis group, serum vitamin A levels were significantly increased (1.36 [1.08-1.97] microg/ml, P = 0.035 vs. baseline, P < 0.001 vs. controls) and 8-iso-PGF2alpha urinary excretion was lowered to control levels (146 [117-198] pg/mg creatinine, P = 0.38 vs. controls). In our study, HFE-related hemochromatosis was associated with increased oxidative stress and hypovitaminemia A in C282Y homozygotes. The increased oxidative stress was reversible by normalization of the iron load by phlebotomy. Thus, phlebotomy is an effective and adequate means for reducing oxidative stress in these patients.

Adult↗
PubMed2005

Determination of a reference value for N(G), N(G)-dimethyl-L-arginine in 500 subjects.

BACKGROUND: Asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of NO-synthase. In the last years ADMA has emerged as a cardiovascular risk factor. The aim of this study was to determine a reference value for ADMA. METHODS: Plasma samples of 500 healthy subjects in the 19-75 year age group were analyzed. Exclusion criteria from this study were smoking, any known significant disease, body-mass-index (BMI) above 30 kg m(-2), elevated plasma lipid levels, impaired renal function, hypertension, and intake of any medication. The ADMA levels were determined by ELISA, (DLD Diagnostics, Hamburg, Germany). RESULTS: Mean ADMA plasma concentration of the total population was 0.69 micromol L(-1) (SD 0.20) and 95% of the measured values were in the range from 0.36 micromol L(-1) to 1.17 micromol L(-1). Women below 50 years of age had lower ADMA levels than men below 50 years of age [0.62 (0.17) micromol L(-1) vs. 0.69 (0.19) micromol L(-1); P = 0.001] and woman above 50 years of age had higher ADMA levels than men above 50 years of age [0.80 (0.22) micromol L(-1) vs. 0.73 (0.20) micromol L(-1); P = 0.036]. A regression analysis of ADMA levels and age was performed for each sex. The regression factor was r = 0.444 for women in a squared regression model (P < 0.001) and r = 0.212 for men in a linear regression model (P < 0.001). CONCLUSION: The study was able to define a reference value for ADMA plasma levels with 0.36-1.17 micromol L(-1) and found sex dependent correlations between ADMA and age. Women showed a significant increase in ADMA plasma levels with onset of menopause.

Adult↗
PubMed2004

Low dialysance of asymmetric dimethylarginine (ADMA)--in vivo and in vitro evidence of significant protein binding.

BACKGROUND: Increased blood levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) predict cardiovascular mortality in patients with end-stage renal disease. Despite its low molecular weight, available information on the impact of hemodialysis (HD) on ADMA plasma levels is controversial. METHODS: We assessed plasma concentrations, dialyzer clearance and total amount of ADMA removed in 30 patients with end-stage renal disease during regular HD. In addition, plasma ADMA levels were assessed in 10 patients with acute renal failure treated with extended HD. RESULTS: Regular HD decreased plasma creatinine (from 774 +/- 42 to 312 +/- 17 micromol/l) and urea (from 24.5 +/- 1.5 to 8.4 +/- 0.5 mmol/l) concentrations significantly (both p < 0.001), whereas plasma ADMA remained unchanged (4.35 +/- 0.19 vs. 4.76 +/- 0.24 micromol/l). ADMA clearance was 92 +/- 6 ml/min, and the total amount removed in the spent dialysate was 37 +/- 4 micromol. The clearances of creatinine (161 +/- 3 ml/min) and of urea (173 +/- 3 ml/min) were significantly higher. Furthermore, even during extended HD, plasma ADMA concentrations did not decrease significantly (1.73 +/- 0.22 vs. 1.63 +/- 0.18 micromol/l). CONCLUSION: In conclusion, dialysance of ADMA is markedly lower than expected from its molecular weight because of significant protein binding of the substance. Since markedly increased ADMA blood concentrations have been linked to cardiovascular complications due to atherosclerosis in patients with ESRD, new strategies should be evaluated to remove this putative uremic toxin.

Arginine↗
PubMed2003

[Drug therapy of coronary heart disease--are therapeutic guidelines being paid attention to?].

Drug therapy of coronary heart disease (CHD) is a life-long treatment. With every change from in-patient to out-patient care and back, changes in medication may occur. If a drug is chosen which provides no proven long-term benefit in terms of reduced morbidity and mortality, the expected therapeutic benefit may be missed. We investigated in 224 patients admitted to the medical departments of two hospitals (one with a specialized Cardiology Unit, one with a General Internal Medicine Unit) the prescriptions for CHD by the general practitioner before admittance into the hospital, the prescriptions recommended at the time of discharge, and the prescriptions made by the general practitioner three months after discharge. Of the drug classes with proven effects on morbidity and mortality (acetylsalicylic acid, beta-blockers, statins, ACE inhibitors), none had sufficiently high prescription rates. Prescription rates at discharge were 30% for beta-blockers and statins, 70% for acetylsalicylic acid, and 60% for ACE inhibitors. Only in patients with acute myocardial infarction were the prescription rates for these drug classes higher at this time point. The presence of contraindications was not of prime importance for the low prescription rates, as even in patients without contraindications prescription rates were not significantly higher than in the total patient cohort. Out of the patients with hypercholesterolemia, one third of those treated in the Cardiology Department and two thirds of those treated in the General Internal Medicine Department were not given any lipid-lowering medication. Prescription rates for those drug classes that provide symptomatic relief but have little impact on mortality rates (calcium channel blockers, nitrates) were high in both hospitals. The present study shows that evidence-based guidelines for the drug treatment of coronary heart disease are not adequately put into practice.

Adrenergic beta-Antagonists↗
PubMed2001

[Homocysteine, endothelial dysfunction and cardiovascular risk: pathomechanisms and therapeutic options].

Elevated homocyst(e)ine plasma concentrations are an independent risk factor for cardiovascular disease. Hyperhomocyst(e)inaemia is common in patients with peripheral arterial occlusive disease, coronary heart disease, cerebrovascular disease, carotid artery stenosis and venous thromboembolism. Endothelial dysfunction may be one underlying cause leading to proatherogenic effects associated with hyperhomocyst(e)inaemia. However, the mechanisms which lead to impaired endothelial function in hyperhomocyst(e)inaemia are not fully understood. Recent evidence suggests that homocyst(e)ine may interact with physiological mediators of the endothelial matrix. Oxidative mechanisms and decreased biological activity of endothelium-derived nitric oxide (NO) may also contribute to homocyst(e)ine-associated endothelial dysfunction. B vitamins are essential cofactors in the metabolism of homocyst(e)ine to methionine via the remethylation-pathway (vitamin B12, folic acid) and to cystathionine via the transsulphuration-pathway (vitamin B6). Dietary deficiencies of folic acid, vitamin B12, and vitamin B6 appear to be common among elderly people in the western world and represent one pathogenic factor related to the incidence of hyperhomocyst(e)inaemia. Several studies have demonstrated that dietary supplementation with folic acid and the vitamins B12 and B6 is an efficient means to decrease plasma homocyst(e)ine. No clinical studies are available to date to prove whether reducing homocyst(e)ine levels to the normal range by supplementary B vitamins will also beneficially affect vascular function or cardiovascular risk. Furthermore it is unknown whether moderately elevated homocyst(e)ine concentrations per se may predispose to development of vascular disease, or whether homocyst(e)ine is an indirect marker of cardiovascular disease. Further investigations will be necessary to elucidate the causal relationship between elevated homocyst(e)ine plasma concentrations and the incidence of cardiovascular events, especially since the therapeutic strategies in hyperhomocyst(e)inaemia would differ depending on the underlying pathophysiological mechanisms.

Adult↗
PubMed2001

Endothelium-dependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina: lack of effect of oral L-arginine on endothelial function, oxidative stress and exercise performance.

OBJECTIVES: This study was designed to determine the effect of two weeks' treatment with L-arginine on the ratio of plasma L-arginine to asymmetric dimethylarginine (ADMA), oxidative stress, endothelium-dependent vasodilatation to acetylcholine, exercise performance and heart rate variability in men with stable angina. BACKGROUND: The ratio of plasma L-arginine:ADMA has been proposed as a determinant of endothelium-dependent dilation; dietary supplementation with L-arginine has been shown to improve endothelium-dependent vasodilation and symptoms in some conditions. METHODS: Men (n = 40) with stable angina, at least one epicardial coronary artery with a stenosis >50% and a positive exercise test were randomized to receive L-arginine (15 g daily) or placebo for two weeks according to a double-blind parallel-group design. Plasma L-arginine, ADMA, 8-epi-prostaglandin F2alpha (a marker of oxidative stress) and forearm vasodilator responses to brachial artery infusion of nitroprusside and acetylcholine (+/-L-arginine) were measured. A standard Bruce protocol exercise test was performed before and at the end of the treatment period. RESULTS: Plasma L-arginine increased after oral L-arginine, whereas ADMA remained unchanged, leading to an increase in the L-arginine/ADMA ratio of 62 +/- 11% (mean +/- SE, p < 0.01). Despite a significant enhancement in acetylcholine response by intra-arterial L-arginine at baseline, this response remained unchanged after oral L-arginine. Measures of oxidative stress and exercise performance after L-arginine/placebo were similar in placebo and active groups. CONCLUSIONS: In men with stable angina, an increase in plasma L-arginine/ADMA ratio after two weeks' oral supplementation with L-arginine is not associated with an improvement in endothelium-dependent vasodilatation, oxidative stress or exercise performance.

Administration, Oral↗
PubMed2001

Relationship of asymmetric dimethylarginine to dialysis treatment and atherosclerotic disease.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Its concentration is elevated in patients with end-stage renal disease (ESRD), in part because it is excreted via the kidneys. In addition, ADMA is degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylamine. Activity of DDAH is decreased by oxidized low density lipoprotein (LDL) or tumor necrosis factor-alpha (TNF-alpha) in vitro yielding increased levels of ADMA. Furthermore, plasma levels of ADMA are elevated in hyperhomocyst(e)inemia and in hypertensive patients on a high salt diet. Data from several experimental studies suggest that ADMA concentrations in a pathophysiologically high range (3 to 10 micromol/L) significantly inhibit vascular NO formation by NO synthase in the presence of L-arginine in isolated human blood vessels, cultured macrophages, and in cultured endothelial cells. It has been well demonstrated that ADMA accumulates in chronic renal failure. Although there is controversy concerning the absolute concentration of ADMA, all authors found a two- to sixfold increase in ADMA levels in patients in chronic renal failure as compared to controls. Different dialysis treatment strategies differentially affect ADMA levels. The presence of atherosclerosis is associated with higher ADMA levels in patients with normal renal function as well as in dialysis patients, but this phenomenon may be unrelated to renal handling of ADMA. Reduced NO elaboration secondary to accumulation of ADMA may be an important pathogenic factor for atherosclerosis in chronic renal failure and ADMA may be a new uremic toxin. Clinical studies on the effect of ADMA are needed to further elucidate its pathophysiological role in atherosclerosis and uremia.

Arginine↗
PubMed2001

The clinical pharmacology of L-arginine.

L-Arginine (2-amino-5-guanidinovaleric acid) is the precursor of nitric oxide, an endogenous messenger molecule involved in a variety of endothelium-mediated physiological effects in the vascular system. Acute and chronic administration of L-arginine has been shown to improve endothelial function in animal models of hypercholesterolemia and atherosclerosis. L-Arginine also improves endothelium-dependent vasodilation in humans with hypercholesterolemia and atherosclerosis. The responsiveness to L-arginine depends on the specific cardiovascular disease studied, the vessel segment, and morphology of the artery. The pharmacokinetics of L-arginine have recently been investigated. Side effects are rare and mostly mild and dose dependent. The mechanism of action of L-arginine may involve nitric oxide synthase substrate provision, especially in patients with elevated levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine. Endocrine effects and unspecific reactions may contribute to L-arginine-induced vasodilation after higher doses. Several long-term studies have been performed that show that chronic oral administration of L-arginine or intermittent infusion therapy with L-arginine can improve clinical symptoms of cardiovascular disease in man.

Animals↗
PubMed2001

Drug interactions of the statins and consequences for drug selection.

Cholesterol-lowering drugs such as HMG-CoA reductase inhibitors ("statins") are increasingly used in hypercholesterolemic patients who suffer from multiple concomitant diseases, and are therefore taking multiple drugs. The statins do not differ in their mechanism of action (pharmacodynamics), but there are differences in the affinity to the target enzyme as well as differences in pharmacokinetic properties, which need to be considered when choosing a statin for a specific patient. The most critical side effect of statins is development of myopathy, which becomes evident as muscle pain, weakness, and elevation of serum creatine kinase activity. The incidence of myopathy is usually low. However, myopathy and rhabdomyolysis are more frequent when statins are combined with other drugs that inhibit cytochrome P450-dependent metabolism of statins in the liver (e.g., itraconazole, erythromycin). Drug interactions can thus significantly increase the risk associated with statin therapy. Oral bioavailability of the statins varies considerably. Besides the absolute rate of oral bioavailability, it is important to know the relative difference between intestinal absorption rate and rate of oral bioavailability in order to assess the potential for drug-drug interactions. Statins that are not metabolized by a single cytochrome P450 isoenzyme, and have a high bioavailability, are the least prone to drug interactions.

Anticholesteremic Agents↗
PubMed2001

Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans.

Hyperhomocyst(e)inaemia is associated with endothelial dysfunction in animals and humans. Mechanisms responsible for endothelial dysfunction in hyperhomocyst(e)inaemia are poorly understood, but may involve impaired bioavailability of endothelium-derived nitric oxide (NO). We hypothesized that acute elevation of homocyst(e)ine by oral methionine loading may stimulate the formation of asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, due to a transmethylation reaction during the formation of homocyst(e)ine from methionine. We studied nine healthy human subjects (five males, four females) aged 29+/-2 years. Flow-mediated vasodilation (FMD) in the brachial artery (endothelium-dependent) and vasodilation induced by nitroglycerine (endothelium-independent) were measured with high-resolution ultrasound before and 8 h after oral methionine (100 mg/kg in cranberry juice) or placebo (cranberry juice), on separate days and in random order. Plasma homocyst(e)ine and ADMA concentrations were measured by specific HPLC methods. After a methionine bolus, elevation of homocyst(e)ine (28.4+/-3.5 micromol/l) was associated with an increased plasma concentration of ADMA (2.03+/-0.18 micromol/l) and reduced FMD (1.54+/-0.92%). Placebo had no effect on these parameters. There was a significant inverse linear relationship between ADMA concentration and FMD (r=-0.49; P<0.05), which was stronger than the relationship between the homocyst(e)ine concentration and FMD (r=-0.36; not significant). We conclude that acute elevation of the homocyst(e)ine concentration impairs vascular endothelial function by a mechanism in which an elevated concentration of ADMA may be involved. This finding may have importance for understanding the mechanism(s) leading to homocyst(e)ine-associated vascular disease, and its potential treatment.

Acute Disease↗
PubMed2000

Endogenous nitric oxide synthase inhibitors are responsible for the L-arginine paradox.

L-Arginine, the substrate of nitric oxide (NO) synthases (NOSs), is found in the mammalian organism at concentrations by far exceeding K(M) values of these enzymes. Therefore, additional L-arginine should not enhance NO formation. In vivo, however, increasing L-arginine concentration in plasma has been shown repeatedly to increase NO production. This phenomenon has been named the L-arginine paradox; it has found no satisfactory explanation so far. In the present work, evidence for the hypothesis that the endogenous NOS inhibitors methylarginines, asymmetric dimethylarginine being the most powerful (IC(50) 1.5 microM), are responsible for the L-arginine paradox is presented.

Animals↗
PubMed2000

LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases.

Asymmetrical dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor. It is formed by protein arginine N-methyltransferases (PRMTs), which utilize S-adenosylmethionine as methyl group donor. ADMA plasma concentration is elevated in hypercholesterolemia, leading to endothelial dysfunction and producing proatherogenic changes of endothelial cell function. Four different isoforms of human PRMTs have been identified. Because the release of ADMA from human endothelial cells is increased in the presence of native or oxidized LDL cholesterol, we investigated the potential involvement of PRMT activity and gene expression in this effect. We found that the production of ADMA by human endothelial cells is upregulated in the presence of methionine or homocysteine and inhibited by either of the methyltransferase inhibitors S-adenosylhomocysteine, adenosine dialdehyde, or cycloleucine. This effect is specific for ADMA but not symmetrical dimethylarginine. The upregulation of ADMA release by native and oxidized LDL is abolished by S-adenosylhomocysteine and by the antioxidant pyrrollidine dithiocarbamate. Furthermore, a methyl-(14)C label is transferred from S-adenosylmethionine to ADMA but not symmetrical dimethylarginine, in human endothelial cells. The expression of PRMTs is upregulated in the presence of native or oxidized LDL. Our data suggest that the production of ADMA by human endothelial cells is regulated by S-adenosylmethionine-dependent methyltransferases. This activity is upregulated by LDL cholesterol, which may be due in part to the enhanced gene expression of PRMTs. In concentrations reached by stimulation of methyltransferases (5 to 50 micromol/L), ADMA significantly inhibited the formation of (15)N-nitrite from L-[guanidino-(15)N(2)]arginine. These findings suggest a novel mechanism by which ADMA concentration is elevated in hypercholesterolemia, leading to endothelial dysfunction and atherosclerosis.

Arginine↗
PubMed2000

Assessment of nitric oxide synthase activity in vitro and in vivo by gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric method for the determination of nitric oxide synthase activity is described. The method is based on the gas chromatographic-mass spectrometric measurement of L-[15N2]arginine-derived [15N]nitrite as its pentafluorobenzyl derivative in the negative-ion chemical ionization mode. Application of the method to the analysis of [15N]nitrite formation by purified neuronal nitric oxide synthase revealed K(M) values of 3.1 microM by Hanes and 4.6 microM by Lineweaver-Burk for L-[15N2]arginine. The corresponding Vmax values were 0.204 and 0.228 micromol [15N]nitrite min(-1) mg(-1) NOS, respectively. N(G)-Nitro-L-arginine and N(G),N(G)-dimethylarginine (asymmetric dimethylarginine) were identified by this method as the most potent enzyme inhibitors. Nitric oxide synthase activity was also assessed in vivo by i.v. injection of L-[15N2]arginine in a rat and determination of plasma [15N]nitrite and [15N]nitrate. The assay described in this work allows for accurate, specific and highly sensitive determination of nitric oxide synthase activity in vitro and in vivo.

Animals↗
PubMed2000

Role of nitric oxide in the vasodilator effect of recombinant human growth hormone in patients with dilated cardiomyopathy.

OBJECTIVE: Dilated cardiomyopathy is characterized by elevated arterial vascular resistance and impaired nitric oxide (NO)-dependent vasodilation. Insulin-like growth factor-I (IGF-I) has been shown to stimulate endothelial NO-synthase resulting in endothelium-dependent vasodilation. Growth hormone (GH) substitution therapy leads in GH-deficient patients to significant increases of IGF-I which may alter systemic vascular resistance by stimulating NO production. This study was designed to evaluate the effects of treatment with recombinant human growth hormone (GH) on NO production and NO-dependent vascular effects in patients with dilated cardiomyopathy. METHODS: 50 patients with dilated cardiomyopathy were randomly assigned to double-blind treatment with 2 I.U. of GH or placebo for 3 months. Central hemodynamics were determined by Swan-Ganz catheter and cardiac output was obtained by the thermodilution method. Serum GH and IGF-I levels were measured and systemic NO production was determined from urinary nitrate and cyclic GMP excretion rates in 42 patients. RESULTS: GH treatment caused in comparison to the placebo group a significant increase of IGF-I by 91 ng/ml (P = 0.0001). Urinary excretion rates of nitrate and cyclic GMP increased also significantly by 38 mumol/mmol creatinine (P = 0.027) and 65 nmol/mmol creatinine (P = 0.003), respectively. The parallel increase of both marker molecules indicates increased systemic NO production during GH treatment. CONCLUSION: GH treatment induces a significant, but moderate increase of systemic NO production in patients with dilated cardiomyopathy. This effect may be mediated by IGF-I stimulating endothelial NO synthase.

Cardiomyopathy, Dilated↗