Alveolar-derived exhaled nitric oxide is reduced in obstructive sleep apnea syndrome

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular diseases, in particular systemic arterial hypertension. We postulated that intermittent nocturnal hypoxia in OSAS may be associated to decreased fractional exhaled nitric oxide (FENO) levels from distal airspaces. METHODS: Multiple flow rate measurements have been used to fractionate nitric oxide (NO) from alveolar and bronchial sources in 34 patients with OSAS, in 29 healthy control subjects, and in 8 hypertensive non-OSAS patients. The effect of 2 days of treatment with nasal continuous positive airway pressure (nCPAP) on FENO was examined in 18 patients with severe OSAS. RESULTS: We found that the mean [+/- SE] concentrations of exhaled NO at a rate of 50 mL/s was 21.8 +/- 1.9 parts per billion (ppb) in patients with OSAS, 25.1 +/- 3.3 ppb in healthy control subjects, and 15.4 +/- 1.7 ppb in hypertensive control patients. The mean fractional alveolar NO concentration (CANO) in OSAS patients was significantly lower than that in control subjects (2.96 +/- 0.48 vs 5.35 +/- 0.83 ppb, respectively; p < 0.05). In addition, CANO values were significantly lower in OSAS patients with systemic hypertension compared to those in normotensive OSAS patients and hypertensive patients without OSAS. The mean values of CANO significantly improved after nCPAP therapy (2.67 +/- 0.41 to 4.69 +/- 0.74 nL/L, respectively; p = 0.01). CONCLUSIONS: These findings suggest that alveolar FENO, and not bronchial FENO, is impaired in patients with OSAS and that this impairment is associated with an increased risk of hypertension. NO production within the alveolar space is modified by treatment with nCPAP.     

Association of plasma dehydroepiandrosterone-sulfate levels with endothelial function in postmenopausal women with coronary risk factors.

Age-related decline of plasma dehydroepiandrosterone-sulfate (DHEA-S) levels may be associated with the risk of cardiovascular disease in women. We investigated whether plasma DHEA-S levels are related to endothelial function in postmenopausal women with coronary risk factors. One hundred and fifteen postmenopausal women (mean age+/-SD: 57+/-5 years; range: 48-65 years) who underwent measurement of flow-mediated vasodilation (FMD) of the brachial artery using ultrasonography were enrolled. Plasma hormone levels were determined in the morning after a 14-h fast, and the relationship between hormone levels and FMD was analyzed. DHEA-S was significantly correlated with %FMD (r=0.392, p<0.001), while estradiol, total testosterone and cortisol were not. %FMD in the highest quartile of DHEA-S was 1.8-fold higher than that in the lowest quartile (5.3+/-1.3 vs. 2.9+/-2.0 [means+/-SD], p<0.01). Multiple regression analysis revealed that DHEA-S was related to %FMD independent of age, body mass index, hypertension, hyperlipidemia, diabetes mellitus and smoking (beta=0.344, p<0.01), and was itself independent of age, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and smoking (beta=0.291, p<0.05). In conclusion, plasma DHEA-S levels were weakly but significantly related to endothelial function in postmenopausal women independent of other coronary risk factors, suggesting a protective effect of DHEA on the endothelium.     

Endothelial function in patients with obstructive sleep apnea syndrome but without hypertension

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) influences endothelial function and causes hypertension. OBJECTIVES: Our aim was to evaluate the role of endothelial dysfunction in the pathogenesis of hypertension in OSAS. METHODS: Twenty-three patients with OSAS but without hypertension and 15 healthy normotensive subjects were investigated. The presence or absence of OSAS was evaluated with a sleep study. Endothelial function was investigated with brachial artery ultrasound examination. RESULTS: Baseline characteristics were equivalent between the two groups. Minimal oxygen saturation and apnea-hypopnea indexes in the OSAS and control groups were 62.9 +/- 16.5 versus 94.9 +/- 1.1% (p < 0.0001) and 53.1 +/- 20.3 versus 3.8 +/- 0.9 (p < 0.0001), respectively. There was not statistically significant difference between basal brachial artery diameters measured in the morning and in the evening in all groups. Flow-mediated dilation (FMD) values measured in the morning were lower than those measured in the evening in both OSAS patients and the control group: FMD of OSAS patients was 6.04 +/- 3.18% in the morning and 10.38 +/- 4.23% in the evening hours (p = 0.001), and FMD of control subjects was 10.9 +/- 2.6% in the morning and 13.9 +/- 2.32 in the evening hours (p = 0.002). Differences in FMD values measured both in the morning and evening hours in OSAS patients were lower compared with those in control subjects (p < 0.0001 in the morning hours and p = 0.003 in the evening hours). CONCLUSIONS: We detected a prominent diurnal deterioration in endothelial function in normotensive OSAS patients compared with healthy subjects. This deterioration may occur due to ongoing hypoxemia during the night and it may be a possible cause of hypertension and atherosclerotic cardiovascular diseases in patients with OSAS.     

Oral L-arginine improves endothelial function in healthy individuals older than 70 years

Ageing is associated with progressive endothelial dysfunction in normal humans. Flow-mediated dilation (FMD) of the brachial artery is impaired in elderly individuals with cardiovascular disease and vascular nitric oxide (NO) bioavailability is reduced. We investigated whether oral L-arginine, the substrate for NO synthesis, can improve impaired FMD in healthy very old people. In a prospective, double-blind, randomized crossover trial, 12 healthy old subjects (age 73.8 +/- 2.7 years) took L-arginine (8 g p.o. two times daily) or placebo for 14 days each, separated by a wash-out period of 14 days. FMD was determined by high-resolution ultrasound in the brachial artery during reactive hyperaemia. Baseline artery diameter was 3.88 +/- 0.18 mm. L-Arginine significantly improved FMD (to 5.7 +/- 1.2%, p < 0.0001), whereas placebo had no effect (-0.25 +/- 0.7%; n.s.). After L-arginine, plasma levels of L-arginine increased significantly (114.9 +/- 11.6 versus 57.4 +/- 5.0 micromol/l), but placebo had no effect. As NO synthesis can be antagonized by its endogenous inhibitor asymmetric dimethyl L-arginine (ADMA), we determined ADMA plasma concentrations, which were elevated at baseline in comparison to healthy middle-aged individuals (3.9 +/- 0.2 versus 1.0 +/- 0.1 micromol/l; p < 0.0001). ADMA remained unchanged during treatment, but L-arginine supplementation normalized the L-arginine/ADMA ratio (p < 0.05). We conclude that in healthy very old age endothelial function is impaired and may be improved by oral L-arginine supplementation, probably due to normalization of the L-arginine/ADMA ratio.     

Impaired flow-mediated vasodilatation and insulin resistance in type 2 diabetic patients with albuminuria

An elevated urinary albumin excretion is associated with an increased risk of cardiovascular disease due to atherosclerosis, but the pathophysiological mechanism underlying this association is poorly understood. We studied 217 diabetic patients, that is, 121 normoalbuminuric patients, 71 microalbuminuric patients, and 25 macroalbuminuric patients. We evaluated flow-mediated dilatation of brachial artery (%FMD, one endothelial function marker associated with endogenous NO production), von Willebrand factor (vWF, endothelial activation marker), high-sensitive CRP (hsCRP, a low-grade inflammation marker), asymmetric dimethyl arginine (ADMA, an endogenous inhibitor of NO synthesis), and insulin sensitivity by steady-state plasma glucose method. %FMD was apparently decreased in microalbuminuric and macroalbuminuric patients compared with normoalbuminuric patients (p<0.001). Moreover, %FMD was significantly correlated with the degree of albuminuria (r=-0.38, p<0.05). On the other hand, vWF and hsCRP did not show significant difference between normoalbuminuric patients and microalbuminuric patients. In diabetic patients with macroalbuminuria, ADMA was significantly elevated compared to those with normoalbuminuria. Insulin sensitivity was significantly associated with urinary albumin excretion rate. These results suggested that endothelial dysfunction which may be due to impaired NO production and insulin resistance underlie the association between diabetic nephropathy and atherosclerosis in diabetic patients.     

Low testosterone level is an independent determinant of endothelial dysfunction in men.

We investigated whether a low plasma testosterone level is related to endothelial dysfunction in men with coronary risk factors. One hundred and eighty-seven consecutive male outpatients (mean age+/-SD: 47+/-15 years) who underwent measurement of flow-mediated vasodilation (FMD) of the brachial artery using ultrasonography were enrolled. The relationship between plasma hormones and FMD was analyzed. Total and free testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were significantly correlated with %FMD (r=0.261, 0.354 and 0.295, respectively; p<0.001), while estradiol and cortisol were not. %FMD in the highest quartile of free testosterone was 1.7-fold higher than that in the lowest quartile. Multiple regression analysis revealed that total and free testosterone were related to %FMD independent of age, body mass index, hypertension, hyperlipidemia, diabetes mellitus and smoking (beta=0.198 and 0.247, respectively; p<0.01), and were independent of age, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, fasting plasma glucose, smoking and nitroglycerin-induced dilation (beta=0.196 and 0.227, respectively; p<0.01). DHEA-S was not significantly related to %FMD in multivariate analysis. In conclusion, a low plasma testosterone level was associated with endothelial dysfunction in men independent of other risk factors, suggesting a protective effect of endogenous testosterone on the endothelium.     

Cardioprotective effect of a biofermented nutraceutical on endothelial function in healthy middle-aged subjects

We tested a biofermented nutraceutical (FPP) that has been previously shown to positively modulate nitric oxide (NO). Forty-two healthy middle-aged subjects were given 3 grams of FPP three times a day for 6 weeks, and tests were repeated at 3 and 6 weeks; the control group was given a placebo. Flow-mediated dilation (FMD) was measured together with NO compounds (nitrogen oxides [NOx]: NO(2)(-)+NO(3)(-)) plasma levels and asymmetrical dimethylarginine (ADMA). In the interventional group, overall FMD significantly increased from 4.2% to 7.3% (p<0.05 vs. placebo). A significant increase in plasma NO and a decrease in ADMA were detected after consumption of FPP (p<0.01). Although larger studies are awaited, it appears that, at least in healthy individuals, such nutraceutical intervention by positively acting on significant cardiovascular parameters can be considered in the armamentarium of a proactive age-management strategy.     

Salt loading on plasma asymmetrical dimethylarginine and the protective role of potassium supplement in normotensive salt-sensitive asians

Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. Because endothelial NO pathway is compromised in patients with salt-sensitive hypertension, we investigated whether the plasma ADMA can be modulated by chronic salt loading in normotensive salt-sensitive persons and its relationship with NO, and we further determined whether or not dietary potassium supplementation can reverse them. Sixty normotensive subjects (aged 20 to 60 years) were selected from a rural community of Northern China. All of the people were sequentially maintained on a low-salt diet for 7 days (3 g/day, NaCl), then a high-salt diet for 7 days (18 g/day), and high-salt diet with potassium supplementation for another 7 days (4.5 g/day, KCl). After salt loading, the plasma ADMA concentrations increased significantly in salt-sensitive subjects (0.89+/-0.02 micromol/L versus 0.51+/-0.02 micromol/L; P<0.05), whereas the plasma NOx levels reduced considerably (41.8+/-2.1 micromol/L versus 63.5+/-2.1 micromol/L; P<0.01). All of the abnormalities normalized when dietary potassium were supplemented (0.52+/-0.03 micromol/L versus 0.89+/-0.02 micromol/L for ADMA and 58.1+/-0.9 micromol/L versus 41.8+/-2.1 micromol/L for NOx). Statistically significant correlations were found among plasma ADMA level, the mean blood pressure, and the level of NO after salt loading in normotensive salt sensitive individuals. Our study indicates that high dietary potassium intake reduces blood pressure and ADMA levels while increasing NO bioactivity in normotensive salt-sensitive but not salt-resistant Asian subjects after salt loading.     

Pulse wave velocity as an indicator of atherosclerosis in obstructive sleep apnea syndrome patients

OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular morbidity and mortality. We investigated the values of brachial-ankle pulse wave velocity as an indicator of atherosclerosis in obstructive sleep apnea syndrome patients. MATERIALS AND METHODS: Brachial-ankle pulse wave velocity (baPWV) was measured in 104 OSAS patients and 104 healthy control subjects matched for age, sex, and body mass index (BMI). BaPWV values were compared in both groups and investigated with respect to the number of risk factors for atherosclerosis, including hypertension, hypercholesterolemia, impaired glucose tolerance, smoking, and obesity. Comparisons were also made between 48 OSAS group cases and 90 control group cases free from hypertension, which has a major impact on baPWV. RESULTS: As compared to the control group, the OSAS group had significantly higher baPWV (1,645+/-349 cm/s vs 1,436+/-278 cm/s, p<0.0001), and values obtained for baPWV were significantly higher in the OSAS group than in the control group even in groups free from hypertension (1,453+/-216 cm/s vs 1,374+/-213 cm/s, p<0.05). In both groups, baPWV rose as the number of risk factors for atherosclerosis increased, but baPWV was higher in the OSAS group than in the control group even in a comparison of individuals entirely free from risk factors (1,400+/-200 cm/s vs 1,198+/-79 cm/s, p<0.05). CONCLUSION: The condition of OSAS itself is considered a possible risk factor for atherosclerosis. We believe that the usefulness of baPWV as an index of atherosclerosis merits further study in the frequently observed cases of OSAS complicated by cardiovascular disease.     

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.     

Concurrent presence of metabolic syndrome in obstructive sleep apnea syndrome exacerbates the cardiovascular risk: a sleep clinic cohort study.

This cross-sectional study was conducted to examine whether the obstructive sleep apnea syndrome (OSAS) is associated with elevation of the pulse wave velocity (PWV) and increase in the plasma levels of C-reactive protein (CRP), both of which are known markers of cardiovascular risk, and also to determine if the concurrent presence of the metabolic syndrome might exacerbate this elevation in the levels of these cardiovascular risk markers in subjects with OSAS. With these objectives, the PWV and serum CRP were measured in 184 subjects attending a sleep clinic. It was found that the PWV and CRP were higher in the subjects with OSAS (n=94) than in those without OSAS (n=90). Furthermore, among the subjects with OSAS, the PWV and CRP were higher in those with the concurrent presence of the metabolic syndrome (n= 41; PWV=1,562+/-19 cm/s; CRP=1.8+/-0.2 mg/l) than in those without metabolic syndrome (n=53; PWV=1,432+/-21 cm/s; CRP=1.2+/-0.1 mg/l) (p<0.05). A general linear model analysis demonstrated that OSAS and metabolic syndrome were independently associated with elevated PWV and increase of the plasma levels of CRP. OSAS appears to be associated with increased cardiovascular risk, as reflected by both elevated PWV and increase of the plasma CRP. The concurrent presence of metabolic syndrome may exacerbate this increase in cardiovascular risk in subjects with OSAS. Therefore, the concurrent presence of metabolic syndrome may constitute an additive cardiovascular risk factor in subjects with OSAS.     

DDAH gene and cardiovascular risk

The crucial role of nitric oxide (NO) for normal endothelial function is well known. In many conditions associated with increased risk of cardiovascular diseases such as hypercholesterolemia, hypertension, abdominal obesity, diabetes and smoking, NO biosynthesis is dysregulated, leading to endothelial dysfunction. The growing evidence from animal and human studies indicates that endogenous inhibitors of endothelial NO synthase such as asymmetric dimethylarginine (ADMA) and NG-monomethyl-L-arginine (L-NMMA) are associated with the endothelial dysfunction and potentially regulate NO synthase. The major route of elimination of ADMA is metabolism by the enzymes dimethylarginine dimethylaminohydrolase-1 and -2 (DDAH). In our recent study 16 men with either low or high plasma ADMA concentrations were screened to identify DDAH polymorphisms that could potentially be associated with increased susceptibility to cardiovascular diseases. In that study a novel functional mutation of DDAH-1 was identified; the mutation carriers had a significantly elevated risk for cardiovascular disease and a tendency to develop hypertension. These results confirmed the clinical role of DDAH enzymes in ADMA metabolism. Furthermore, it is possible that more common variants of DDAH genes contribute more widely to increased cardiovascular risk.     

Plasma nitroso compounds are decreased in patients with endothelial dysfunction.

OBJECTIVES: We investigated whether plasma nitros(yl)ated species (RXNOs) that mediate systemic nitric oxide (NO) bioactivity are depleted in individuals with cardiovascular risk factors and endothelial dysfunction. BACKGROUND: Endothelium-derived NO acts not only as a regional messenger but exerts significant systemic effects via formation of circulating RXNOs delivering NO to sites of impaired production. METHODS: Endothelial function was assessed in 68 patients with one to four major cardiovascular risk factors (RF) and 39 healthy control subjects (C) by measurement of flow-mediated dilation (FMD) of the brachial artery using high-resolution ultrasound. In parallel, plasma RXNOs were determined by reductive gas phase chemiluminescence. RESULTS: Increasing numbers of risk factors were accompanied by a progressive decrease in FMD: 6.5 +/- 0.4% (C); 4.7 +/- 0.5% (one RF); 2.8 +/- 0.4% (two RF); 2.2 +/- 0.4% (three RF); and 1.0 +/- 0.3% (four RF). Progressively impaired vascular function was associated with a concomitant decrease in plasma RXNOs (p < 0.01): 39 +/- 2 nmol/l (C); 30 +/- 2 nmol/l (one RF); 24 +/- 3 nmol/l (two RF); 22 +/- 3 nmol/l (three RF); and 15 +/- 2 nmol/l (four RF), with univariate correlation between FMD and RXNO (r = 0.41, p < 0.001). In a multivariate regression model, RXNO was an independent predictor of endothelial function. CONCLUSIONS: Endothelial dysfunction in patients with cardiovascular risk factors is associated with decreased levels of circulating RXNOs. Plasma RXNOs may be diagnostically useful markers of NO bioavailability and a surrogate index of endothelial function. Whether the observed decrease in concentration reflects impaired NO formation, accelerated decomposition, and/or consumption of RXNOs and whether these processes play a causal role in the pathophysiology of arteriosclerosis remain to be investigated.     

Relationship between salt intake,nitric oxide and asymmetric dimethylarginine and its relevance to patients with end-stage renal disease

Patients with essential hypertension (n = 24) were administered a low-salt diet (2 g NaCl/day), a high-salt diet (20-23 g) and then a low-salt diet for 7 days, and plasma levels of nitrate and nitrite (NOx) and asymmetric dimethylarginine (ADMA) were examined. There was a negative correlation between the percent changes in mean blood pressure and the plasma NOx concentration after salt loading and restriction. The percent change in plasma ADMA concentration was negatively correlated with that in the plasma NOx concentration after salt loading and restriction. In patients with end-stage renal disease (n = 51), the plasma ADMA concentration was positively correlated with the duration of dialysis treatment. The frequency of cardiovascular events was greater in patients with a plasma ADMA level of >/=3 microM than in those with a plasma AMDA level of <3 microM. The results indicate that ADMA is not only a modulator of salt sensitivity in hypertension but also a cardiovascular risk factor in end-stage renal disease.     

Plasma concentrations of nitric oxide and asymmetric dimethylarginine in human alcoholic cirrhosis

BACKGROUND/AIMS: The liver plays a prominent role in the metabolism of asymmetric dimethyl-l-arginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. This study was designed to determine whether plasma levels of ADMA and NO production are altered in patients with compensated and decompensated alcoholic cirrhosis. METHODS: Plasma levels of l-arginine, ADMA, symmetric dimethylarginine (SDMA) and NO (nitrite plus nitrate, NOx) were measured in nine patients with compensated alcoholic cirrhosis (Child-Pugh A) and 11 patients with advanced cirrhosis (Child-Pugh B-C). Seven healthy volunteers served as controls. RESULTS: ADMA and NOx concentrations in decompensated cirrhosis were higher than in the compensated group and control group (ADMA: 1.12+/-0.08 vs. 0.58+/-0.05 and 0.58+/-0.07micromol/l, respectively; P<0.05; NOx 97.90+/-10.27 vs. 37.42+/-3.91 and 40.43+/-5.30micromol/l, respectively; P<0.05). There was a positive correlation between the clinical score of the patients and concentrations of ADMA (r(2)=0.547, P<0.01) and NOx (r(2)=0.689, P<0.01). SDMA and l-arginine levels were not significantly different between the three groups. CONCLUSIONS: The results suggest that hepatocellular damage is a main determinant of elevated ADMA concentration in advanced alcoholic cirrhosis. By inhibiting NO release from vascular endothelium, ADMA might oppose the peripheral vasodilation caused by excessive NO production in severe cirrhosis.     

Increased circulating concentrations of asymmetric dimethylarginine (ADMA) in white coat hypertension

Elevated plasma levels of the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) contribute to endothelial dysfunction and seem to be a predictor for cardiovascular mortality. Elevated ADMA plasma concentrations have been demonstrated in patients with hypertension. However, the plasma concentrations of ADMA in white coat hypertension (WCH) has not been previously studied. The aim of this study was to evaluate ADMA in WCH and compare with normotensive (NT) and hypertensive (HT) patients. We also evaluated the relation between ADMA and NO in these three groups. For this purpose, 34 NT, 34 white coat hypertensive (clinical hypertension and ambulatory daytime blood pressure <135/85 mmHg) and 34 HT patients were recruited in this study. The subjects were matched for age, gender, body mass index (BMI) and the patients with smoking habit, dyslipidaemia and diabetes mellitus were excluded. The ADMA levels were determined by high performance liquid chromatography. Plasma ADMA levels were significantly higher in WCH group than in the NT group (3.21+/-0.49 micromol/l vs 2.84+/-0.58 micromol/l, P=0.046). It was significantly higher in the HT group than in the NTs (4.24+/-0.38 micromol/l, P<0.001). There was also a significant difference between the HT and WCH groups (P<0.001). The WCH subjects had significantly higher levels of NO than the HTs (41.68+/-2.23 vs 32.18+/-2.68 micromol/l; P<0.001) and significantly lower values than the NTs (48.24+/-4.29 micromol/l; P<0.001). In WCH and HT group, there was a negative correlation between ADMA and NO (r=-0.515, P=0.003 and r=-0.389, P=0.034, respectively). In NT subjects, there was no correlation between these two parameters (r=-0.287, P=0.124). The correlation between ADMA and NO was stronger in WCH group than in HT group. Although NO levels in HT patients were lower than WCHs and ADMA levels were higher in HT patients than WCHs, the negative correlation of these two parameters were more pronounced in WCH group. Decreased NO and increased ADMA levels in WCH may indicate endothelial dysfunction. Our data indicate also that WCH represent an intermediate group between NT and HT when endothelial dysfunction is concerned.     

Significance of asymmetric dimethylarginine (ADMA) concentrations during coronary circulation in patients with vasospastic angina.

The basal activity of nitric oxide (NO) is reduced in spastic arteries of patients with vasospastic angina (VSA). Elevated concentrations of ADMA are associated with reduced NO production and impaired endothelium-dependent vasodilatation. The aim of this study was to elucidate the role of ADMA and its relationship to NO end-products (NOx; nitrate + nitrite) during coronary circulation in patients with VSA. The plasma ADMA and NOx concentrations during coronary circulation were evaluated in 16 VSA and 16 control patients. Blood samples were obtained from the coronary sinus (V) and the ostium of the left coronary artery (A), and the (V-A) differences of ADMA and NOx were determined. The coronary sinus plasma ADMA concentration in patients with VSA was higher than that in the control. The coronary sinus - arterial (V-A) difference of NOx was negative in the VSA group and approximately zero in the control group (VSA group =-1.4 micromol/L, control group =-0.1 micromol/L, p=0.0005). Furthermore, in the VSA patients, there was a negative correlation between the (V-A) difference of NOx and the basal coronary artery tone at the site of spasm (r=-0.60, p=0.015). A significant negative correlation between the (V-A) differences of NOx and ADMA was observed in patients with VSA (r=-0.52, p<0.05), but not in those of the control. Higher ADMA concentrations might cause the reduced formation of NO that underlies the pathophysiology of coronary vasospasm.     

Effect of nasal continuous positive airway pressure treatment on plasma adrenomedullin levels in patients with obstructive sleep apnea syndrome: roles of nocturnal hypoxia and oxidant stress.

Obstructive sleep apnea syndrome (OSAS) is recognized as one of the risk factors of hypertension and cardiovascular disorders. In the current study, we hypothesized that the hypoxic stress and oxidative stress caused by obstructive sleep apnea would increase circulating adrenomedullin (ADM) levels in untreated OSAS patients as compared to an age and body mass index (BMI)-matched control group and an age-matched, but normal-BMI control group. We further hypothesized that nasal continuous positive airway pressure (nCPAP) treatment may decrease OSAS-induced hypoxic stress, oxidative stress and ADM levels. To examine these hypotheses, we measured circulating ADM and reactive oxygen species (ROS) from leukocytes before and after nCPAP therapy in OSAS patients. The circulating levels of ADM and amount of ROS in untreated OSAS patients were significantly greater than those in the controls. No differences in ADM levels were found between the increased-BMI controls and normal-BMI controls. We observed that nCPAP treatment decreased sleep apneas, nocturnal oxyhemoglobin desaturation, the circulating ADM, and ROS production by leukocytes in OSAS patients. The ADM levels were associated with the magnitude of oxyhemoglobin desaturation rather than the number of sleep apneas. These observations suggest that nCPAP therapy could reduce OSAS-induced nocturnal hypoxemia, generation of ROS, and ADM in patients with OSAS.     

Endothelial function in obstructive sleep apnea and response to treatment

Impaired endothelium-dependent vascular relaxation is a prognostic marker of atherosclerosis and cardiovascular disease. We evaluated endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent nitroglycerin (NTG)-induced dilation of the brachial artery with Doppler ultrasound in 28 men with obstructive sleep apnea (OSA) and 12 men without OSA. Subjects with OSA (apnea-hypopnea index; mean +/- SD, 46.0 +/- 14.5) had lower FMD compared with subjects without OSA (5.3 +/- 1.7% vs. 8.3 +/- 1.0%, p < 0.001), and major determinants of FMD were the apnea-hypopnea index and age. There was no significant difference in NTG-induced dilation. Subjects with OSA were randomized to nasal continuous positive airway pressure (nCPAP) or observation for 4 weeks. Subjects on nCPAP had significant increase in FMD, whereas those on observation had no change (4.4% vs. -0.8%, difference of 5.2%, p < 0.001). Neither group showed significant change in NTG-induced vasodilation. Eight subjects who used nCPAP for over 3 months were reassessed on withdrawing treatment for 1 week. On nCPAP withdrawal, FMD became lower than during treatment (p = 0.02) and were similar to baseline values. Our findings demonstrated that men with moderate/severe OSA have endothelial dysfunction and treatment with nCPAP could reverse the dysfunction; the effect, however, was dependent on ongoing use.     

Effect of nasal continuous positive airway pressure in men on global left ventricular myocardial performance in patients with obstructive sleep apnea syndrome

The influence of obstructive sleep apnea syndrome (OSAS) on left ventricular function remains controversial. We examined the influence of OSAS on global left ventricular function using the myocardial performance index (Tei index) and plasma brain natriuretic peptide (BNP) level and investigated the effect of nasal continuous positive airway pressure (nCPAP) on these parameters. We obtained echocardiographic indexes including the Tei index and BNP concentrations from 27 patients with OSAS whose mean apnea-hypopnea index was 42.2+/-21.5 events/hour and who were undergoing nCPAP and from 22 control subjects. We defined global left ventricular dysfunction (GLVD) as a Tei index >or=0.50 and high BNP as >or=20 pg/ml. Compared with controls, the Tei index of patients with OSAS was significantly increased (p <0.01) and prevalence of GLVD was high (19%, p<0.05). The correlation between the Tei index and apnea-hypopnea index was significant (r=0.447, p<0.05). Although BNP levels were higher in patients with OSAS than in controls, the difference did not reach significance. BNP level was high in 37% of patients with OSAS and in only 9% of controls (p<0.05). The Tei index of patients with OSAS was significantly decreased after 1 month and 3 months of nCPAP (p<0.01), and prevalence of GLVD significantly decreased from 19% to 4% (p<0.05). In contrast, BNP significantly decreased at 3 months after nCPAP (p<0.05). In conclusion, patients with moderate to severe OSAS frequently have impaired global left ventricular myocardial performance, which can be reversed at the early stage after starting nCPAP.