Asymmetric dimethylarginine and symmetric dimethylarginine prospectively relates to carotid wall thickening in black men: the SABPA study.

The relationship of both asymmetric (ADMA) and symmetric (SDMA) dimethylarginine with carotid wall thickness is inconclusive especially among black populations. We aimed to compare carotid intima media thickness (cIMT) and dimethylarginine levels in 75 black and 91 white men at baseline and after a 3-year follow-up, and to investigate associations of percentage change in cIMT with percentage change in dimethylarginine levels (ADMA and SDMA). Plasma levels of ADMA and SDMA were determined with a liquid chromatography mass spectrometry method and B-mode ultrasonography was used to determine the cIMT at baseline and follow-up. In black men, mean cIMT (p = 0.79) and ADMA levels (p = 0.67) remained the same, but SDMA levels were lower (p < 0.001) when comparing baseline and follow-up. In white men, cIMT increased (p < 0.001), but both mean ADMA and SDMA levels decreased (p < 0.001) over time. In black men, percentage change in cIMT was positively associated with percentage change in ADMA (R 2 = 0.49; ß = 0.46; p < 0.001) and percentage change in SDMA (R 2 = 0.46; ß = 0.41; p < 0.001). These associations were absent in the white men. Despite lower mean SDMA and similar ADMA and cIMT in black men, percentage change in cIMT was independently associated with percentage change in ADMA and percentage change in SDMA. These results suggest an important role for ADMA and SDMA lowering strategies to delay carotid wall thickening, especially in black populations prone to the development of cardiovascular disease.

A comparison of the association between glomerular filtration and L-arginine status in HIV-infected and uninfected African men: the SAfrEIC study.

Hypertension, a major risk factor for cardiovascular disease worldwide, is increasing significantly in urbanised South Africans. Impaired glomerular filtration is a potential contributor to hypertension. Although HIV infection is widespread, little is known regarding its contribution to diminished estimated glomerular filtration rate (eGFR) and, in turn, hypertension in Africans. We compared eGFRs and cardiovascular profiles of newly identified HIV infected African men (N=53) not yet undergoing anti-retroviral therapy, and uninfected African men of similar age and anthropometry. The aim of the study was to determine whether eGFR is diminished in treatment naive HIV infected individuals and whether eGFR is associated with a potential modulator of hypertension, namely serum L-arginine. Cardiovascular risk factor profiles of HIV infected and uninfected men were similar. In men with healthy eGFRs >90 ml min(-1) per 1.73 m(2), eGFR was significantly lower with HIV infection (114 (90; 147)) compared with that in uninfected men: (120 (91; 168)), P=0.043. Despite the absence of clinically-diagnosed renal dysfunction, eGFR associated significantly with serum L-arginine only in HIV infected men (R(2)=0.277, ß=-0.299, P=0.034), whereas L-arginine did not stay in the model for uninfected men. This difference suggests that the fate of L-arginine as a substrate for nitric oxide generation may be altered in HIV infected individuals. Subsequently this is likely to escalate endothelial dysfunction, contributing to later hypertension and cardiovascular disease. Our findings show that while glomerular filtration rate is not associated with L-arginine in uninfected men, it is diminished and significantly negatively associated with serum L-arginine in HIV infected men.

Ethnicity-specific differences in L-arginine status in South African men.

The aetiology for an increasing incidence of hypertensive cardiovascular disease amongst Africans in southern Africa is unclear. Hypertension may be induced by inadequate release of L-arginine-derived nitric oxide impairing vascular tone regulation. In addition, asymmetric dimethylarginine (ADMA) is associated with cardiovascular disease. We compared profiles of L-arginine in African and Caucasian men of similar age with cardiovascular risk factors. We studied 163 Caucasian and 132 African men, respectively, (20 to 70 years) measuring serum L-arginine, ADMA, creatinine, urea, symmetric dimethylarginine (SDMA) and blood pressure. L-arginine levels were significantly lower, whereas blood pressure and pulse wave velocity were significantly higher in African men. Simple linear regression showed ADMA more strongly associated with L-arginine in Caucasians (r=0.59 vs 0.19), whereas association of SDMA with L-arginine was significant only in Caucasians (r=0.43 vs 0.001). The stronger association of L-arginine with ADMA in Caucasian men was confirmed by multiple regression analysis (ß=0.46 vs 0.25).Our findings show that the relationship of cardiovascular risk factors with serum L-arginine and some of its catabolites is different in African and Caucasian men and that this may be associated with a relatively higher prevalence of hypertension in African men.

A survey on clinical study participation and study infrastructure at non-university hospitals in Germany.

OBJECTIVE: In order to participate in multicenter clinical trials a fair amount of infrastructure and human resources has to be provided by hospitals. Therefore clinical trials are carried out predominantly in university hospitals. Data concerning participation in clinical trials and the infrastructure of study centers in non-university hospitals in Germany do not exist. A survey was thus conducted to evaluate the current status of clinical study performance in non-university hospitals. MATERIALS AND METHODS: A questionnaire comprising 10 questions covering hospital infrastructure, local study history, and the individual interest in performing studies was sent to 790 non-university hospitals in Germany. RESULTS: 58.7% of questionnaires were returned for evaluation. 74.1% of nonuniversity hospitals participate in clinical studies. Hospital size is a significant predictor of study participation. 25.5% of hospitals have established a multidisciplinary study center. 86.2% have a certified study nurse and in 34.5% this nurse is the only person running the study center. Only 25.5% of hospitals were not interested in participating in clinical studies at all, even if an individual tailored concept were to be offered. CONCLUSIONS: The demand for more hospitals to participate in clinical trials is urgent since high quality studies are a fundamental part of clinical research. Even though 75% of non-university hospitals in Germany already participate in clinical trials, it may be possible to increase this number. In addition by establishing and developing study centers in hospitals the quality of studies will presumably rise, and due to the concentration of study resources, the number of clinical trials may increase.

Asymmetric dimethylarginine as an independent risk marker for mortality in ambulatory patients with peripheral arterial disease.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis causing endothelial dysfunction, an early sign of atherogenesis. Symmetric dimethylarginine (SDMA) does not inhibit NO synthases. Peripheral arterial disease (PAD) is a systemic indication of atherosclerosis. METHODS: We assessed the associations between both ADMA and SDMA blood levels and major cardiovascular and cerebrovascular events or death from any cause within a 5-year follow-up in the multicentre getABI trial. From a cohort of 6821 primary care patients, aged ≥65 years, all 1260 patients with prevalent PAD were compared with a random sample of 1187 non-PAD controls. A total of 11,544 patient-years were documented. Multivariate risks were calculated by Cox proportional hazard models, adjusting for PAD, renal dysfunction and other important cardiovascular risk factors. RESULTS: We documented 390 deaths, 296 cardiovascular events and 98 cerebrovascular events. Increased ADMA levels in the 4th quartile were significantly associated with total mortality [hazard ratio (HR) 1.41; 95% CI 1.14-1.74] and with cardiovascular events (HR 1.32; 95% CI 1.03-1.69), but there was a nonsignificant association with cerebrovascular events (HR 1.50; 95% CI 0.98-2.29). Increased SDMA was only just significantly associated with mortality (HR 1.27; 95% CI 1.01-1.59). In PAD patients compared with non-PAD controls, only mean SDMA concentration was considerably increased (0.52 µmol L(-1) vs. 0.48 µmol L(-1); P < 0.001) mainly because of a highly significant association with impaired renal function. CONCLUSION: These data suggest that ADMA but not SDMA is an independent risk marker for death from any cause or from cardiovascular events. The association between SDMA and mortality is in part explained by a close link between SDMA and renal function.

Redox-generated isoprostanes are associated with residual platelet activity in aspirin-treated patients with stable coronary heart disease.

AIM: Insufficient platelet inhibition by low-dose aspirin is associated with poor prognosis in patients with coronary heart disease (CHD). We sought to investigate the prevalence of this phenomenon in patients with stable CHD and to study whether oxidative stress plays a role in its pathogenesis. METHODS AND RESULTS: We studied the platelet response to long-term (≥ 6 months) low-dose (100 mg per day) aspirin in 130 consecutive patients with stable CHD (age 66 ± 8 years, 83% male). Among a wide distribution of platelet responses to collagen, ADP, and arachidonic acid, the vast majority of patients in the highest tertile of residual platelet activity (defined as 'aspirin low-responders') were characterized by lack of platelet inhibition by aspirin in vitro, significantly although not completely suppressed platelet TXB2 production and COX-1 activity, and significantly higher urinary 8-iso-prostaglandin F(2α) excretion [186 (147-230) vs. 230 (188-318) pg per mg creatinine; median (IQR), P < 0.001; measured by GC-MS]. CONCLUSION: A relevant proportion of patients with CHD show insufficient platelet inhibition by low-dose aspirin. Oxidative stress and lipid peroxidation causing isoprostane formation may underlie inadequate platelet inhibition in an aspirin-insensitive manner in patients with cardiovascular disease.

Interaction of angiotensin receptor type 1 blockers with ATP-binding cassette transporters.

ATP-binding cassette (ABC)-transporters, such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs) and breast cancer resistance protein (BCRP/ABCG2) transport numerous drugs thus regulating their absorption, distribution and excretion. Angiotensin receptor type 1 blockers (ARBs), used to treat hypertension and heart failure, are commonly administered in combination therapy. However, their interaction potential is not well studied and their effect on ABC-transporters remains elusive. The study therefore aimed to elucidate the effect of various ARBs (telmisartan, candesartan, candesartan-cilexetil, irbesartan, losartan, olmesartan, olmesartan-medoxomil, eprosartan) on ABC-transporter activity in vitro. P-gp inhibition was assessed by calcein assay, BCRP inhibition by pheophorbide A efflux assay, and MRP2 inhibition by a MRP2 PREDIVEZ Kit. Induction of P-gp, BCRP and MRP2 was assessed by real time reverse transcriptase polymerase chain reaction and for P-gp also in a functional assay. Telmisartan was identified as one of the most potent inhibitors of P-gp currently known (IC(50)=0.38+/-0.2 microM for murine P-gp) and it also inhibited human BCRP (IC(50)=16.9+/-8.1 microM) and human MRP2 (IC(50)=25.4+/-0.6 microM). Moreover, the prodrug candesartan-cilexetil, but not candesartan itself, significantly inhibited P-gp and BCRP activity. None of the compounds tested induced mRNA transcription of P-gp or BCRP but eprosartan and olmesartan induced MRP2 mRNA expression. In conclusion, telmisartan substantially differed from other ARBs with respect to its potential to inhibit ABC-transporters relevant for drug pharmacokinetics and tissue defense. These findings may explain the known interaction of telmisartan with digoxin and suggest that it may modulate the bioavailability of drugs whose absorption is restricted by P-gp and possibly also by BCRP or MRP2.

Asymmetric dimethylarginine is associated with parameters of glucose metabolism in Caucasian but not in African women from South Africa.

AIM: Ethnic differences in obesity and obesity related disorders prompted us to search for possible contributors. The impact of the novel cardiovascular risk factor asymmetric dimethylarginine (ADMA) has been never determined in the African population. The present observational study aimed to compare ADMA levels between healthy African (102) and Caucasian women (115) from South Africa, and its impact on glucose metabolism. METHODS: All participants underwent an oral glucose tolerance test with measurements of glucose, insulin, C-peptide, proinsulin and free fatty acids before and after 30, 60, 90, 120 minutes. Fasting serum ADMA was measured by ELISA assay and obesity was determined by anthropometry. RESULTS: Serum ADMA did not differ between the ethnic groups. After stratification according to ADMA quartiles Caucasian women in the upper quartile had significantly higher body mass index and waist circumference as well as elevated insulin resistance, insulin, C-peptide and proinsulin levels with no differences in serum glucose compared to women in the lowest quartile. There was a significant stronger postchallenge insulin response in Caucasian women of the upper quartile. No differences were found in African women. CONCLUSIONS: Despite similar ADMA levels in both ethnic groups ADMA was positively correlated with parameters of glucose metabolism in the Caucasian but not in the African women from South Africa.

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.

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.

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.

[Drug therapy of coronary heart disease--are therapeutic guidelines being paid attention to?]. / Arzneimittelverordnungen bei koronarer Herzkrankheit: Werden die Therapieempfehlungen beachtet?

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.

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.

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.

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.

[Homocysteine, endothelial dysfunction and cardiovascular risk: pathomechanisms and therapeutic options]. / Homocyst(e)in, endotheliale Dysfunktion und kardiovaskuläres Risiko. Pathomechanismen und therapeutische Optionen.

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.

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.