Background-Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, predicts mortality in cardiovascular disease and has been linked to cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). In this prospective study, we assessed whether circulating ADMA, arginine:ADMA ratio, and nitrite/nitrate levels were associated with survival and cerebral vasospasm in SAH patients. Methods-One hundred and eleven patients were observed day 1 to 15 after SAH, with serial measurements of transcranial Doppler flow velocities (V MCA ) and plasma biomarkers. Clinical status was assessed by the World Federation of Neurosurgical Societies grading scale. Results-Overall 30-day mortality was 18%, but differed between patients grouped by low, midrange, and high arginine:ADMA ratio in the first week after SAH. Mortality rates were 14/37, 1/37, and 5/37 in the 3 groups, respectively (P-logrank=0.0003). Cox regression showed that low versus midrange or high arginine:ADMA was associated with a hazard ratio of 4.1 independent of World Federation of Neurosurgical Societies grade (95% confidence interval, 1.5-10.9; P=0.006). ADMA or arginine:ADMA had no association to V MCA , but there was an inverse relationship between V MCA and nitrite/nitrate levels (P<0.0001). The NOS3 894G/G genotype was associated with 15% lower V MCA (P=0.01). ATbG-NOS3 haplotype homozygosity was associated with up to 64% higher nitrite/nitrate levels (P=0.003). Conclusions-This

TCCD measurement variability is wider in patient measurements than in controls. This discrepancy can largely be explained by a higher degree of error in patients with angiographic vasospasm. Despite the considerable measurement variability in TCCD, values are predictive of outcome in SAH.

In this Danish population, ACE haplotypes and the I/D polymorphism did not contribute significantly to the overall risk of intracranial aneurysm rupture. Larger studies are needed to delineate the association between ACE polymorphism and ruptured middle cerebral artery aneurysms.

Object. The nitric oxide system has been linked to the pathogenesis of aneurysmal subarachnoid hemorrhage (SAH). The authors performed a case-control study to investigate the association between SAH and common genetic variants within the endothelial nitric oxide synthase gene (NOS3).Methods. Three hundred thirty-three Caucasian SAH patients and 498 controls were genotyped for the -922A > G (rs 1800779), -786T > C (rs2070744), and 894G > T (rs1799983) single nucleotide polymorphisms and the intron-4 27-bp variable number of tandem repeats polymorphism (27-bp-VNTR).Results. The b/b (5 repeats) genotype of the 27-bp-VNTR was overrepresented in cases (77%) versus controls (69%) (p = 0.02). In male patients the b/b genotype was found in 85% compared with 67% in male controls, whereas in women, the frequencies were 73% and 72%, respectively. This corresponds to an odds ratio of 2.8 (95% CI 1.5-5.6, p = 0.0005) for SAH in men with the b/b genotype versus men with a/b or a/a. In women, no such association was found (OR 1.1, 95% CI 0.7-1.6, p = 0.76). Stepwise logistic regression including arterial hypertension, smoking, sex, and age with interactions yielded similar effect estimates of the 27-bp-VNTR. Haplotype analysis revealed that no single haplotype containing the b-allele was responsible for the observed genotype effect.Conclusions. The authors' results suggest that the NOS3 27-bp-VNTR b/b genotype independent of other risk factors act in concert with male sex to substantially increase risk of SAH. This effect is not mediated by any single NOS3 haplotype.

Peripheral flow-mediated vasodilation is attenuated in the first days after SAH indicating acute systemic endothelial dysfunction. Impairment of endothelial function after SAH correlates with imbalance of the arginine/ADMA pathway.

BackgroundSchizophrenia is associated with increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of the nitric oxide synthase, and the L-arginine:ADMA ratio are markers of endothelial dysfunction that predict mortality and adverse outcome in a range of cardiovascular disorders. Increased ADMA levels may also lead to increased oxidative stress. We hypothesized that ADMA and the L-arginine:ADMA ratio are increased in somatically healthy schizophrenia patients treated with atypical antipsychotics (AAP), and that the ADMA and the L-arginine: ADMA ratio are positively correlated to measures of oxidative stress.MethodsWe included 40 schizophrenia patients treated with AAP, but without somatic disease or drug abuse, and 40 healthy controls. Plasma concentrations of ADMA and L-arginine were determined by high-performance liquid chromatography. Data were related to markers of systemic oxidative stress on DNA, RNA and lipids, as well as measures of medication load, duration of disease and current symptomatology.ResultsPlasma ADMA and the L-arginine:ADMA ratio did not differ between schizophrenia patients and controls. Furthermore, ADMA and the L-arginine:ADMA ratio showed no correlations with oxidative stress markers, medication load, or Positive and Negative Syndrome Scale scores.ConclusionsSchizophrenia and treatment with AAP was not associated with increased levels of plasma ADMA or the L-arginine:ADMA ratio. Furthermore, plasma levels of ADMA were not associated with levels of systemic oxidative stress in vivo.

Cerebral non-oxidative carbohydrate consumption may be driven by a β2-adrenergic mechanism. This study tested whether the 46G > A (G16R) single nucleotide polymorphism of the β2-adrenergic receptor gene (ADRB2) influences the metabolic and cerebrovascular responses to administration of adrenaline. Forty healthy Caucasian men were included from a group of genotyped individuals. Cardio- and cerebrovascular variables at baseline and during a 60-min adrenaline infusion (0.06 μg kg−1 min−1) were measured by Model flow, near-infrared spectroscopy and transcranial Doppler sonography. Blood samples were obtained from an artery and a retrograde catheter in the right internal jugular vein. The ADRB2 G16R variation had no effect on baseline arterial glucose, but during adrenaline infusion plasma glucose was up to 1.2 mM (CI95: 0.36–2.1, P < 0.026) higher in the Gly16 homozygotes compared with Arg16 homozygotes. The extrapolated steady-state levels of plasma glucose was 1.9 mM (CI95: 1.0 –2.9, PNLME < 0.0026) higher in the Gly16 homozygotes compared with Arg16 homozygotes. There was no change in the cerebral oxygen glucose index and the oxygen carbohydrate index during adrenaline infusion and the two indexes were not affected by G16R polymorphism. No difference between genotype groups was found in cardiac output at baseline or during adrenaline infusion. The metabolic response of glucose during adrenergic stimulation with adrenaline is associated to the G16R polymorphism of ADRB2, although without effect on cerebral metabolism. The differences in adrenaline-induced blood glucose increase between genotypes suggest an elevated β2-adrenergic response in the Gly16 homozygotes with increased adrenaline-induced glycolysis compared to Arg16 homozygotes.

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