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Biomedical subjects

Rainer H Böger

Publications and source records attributed to Rainer H Böger.

At least 37 records · Page 2Linked to original sources
PubMed2004

Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease.

OBJECTIVES: We evaluated whether renin-angiotensin system (RAS) blockade attenuates cardiovascular events. BACKGROUND: Because inflammation and enhanced thrombogenesis are hallmarks of atherosclerosis, we assessed whether RAS inhibition elicits anti-inflammatory and anti-aggregatory effects. METHODS: Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), metalloprotease 9 (MMP-9), and interleukin 10 (IL-10) were determined in patients with coronary artery disease (CAD) and arterial hypertension six to eight weeks after coronary angioplasty (low-density lipoprotein serum levels <150 mg/dl). Patients were randomized double-blind to either 20 mg enalapril (ENAL, n = 27) or 300 mg irbesartan (IRB, n = 21) for 3 months. Blood samples were drawn at baseline and at three months. Thromboxane A2-induced platelet aggregation was determined turbidimetrically; urine bicyclo-prostaglandin E2 (PGE(2)) and inflammatory markers were measured by enzyme-linked immunosorbent assay technique. RESULTS: Both treatment regimens enhanced serum IL-10 levels (IRB p < 0.001, ENAL p < 0.03) and reduced serum MMP-9 protein (IRB p < 0.001, ENAL p < 0.05) and MMP-9 activity (IRB p < 0.005, ENAL p < 0.05). Only IRB reduced serum IL-6 and hsCRP levels significantly compared with baseline (p < 0.01), whereas ENAL did not (hsCRP p < 0.02 IRB vs. ENAL, p < 0.01 IRB vs. ENAL). Platelet aggregation was only reduced by IRB (p < 0.001, ENAL p < 0.06, IRB vs. ENAL p < 0.001) while urine PGE(2) levels remained unchanged. CONCLUSIONS: Angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor (AT1) blockade reduced serum MMP-9 protein/activity to a similar extent, and only AT1 blockade reduced hsCRP, IL-6, and platelet aggregation in patients with CAD. Thus, AT1-blockade appears to exert stronger systemic anti-inflammatory and anti-aggregatory effects compared with ACE inhibition.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

FK778 attenuates lymphocyte-endothelium interaction after cardiac transplantation: in vivo and in vitro studies.

BACKGROUND: The malononitrilamide FK778 is a novel derivate of leflunomide and interacts with T- and B-cell function by inhibiting de novo pyrimidine synthesis. We investigated the effects of FK778 upon acute cardiac allograft rejection and upon adhesion molecule upregulation in experimental transplantation and by using in vitro cell culture. METHODS: Heterotopic, abdominal cardiac transplantations were performed in the Brown Norway (BN) to Lewis (Lew) rat model. The study groups received daily low- or high-dose FK778 immunosuppression. FK778 plasma levels were quantified by HPLC. Grafts were harvested on the fifth postoperative day for histologic and immunohistologic examinations using computerized morphometry. Purified BN aortic endothelial cell cultures were pretreated with low- or high-dose FK778 according to FK778 plasma levels and were stimulated with tumor necrosis factor (TNF)-alpha. Adhesion molecule expression was quantified by immunofluorescence, FACS analysis, and Western blotting. Lymphocyte-endothelium adhesion assays were performed using purified Lew lymphocytes and radiolabeled TNF-alpha was used for receptor binding assays. RESULTS: FK778 treatment dose-dependently reduced graft mononuclear infiltration of CD4(+), CD8(+), and ED1(+) cells, but only high-dose FK778 treatment significantly reduced early upregulation of ICAM-1 and VCAM-1 in vivo. FK778 also dose-dependently reduced TNF-alpha-stimulated endothelial adhesion molecule upregulation in vitro, whereas the effect on VCAM-1 was more dominant. We did not find evidence that FK778 interferes with surface receptor binding of TNF-alpha. Lymphocyte adhesion to endothelial cell monolayers was significantly attenuated by FK778. CONCLUSION: Besides its inhibitory effect on pyrimidine synthesis, FK778 directly reduces endothelial adhesion molecule upregulation and attenuates lymphocyte-endothelium interaction, which is a critical step in graft rejection.

Acute Disease↗
PubMed2004

Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice.

BACKGROUND AND PURPOSE: Hyperhomocysteinemia is an emerging risk factor for stroke, but little is known about effects of hyperhomocysteinemia on cerebral vascular function. We tested the hypothesis that chronic hyperhomocysteinemia in mice causes endothelial dysfunction in cerebral arterioles through a mechanism that involves superoxide. METHODS: Mice heterozygous for a targeted disruption of the cystathionine beta-synthase gene (Cbs+/-) and their wild type littermates (Cbs+/+) were fed either a control diet or a high-methionine diet for 10 to 12 months. RESULTS: Plasma total homocysteine was elevated with the high-methionine diet compared with the control diet for both Cbs+/+ (7.9+/-1.0 versus 5.0+/-0.5 micromol/L; P<0.05) and Cbs+/- (20.5+/-3.1 versus 8.2+/-0.9 micromol/L; P<0.001) mice. Dilatation of cerebral arterioles ( approximately 30 microm baseline diameter) was measured in vivo in response to the endothelium-dependent dilator acetylcholine or the endothelium-independent dilator nitroprusside. Vasodilatation to acetylcholine was impaired with the high-methionine diet compared with the control diet for both Cbs+/+ and Cbs+/- mice (P<0.01). Dilatation of arterioles to acetylcholine was restored toward normal by the superoxide scavenger tiron (P<0.05). Vasodilatation to nitroprusside was not influenced by Cbs genotype or diet. Dihydroethidium (DHE) staining for vascular superoxide was elevated in Cbs+/- mice fed the high-methionine diet and was inhibited by apocynin or Nomega-nitro-l-arginine methyl ester, implicating NAD(P)H oxidase and nitric oxide synthase as potential sources of superoxide. CONCLUSIONS: Superoxide is a key mediator of endothelial dysfunction in the cerebral circulation during diet-induced hyperhomocysteinemia.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed2004

Effects of carvedilol on oxidative stress in human endothelial cells and healthy volunteers.

OBJECTIVE: Carvedilol is a nonselective beta- and alpha(1)-receptor antagonist with additional antioxidant properties in vitro. In this study, we assessed the antioxidative potential of carvedilol in cell culture and in antihypertensive doses in healthy men. METHODS: In vitro, human cultured endothelial cells were treated with native low-density lipoprotein (LDL), oxidized LDL or tumor necrosis factor (TNF)alpha in the absence and in the presence of carvedilol (40 micro M); 8-iso-prostaglandin (PG)F(2alpha), as parameter of oxidative stress, was determined in the supernatants. In a double-blind, randomized, cross-over study, 17 healthy men received 25 mg carvedilol b.i.d., 100 mg metoprolol b.i.d. or placebo for 6 days. After each treatment, systemic oxidative stress was assessed by measuring urinary excretion of 8-iso-PGF(2alpha) and 2,3-dinor-5,6-dihydro-8-iso-PGF(2alpha), and the plasma concentration of 3-nitrotyrosine by means of gas chromatography-tandem mass spectrometry. In addition, thiobarbituric acid-reactive substances (TBARS) in plasma were assessed using spectrophotometry. RESULTS: Native LDL and oxidized LDL induced 8-iso-PGF(2alpha) production in endothelial cells. Carvedilol significantly reduced this effect (e.g., for oxidized LDL: 2.66+/-0.22 pg vs 1.46+/-0.14 pg 8-iso-PGF(2alpha) per micro g protein, P<0.05). In healthy volunteers, carvedilol and metoprolol markedly decreased blood pressure and heart rate, but had no statistically significant effect on any indicator of oxidative stress measured. Remarkably, a trend toward reduction of urinary isoprostanes and 3-nitrotyrosine in plasma by both active treatments was observed, suggesting a non-specific antioxidative effect by beta blockade. CONCLUSIONS: In vitro, the antioxidative potential of carvedilol was confirmed. In healthy men, antihypertensive doses of carvedilol exert no specific inhibition of oxidative stress.

Adrenergic Antagonists↗
PubMed2004

Urinary 8-iso-prostaglandin F2alpha as a risk marker in patients with coronary heart disease: a matched case-control study.

BACKGROUND: Oxidative stress is involved in the pathophysiology of atherosclerosis, diabetes mellitus, hypertension, obesity, and cigarette smoking, all of these being risk factors for coronary heart disease (CHD). We tested the hypothesis that risk factors of CHD are associated with abundant systemic oxidative stress. METHODS AND RESULTS: We conducted a case-control study with 93 CHD patients and 93 control subjects frequency-matched by age and sex. Urinary excretion of the F2-isoprostane 8-iso-prostaglandin (PG) F2alpha and its major urinary metabolite, 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha, were measured by gas chromatography-tandem mass spectrometry. Body mass index, systolic blood pressure, and C-reactive protein were elevated in CHD patients (P<0.01). Urinary 8-iso-PGF2alpha and 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha also differed, from 77 (interquartile range, 61-101) to 139 (93-231) pmol/mmol creatinine and from 120 (91-151) to 193 (140-275) pmol/mmol in control subjects and case subjects, respectively (P<0.001). 8-iso-PGF2alpha and its metabolite were highly correlated (Spearman's rho=0.664, P<0.001). HDL cholesterol was diminished in CHD patients (P<0.001). All of these characteristics predicted CHD in univariate analysis. In a multivariate model, the odds ratios were increased only for 8-iso-PGF2alpha (> or =131 pmol/mmol, P<0.001) and C-reactive protein (>3 mg/L, P<0.01), ie, by 30.8 (95% CI, 7.7-124) and 7.2 (1.9-27.6), respectively. 8-iso-PGF2alpha was found to be a novel marker in addition to known risk factors of CHD, ie, diabetes mellitus, hypercholesterolemia, hypertension, and smoking. Urinary excretion of 8-iso-PGF2alpha correlated with the number of risk factors for all subjects (P<0.001 for trend). CONCLUSIONS: 8-iso-PGF2alpha is a sensitive and independent risk marker of CHD.

Adult↗
PubMed2004

Hypercholesterolemia impairs basal nitric oxide synthase turnover rate: a study investigating the conversion of L-[guanidino-(15)N(2)]-arginine to (15)N-labeled nitrate by gas chromatography--mass spectrometry.

Endothelial function is impaired in hypercholesterolemia and atherosclerosis, which is probably due to reduced biological activity of endothelium-derived nitric oxide (NO). NO is synthesized in functionally intact endothelium by oxidation of the terminal guanidino nitrogen atom(s) of the amino acid precursor, L-arginine. We applied stable isotope dilution techniques and gas chromatographic-mass spectrometric approaches to investigate metabolism of L-[guanidino-(15)N(2)]-arginine to (15)N-labeled nitrate in hypercholesterolemic rabbits and controls. After 4 weeks on control or 1% cholesterol-enriched diet, rabbits received 267 +/- 6 micromol of L-[guanidino-(15)N(2)]-arginine/kg of body weight via gastric cannulation. (15)N-isotope content of L-arginine in plasma and in platelet lysates increased 2h later in both groups, and almost returned to baseline until 24h. (15)N-isotope content of plasma nitrite and nitrate also increased in both groups at 2h, and had almost returned to natural content 24h later. (15)N-isotope content of urinary nitrate was significantly increased in control animals in urines collected from 0 to 12, 12 to 24, and had returned to baseline in the urine sample collected from 24 to 48 h. In the cholesterol group only a slight, insignificant elevation of (15)N-isotope content was observed for urinary nitrate. The extent of conversion of L-[guanidino-(15)N(2)]-arginine to (15)N-labeled nitrate was strongly and inversely correlated to plasma concentration of the endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), which was elevated in cholesterol-fed rabbits (R=0.77; p < 0.05). Our data show that baseline NO synthase turnover rate is reduced in rabbits during early hypercholesterolemia. Our study gives evidence that the mechanism of the impaired conversion of L-[guanidino-(15)N(2)]-arginine to (15)N-labeled nitrate most likely involves inhibition of NO synthase by ADMA, which is present in elevated concentrations in hypercholesterolemia.

Animals↗
PubMed2004

Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the "L-arginine paradox" and acts as 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). Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NO synthase. ADMA inhibits vascular NO production in concentrations found in pathophysiological conditions; ADMA also causes local vasoconstriction when it is infused intraarterially. Thus, elevated ADMA levels may explain the "L-arginine paradox," i.e., the observation that supplementation with exogenous L-arginine improves NO-mediated vascular functions in vivo, although its baseline plasma concentration is about 25-fold higher than the Michaelis-Menten constant K(m) of the isolated, purified endothelial NO synthase in vitro. The biochemical and physiological pathways related to ADMA are well understood: Dimethylarginines are the result of degradation of methylated proteins; the methyl group is derived from S-adenosylmethionine. Both ADMA and its regioisomer, symmetric dimethylarginine, are eliminated from the body by renal excretion, whereas only ADMA is metabolized via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). DDAH activity and/or expression may therefore contribute to the pathogenesis of endothelial dysfunction in various diseases. Plasma ADMA levels are increased in humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, and chronic heart failure. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation. In several prospective and cross-sectional studies, ADMA evolved as a marker of cardiovascular risk. With increasing knowledge of the role of ADMA in the pathogenesis of cardiovascular disease, ADMA is becoming a goal for pharmacotherapeutic interventions. Among other potential strategies that are currently being tested, administration of L-arginine has been shown to improve endothelium-dependent vascular functions in subjects with high ADMA levels. Finally, ADMA has gained clinical importance recently because several studies have shown that ADMA is an independent cardiovascular risk factor.

Animals↗
PubMed2004

Acetylsalicylic acid inhibits monocyte adhesion to endothelial cells by an antioxidative mechanism.

The adhesion of monocytes to vascular endothelium increases in the presence of high levels of low density lipoprotein (LDL). LDL changes oxidative status of endothelial cells leading to an increased expression of cell adhesion molecules. Acetylsalicylic acid (ASA) has been shown to exert antioxidant effects in high and very high concentrations. This study was designed to demonstrate the influence of acetylsalicylic acid and its major metabolite, salicylic acid (SA), on the adhesion of monocytes to LDL-stimulated endothelial cells. Monocyte adhesion to endothelial cells was concentration-dependently inhibited by both salicylates upon stimulation of endothelial cells with TNF-alpha, oxidized LDL (oxLDL), and native LDL (nLDL). The inhibitory effect of ASA was more potent than that of SA, whereas the cyclooxygenase inhibitor ibuprofen had no effect. F2-isoprostane release from LDL-stimulated endothelial cells was reduced by simultaneous incubation with ASA or SA, whereas ibuprofen had no effect. LDL-induced activation of the transcription factor NF-kappaB was inhibited by ASA, and ferritin protein was increased when endothelial cells were incubated with this drug. These results show that acetylsalicylic acid and-less potently-salicylic acid inhibit monocyte adhesion to LDL-stimulated endothelial cells by antioxidative effects. For ASA, the observed inhibition of monocyte adhesion was accomplished with concentrations that can be reached after single oral doses of 500 mg of ASA.

Antioxidants↗
PubMed2004

Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA.

Hyperhomocysteinemia is associated with an enhanced risk for cardiovascular disease. Patients with peripheral arterial disease (PAD) show an increased prevalence of hyperhomocysteinemia. A decreased biological activity of nitric oxide (NO) may contribute to homocysteine-associated endothelial dysfunction. This study was designed to investigate whether elevated levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) are involved in endothelial dysfunction in patients with chronic hyperhomocysteinemia and PAD. A total of 76 patients (58 males and 18 females; mean age 65.2 +/- 2.0 years) with PAD were included in the analysis and characterized according to demographic variables and cardiovascular risk factors. Flow-dependent vasodilation (FDD) was determined by high-resolution ultrasound in the radial artery. Total plasma homocysteine (plasma tHcy) and ADMA levels were measured by HPLC. Urinary nitrate was quantified using gas chromatography-mass spectrometry. Patients with plasma tHcy in the highest tertile (n = 27; i.e. > 10.6 micromol/l) had a mean plasma level of 14.4 +/- 1.21 mol/l compared with 9.9 +/- 0.1 micromol/l in those patients in the middle tertile (n = 22; p < 0.05) and 9.4 +/- 0.1 micromol/l in those in the lowest tertile (n = 27; i.e. <9.6 micromol/l; p < 0.05). The hyperhomocysteinemic individuals (highest tertile) had a significantly decreased FDD compared with healthy age-matched controls (n = 15) (7.6 +/- 1.0 vs 13.0 +/- 0.4%; p < 0.05), higher plasma ADMA concentrations (4.0 +/- 0.3 vs 2.6 +/- 0.3 micromol/l; p < 0.05), and a lower urinary nitrate excretion rate (89.5 +/- 13.4 vs 131.3 +/- 17.9 micromol/mmol creatinine; p < 0.05) compared with patients with plasma tHcy in the lowest tertile. Multivariate regression analysis including plasma tHcy, ADMA, total cholesterol, diabetes mellitus, smoking, and systolic blood pressure revealed ADMA as the only significant factor determining FDD (p < 0.05). In conclusion, we demonstrated a stronger relationship between impaired endothelial function and elevated ADMA levels in comparison with plasma tHcy concentrations in patients with PAD and chronic hyperhomocysteinemia. This may raise the question of whether different therapeutical options that interact indirectly with plasma tHcy, i.e. treatment with ACE inhibitors and AT1-receptor blockers to reduce ADMA plasma concentrations or L-arginine, could be a beneficial tool for treating patients with hyperhomocysteinemia.

Adult↗
PubMed2004

Determination of asymmetric dimethylarginine (ADMA) using a novel ELISA assay.

Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase (NOS). Elevated ADMA plasma levels have been reported in connection with diseases associated with an impaired endothelial L-arginine-NO pathway and endothelial dysfunction, such as atherosclerosis, hypercholesterolemia, chronic heart failure, diabetes mellitus, and hypertension. NO production by NOS is decreased due to elevated ADMA levels. In fact, there is increasing interest in determination of ADMA levels in samples of various origins. The aim of this work was to develop a precise and easy immunoassay in contrast to the existing methods, such as HPLC, liquid chromatography-mass spectrometry (LC-MS) and gas chromatography (GC)-MS. We determined cross-reactivity in our immunoassay of 1.2% for symmetric dimethylarginine and <0.02% for L-arginine. The limit of quantitation was 0.05 micromol/l. We found good correlation of the values measured when we compared our assay with LC-tandem MS (n = 29; r = 0.984; p < 0.0001). We determined ADMA levels in human serum and plasma, mouse and rat plasma, and cell culture supernatant. For human plasma we found a mean of 0.65 micromol/l in healthy subjects. In the plasma of mice and rats we found mean concentrations of 1.05 and 1.09 micromol/l, respectively.

Animals↗
PubMed2003

The emerging role of asymmetric dimethylarginine as 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). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. ADMA inhibits vascular NO production at concentrations found in pathophysiological conditions (i.e., 3-15 micromol/l); ADMA also causes local vasoconstriction when it is infused intraarterially. The biochemical and physiological pathways related to ADMA are now well understood: dimethylarginines are the result of the degradation of methylated proteins; the methyl group is derived from S-adenosylmethionine. Both ADMA and its regioisomer, SDMA, are eliminated from the body by renal excretion, whereas only ADMA, but not SDMA, is metabolized via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). DDAH activity and/or expression may therefore contribute to the pathogenesis of endothelial dysfunction in various diseases. ADMA is increased in the plasma of humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, and chronic heart failure. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation. In several prospective and cross-sectional studies, ADMA evolved as a marker of cardiovascular risk. With our increasing knowledge of the role of ADMA in the pathogenesis of cardiovascular disease, ADMA is becoming a goal for pharmacotherapeutic intervention. Among other treatments, the administration of L-arginine has been shown to improve endothelium-dependent vascular function in subjects with high ADMA levels.

Amidohydrolases↗
PubMed2003

Angiotensin II type 2 receptor inhibits vascular endothelial growth factor-induced migration and in vitro tube formation of human endothelial cells.

Endothelial cell migration and tube formation in response to vascular endothelial growth factor (VEGF) play an important role in the process of angiogenesis. Recent data indicate that angiotensin type 2 (AT2) receptor stimulation is antiangiogenic. Therefore, we studied the effect of angiotensin II (Ang II) on VEGF-induced migration and in vitro tube formation of human endothelial cells. Ang II inhibited VEGF-induced migration of EA.hy926 cells, human coronary artery (HCA) and human dermal microvascular (HDM) endothelial cells (ECs) as well as tube formation by HDMECs. The AT2 receptor antagonist PD123,319 but not the AT1 receptor antagonist losartan blocked the inhibitory effect of Ang II. The inhibitory effect of Ang II on VEGF-induced migration of endothelial cells was mimicked by the specific AT2 receptor agonist CGP-42112A. The phosphorylation of Akt and its downstream effector endothelial NO synthase (eNOS) is pivotal to VEGF-induced angiogenesis. We therefore investigated the effect of Ang II on VEGF-induced Akt and eNOS phosphorylation. Ang II diminished the VEGF-induced phosphorylation of Akt and eNOS in endothelial cells, whereas the autophosphorylation of VEGF receptors was unaffected. CGP-42112A again mimicked and PD123,319 but not losartan blocked the inhibitory effect of Ang II. Treatment of endothelial cells with pertussis toxin (PTX) totally abolished the AT2 receptor-mediated inhibition of VEGF-induced endothelial cell migration and blocked the inhibition of Akt and eNOS phosphorylation. In conclusion, this study indicates that AT2 receptor stimulation inhibits VEGF-induced endothelial cell migration and tube formation via activation of a PTX-sensitive G protein. These findings may explain the reported antiangiogenic properties of the AT2 receptor.

Angiotensin II↗
PubMed2003

ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins.

OBJECTIVES: Hyperhomocyst(e)inemia is a risk factor for atherosclerotic vascular disease, and it is associated with endothelial dysfunction. Mechanisms responsible for endothelial dysfunction in hyperhomocyst(e)inemia may involve impaired bioavailability of NO, possibly secondary to accumulation of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) and increased oxidative stress. We investigated whether oral treatment with B vitamins or L-arginine normalizes endothelium-dependent, flow-dependent vasodilation (FDD) in patients with peripheral arterial occlusive disease (PAOD) and hyperhomocyst(e)inemia. METHODS: 27 patients with PAOD and hyperhomocyst(e)inemia were assigned to oral treatment with combined B vitamins (folate, 10 mg; vitamin B-12, 200 microg; vitamin B-6, 20 mg/day), L-arginine (24 g/day) or placebo, for 8 weeks in a double-blind fashion. FDD was determined by high-resolution ultrasound in the radial artery. RESULTS: Vitamin B supplementation significantly lowered plasma homocyst(e)ine concentration from 15.8+/-1.8 to 8.7+/-1.1 micromol/l (P<0.01). However, B vitamins had no significant effect on FDD (baseline, 7.8+/-0.7%, B vitamins, 8.3+/-0.9%, placebo 8.9+/-0.7%; P=n.s.). In contrast, L-arginine treatment did not affect homocyst(e)ine levels, but significantly improved FDD (10.2+/-0.2%), probably by antagonizing the impact of elevated ADMA concentration (3.8+/-0.3 micromol/l) and reducing the oxidative stress by lowering urinary 8-iso-prostaglandin F(2alpha) (baseline, 76.3+/-7.1 vs. 62.7+/-8.3 pmol/mmol creatinine after 8 weeks). CONCLUSIONS: Oral supplementation with combined B vitamins during 8 weeks does not improve endothelium-dependent vasodilation in PAOD patients with hyperhomocyst(e)inemia, whereas L-arginine significantly improved endothelial function in these patients. Thus, accumulation of ADMA and increased oxidative stress may underlie endothelial dysfunction under hyperhomocyst(e)inemic conditions. These findings may have importance for evaluation of homocyst(e)ine-lowering therapy.

Aged↗
PubMed2003

Old and new cardiovascular risk factors: from unresolved issues to new opportunities.

With the aim of identifying areas that may deserve some further thinking the present review deliberately points out controversial issues in cardiovascular research and risk assessment. In the first part of the review general aspects are addressed regarding the evaluation of risk factors. A first point of concern is the frequent practice of combining different vascular events and effects in different vascular beds into a single endpoint. Furthermore, verification of vascular events in clinical reality may be surprisingly inaccurate. Problems in risk assessment also arise from overlapping properties (shared pathophysiological pathways) of traditional risk factors like hypertension, obesity and diabetes. In the second part of the review unresolved issues concerning selected established and emerging risk factors are discussed. The difficulty of establishing causality in cardiovascular disease is addressed, using modification of LDL cholesterol and accumulating evidence for pleiotropic effects of the LDL cholesterol-lowering statins as an example. As an alternative or supplement to the notion of LDL-related cardiovascular risk it is proposed to distinguish between statin-sensitive and statin-insensitive cardiovascular risk. Finally the future prospects of selected new and emerging risk factors like CRP, homocysteine, asymmetrical dimethylarginine (ADMA), oxLDL, and isoprostanes are evaluated. In summary, imprecise terminology and varying definitions of "cardiovascular risk" may lead to a considerable blurring of our current risk estimates, which may also explain some presently controversial issues. With several new risk factors and substantial changes in lifestyle and treatment patterns on the horizon major changes in the hierarchy of risk factors may be inevitable.

Cardiovascular Diseases↗
PubMed2003

ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase. By competitively displacing L-arginine from the substrate binding site of NO synthase, ADMA interferes with many of the physiological functions of NO, like endothelium-dependent vasodilation and leukocyte adhesion. ADMA, like its biologically inactive regioisomer, symmetric dimethylarginine (SDMA), can be found in human plasma and urine in low concentrations. The concentrations of both dimethylarginines are increased in patients with end-stage renal disease, which may explain at least in part endothelial dysfunction and cardiovascular complications in this patient population. In addition, the metabolism of ADMA, but not SDMA, occurs via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Data from experimental studies suggest that ADMA inhibits vascular NO elaboration at concentrations that can be measured in plasma of patients with renal disease. Interestingly, ADMA and SDMA are poorly eliminated during hemodialysis. This is probably due to a high level of binding of both molecules to plasma proteins. High ADMA concentrations in patients with end-stage renal disease may contribute to their excess cardiovascular event rate, as in clinical studies a relationship between ADMA and carotid artery intimal thickening was found. Moreover, in a prospective study we demonstrated recently that determination of ADMA plasma concentration is useful to predict future cardiovascular event rate and total mortality in this patient population. As other researchers reported observations that are in line with our findings, there is evidence that ADMA may be a novel cardiovascular risk factor.

Arginine↗