NO Metabolite Levels Research Articles

Genderspecific differences of homocysteinemia and its influence on oxidative stress parameters and endothelial function in patients with stable forms of coronary heart disease

One of the early manifestations of atherosclerotic lesions is endothelial dysfunction developing under conditions of reduced nitric oxide production, hyperhomocysteinemia, and oxidative stress. Bearing in mind high interest shown to gender-specific peculiarities of cardiovascular diseases, it appears important to study the relationship between these features in men and women with stable forms of coronary heart disease (CHD). Material and methods. The study included 102 patients with sable COPD divided into 2 groups (men and women) and 40 practically healthy subjects. Plasma homocysteine levels were measured by high-resolution gas-liquid chromatography with fluorescent detector with the use of Eko-Novo Milikhrom A-02 apparatus (Russia). Standard methods were used to measure plasma lipids, products of their peroxidation (dienic conjugates and products reacting with 2-thibarbituric acid), antioxidant enzymes (glutathioneperoxidase, and superoxide dismutase in erythrocytes), activity of the ceruloplasmin-transferrin system (by electron paramagnetic resonance method), final metabolites of nitric oxide using the Gries reaction. The endothelial function was studies by ultrasound with the evaluation of endothelium-dependent vasodilation. Results. The mean levels of homocystein and final NO metabolites in men with stable CHD were 1.5 times higher (р=0,01) and 12% lower (р = 0,03) than in women. Endothelial dysfunction was more pronounced in men (р< 0,05). Conclusion. Patients with CHD exhibit significant gender-specific differences in blood levels of of homocystein and final NO metabolites as well as in endothelium-dependent vasoreactivity associated with intensification of lipid peroxidation and impairment of antioxidative protection.

Antenatal/early postnatal hypothyroidism alters arterial tone regulation in 2-week-old rats.

The mechanisms of vascular alterations resulting from early thyroid hormones deficiency are poorly understood. We tested the hypothesis that antenatal/early postnatal hypothyroidism would alter the activity of endothelial NO pathway and Rho-kinase pathway, which are specific for developing vasculature. Dams were treated with propylthiouracil (PTU, 7 ppm) in drinking water during gestation and 2 weeks after delivery, and their progeny had normal body weight but markedly reduced blood levels of thyroid hormones (ELISA). Small arteries from 2-week-old male pups were studied using wire myography, qPCR and Western blotting. Mesenteric arteries of PTU pups, compared to controls, demonstrated smaller maximum response to α1-adrenergic agonist methoxamine and reduced mRNA contents of smooth muscle differentiation markers α-actin and SERCA2A. Inhibition of basal NO synthesis by l-NNA led to tonic contraction of mesenteric arteries and augmented their contractile responses to methoxamine; both l-NNA effects were impaired in PTU pups. PTU pups demonstrated lower blood level of NO metabolites compared to control group (Griess reaction). Rho-kinase inhibitor Y27632 strongly reduced mesenteric arteries responses to methoxamine in PTU pups, that was accompanied by elevated Rho-kinase content in their arteries in comparison to control ones. Unlike mesenteric, saphenous arteries of PTU pups, compared to controls, had no changes in α-actin and SERCA2A contents and in responses to l-NNA and Y27632. In conclusion, thyroid hormones deficiency suppresses the anticontractile effect of NO and potentiates the procontractile Rho-kinase effects in mesenteric arteries of 2-week-old pups. Such alterations disturb perinatal cardiovascular homeostasis and might lead to cardiovascular pathologies in adulthood.

Electrical Activity of the Cerebral Structures and Regulatory Effects of NO, Steroid Hormones, and BDNF in Rats with Experimental Alcohol Addiction

In a chronic experiment on rats with induced alcohol addiction, it was shown that chronic alcoholization leads to decreases in the levels of cortisol and testosterone in the hypothalamus, amygdalar complex, and blood serum. Functional changes in the hippocampus and nucl. accumbens are believed to play a leading role in the formation of the alcohol withdrawal syndrome. Under these conditions, the level of NO metabolites in the above structures decreases against the background of increased BDNF concentrations in blood serum.

ОКСИД АЗОТА – БИОХИМИЧЕСКИЙ МАРКЕР ПАТОГЕНЕЗА ТУБЕРКУЛЕЗНОГО ПРОЦЕССА

Role of nitric oxide in the pathogenesis of pulmonary tuberculosis has been studied in 77 patients with new infiltrate pulmonary tuberculosis and 34 patients with fibrous cavernous pulmonary tuberculosis. The level of cumulative and endogenous nitrite depended on the clinical form of tuberculosis: in infiltrate pulmonary tuberculosis patients it was within the limits of reference ranges, and in fibrous cavernous pulmonary tuberculosis patients it was significantly lower. Results of statistical analysis point out at the significant homogeneity (monofunctionality) of the set of rates, defining the level of NO metabolites in blood serum in infiltrate pulmonary tuberculosis, namely: impact of adenosine deaminase, levels of α1-protease inhibitor, ceruleoplasmin and age. On the contrary in case of fibrous cavernous pulmonary tuberculosis the diverse (multi-functional) complexes were detected including clinical blood rates providing influence on the reduction of NO level in blood. Nitric oxide in the patients with both clinical forms of tuberculosis correlated with classical markers of system inflammatory response, thus nitric oxide can be regarded as an integral component of inflammatory response with potential evaluation of prognosis of specific lesions during follow-up of changes.

Role of Nitric Oxide Synthase on Blood Pressure Regulation and Vascular Function in Pregnant Rats on a High-Fat Diet.

While obesity is a leading risk factor for preeclampsia, the mechanisms whereby obese women are more susceptible to pregnancy-induced hypertension are unclear. As high-fat diet (HFD) is an important contributor to the development of obesity, we tested the hypothesis that pregnant rats on HFD have hypertension and endothelial dysfunction due to reduced nitric oxide synthase (NOS). Twelve-week-old Sprague-Dawley female rats were fed normal diet (ND, 13% fat kcal) or HFD (40% fat kcal) for 9 weeks. Timed-pregnant rats were then generated and the effect of HFD on mean arterial blood pressure (MAP) and vascular function was assessed on gestational day (GD) 19. MAP was not different between HFD and ND pregnant rats. Intriguingly, sensitivity to acetylcholine-induced endothelium-dependent vasorelaxation was enhanced in small mesenteric arteries of HFD dams compared to ND controls (logEC50 -7.9 ± 0.3 vs. -6.7 ± 0.3 M; P < 0.05). Additionally, HFD dams exhibited higher mesenteric artery expression of NOS3 and plasma levels of NO metabolites than ND controls (1738.0 ± 316.4 vs. 1094.0 ± 82.5 pg/mg and 72.5 ± 8.7 vs. 39.7 ± 4.5 µM, respectively; both P < 0.05). Further, to determine the role of NOS in modulating blood pressure in HFD pregnant rats, animals were treated with the nonselective inhibitor Nω-Nitro-l-arginine methyl ester hydrochloride (100 mg/l, drinking water) from GD 14 to 19. It was found that NOS inhibition increased MAP equally in HFD and ND groups. Contrary to our initial hypothesis, HFD dams were normotensive and presented increased endothelial function and NO/NOS3 levels. This enhanced NOS-mediated vascular function does not appear to have a major impact on blood pressure regulation of HFD-fed pregnant rats.

CHARACTERISTIC OF MECHANISMS OF ANTIULCEROGENIC ACTION OF AGENTS OF VANILLOID RECEPTORS (TRPV1) ON THE MODEL OF GASTROPATHY INDUCED BY ACETYLSALICYLIC ACID

One of the main problems of the use of acetylsalicylic acid (ASA) is its withdrawal or initial “non-prescription” resulted from the prior developed or potential side effects in the gastrointestinal tract. In this case, the reasons for the abolition of ASA are not only serious complications in the form of gastrointestinal bleeding or perforations, but also dyspeptic phenomena that are accompanied by the ongoing development of aspirin-induced gastroenteropathy. The aim of the study. To characterize the mechanisms of antiulcerogenic action of agonist TRPV1 (transient receptor potential vanilloid 1) vanillin (100 mg/kg) on the model of subchronic ASA-induced gastropathy in rats. Materials and methods. The study was performed on 35 mature male rats. Gastropathy induced by ASA was simulated by a fiveday intragastric (i.g.) introduction via the orogastric probe of an ASA suspension of 150 mg/kg/ day during 5 days. Omeprazole (50 mg/kg, i.g.) and vanillin (100 mg/kg, i.g.) were administered in the form of suspensions 60 minutes prior to the use of ASA. The concentration of malonic dialdehyde, and the activity of catalase were determined in the homogenates of gastric mucosa. The prooxidant/antioxidant ratio (ProAntidex) was calculated dased on the ratio of catalase activity (mcat/kg) and the concentration of malondialdehyde (MDA concentration (umol/kg). The content of NO metabolites in the stomach tissues was determined by the method of Miranda K.M. et al. Results and discussion. Preventive prophylactic use of vanillin (100 mg/kg) leads to the decrease in the intensity of processes of lipid peroxidation in the gastric mucosa caused by the action of ASA (150 mg/kg). This was indicated by a statistically significant (p≤0.05) decrease of 26.4% in MDA content and an increase in catalase activity by 29.0% relatively to those animals with ASA-induced gastropathy without correction. Also, the use of vanillin resulted in a statistically significant (p≤0.05) increase in the content of NO metabolites by 68.0% (841.4 ± 35.95 umol / g) relatively to the animals of the control group. With the combined use of vanillin and omeprazole, a statistically significant (p≤0.05) absolute normalization of the NO metabolite level (927.4 ± 34.78 mmol/g) in the gastric mucosa was established, which corresponded to the indices of intact animals. Conclusion. The study showed that the activation of vanilloid (capsaicinoid) receptors due to the use of TRPV1 agonist, in particular vanillin, can reduce deistvie ulcerogenic NSAID, including ASA, that allows to consider the TRPV1 agonists as a new class gastroprotective drugs.

ENDOTHELIAL DYSFUNCTIONS AND THEIR CORRECTION IN WOMEN WITH EARLY POSTMENOPAUSE

Aim. To evaluate the nature of the dysfunction of the endothelium in postmenopausal women with climacteric syndrome, peculiarities of its changes during long-term use of a fixed low-dose combination of 17β-estradiol 1 mg/drosperidone 2 mg daily (Е2 1 mg/DRSP 2 mg). Material and methods. A non-randomized, uncontrolled study included 162 women in early postmenopausal period with climacteric syndrome. Patients were divided into 2 groups. Patients of the main group (n=84) received menopausal hormone therapy (MHT) with the fixed combination of Е2 1 mg/DRSP 2 mg. Patients of the control group (n=78) did not receive MHT. The duration of the follow-up was 5.2 years. The endothelium dependent vasodilation (EDVD) of brachial artery was assessed by reactive hyperemia. Endothelial dysfunction (ED) markers - plasma levels of endothelin-1 (ET-1), NO metabolites, asymmetric dimethylarginine (ADMA) and von Willebrand factor antigen (vWF:Ag) - were studied by a highly sensitive quantitative enzyme-linked immunosorbent assay. Results. The examined postmenopausal women with climacteric syndrome had significant increase in the concentration of ET-1 up to 1.0 (0.7-1.3) fmol/ml, increased levels of vWF:Ag up to 0.835 (0.760-0.990) U/ml and reduction in the level of the total content of stable metabolites of nitric oxide (NOx) to 39.2 (35.4-43.7) μmol/l. Disorders of EDVD of the brachial artery were observed in 50 (59.5%) women of the main group and in 45 (57.6%) women of the control group (p=0.7). The relationships between EDVD parameters and levels of ADMA (r=-0.31, p=0.029) and NOx (r=0.31, p=0.002) were revealed. In patients with impaired EDVD, a significant decrease in the level of stable NO metabolites and an increase in ADMA and ET-1 levels were detected. A significant increase in the EDVD of the brachial artery was observed throughout the follow-up period. Besides an increase in NO metabolites level, and decrease in the ET-1 and ADMA levels were found by the 12th month of MHT. Conclusions. Disorders of endothelial function were found in the majority of women in early postmenopausal period, the most marked changes were in patients with impaired vasoreactivity of brachial artery. Favorable changes in vascular endothelium function were observed during long-term MHT with the fixed combination of Е2 1 mg/DRSP 2 mg.

PP.29.10] EFFECTS OF AMLODIPINE AND ATORVASTATIN ON ENDOTHELIAL VASOACTIVE MEDIATORS IN PATIENTS WITH METABOLIC SYNDROME

Objective: To study the effects of the amlodipine and atorvastatin on the blood levels of endothelial vasoactive mediators in patients with metabolic syndrome (MS).Design and method: In our study we included 60 patients with MS and mild arterial hypertension. Patients were randomized into three treatment groups: monotherapy with amlodipine, monotherapy with atorvastatin and a combination therapy with amlodipine and atorvastatin. Office blood pressure (BP), NO metabolite levels («Shimadzu», Japan), endothelin-1 (ET-1) («Biomedica Gruppe», Austria), thromboxane B2 (TxB2) and 6-keto-prostaglandin F1α (6-ketoPG F1.α) (Assay designs) were performed at baseline and after 24 weeks of the therapy. In the control group was had 20 healthy volunteers. Data were represented as median (Med) and 25%-75% interquartile range or mean and standard deviation. p-value < 0,05 was considered as statistically significant Results: Monotherapy with amlodipine and combination therapy with amlodipine and atorvastatin were associated with the significant decreased office BP. Initially TxB2, 6-ketoPG F1α, ET-1 levels were significantly higher at patients with MS then in control group. Difference in NO metabolite level didn’t reach statistical significance. Monotherapy with amlodipine and atorvastatin or in a combination showed significant improvements in several studied parameters of endothelial vasoactive mediators. The results are shown in table 1. Conclusions: Amlodipine and atorvastatin treatment was showed positive effects on the levels of vasoactive mediators thereby leading to the improvement of endothelial function in patients with MS.

Endothelial nitric oxide weakens arterial contractile responses and reduces blood pressure during early postnatal development in rats

ObjectiveDuring maturation the vascular system undergoes structural and functional remodeling. At the systemic level it results in a gradual increase of arterial blood pressure during postnatal ontogenesis. The mechanisms of maintaining the blood pressure at a comparatively low level during the early postnatal development are not completely understood. Recently we showed that the hindlimb arteries of young (1-2 wk-old) rats exhibited an enhanced endothelial NO-pathway activity, which weakened their contractile responsiveness compared to the arteries of adult rats. Here we tested the hypothesis that an increased tonic endothelial NO production can take place in the whole vascular system leading to a decreased level of systemic blood pressure in young rats. Design and MethodsSegments of small mesenteric, saphenous, sural and intrarenal arteries were isolated from the young (2 wk-old), juvenile (4 wk-old) and adult (10-12 wk-old) male rats and tested in a wire isometric myograph. Anticontractile effect of NO was evaluated by the effects of NOS inhibitor L-NNA on both arterial spontaneous tone and constrictor responses to methoxamine (α1-adrenoceptor agonist). In addition, eNOS and arginase-2 mRNA expression in arterial preparations by qPCR and serum nitrite/nitrate levels by Griess reaction were estimated. Blood pressure with an intra-carotid artery catheter was measured in conscious rats. ResultsIn all arteries of 2 wk rats except the renal ones, L-NNA exposure resulted in a considerable tonic contraction and a remarkable enhancement of contractile responses to methoxamine. The effect of L-NNA gradually decreased with age and by 10–12 weeks became very small in the mesenteric arteries and disappeared in the sural and saphenous arteries. Although no difference in eNOS mRNA expression was found, the content of arginase-2 mRNA was significantly lower in young rats compared to adults. Serum levels of NO metabolites were two-fold higher in 2 wk-old rats than in adult rats. Along with that, arterial blood pressure was by half lower but rose more prominently after administration of l-NAME in young rats than in adults. ConclusionsIn young rats, tonic release of NO by the endothelium considerably weakens contractile responses of arteries supplying intestine, skin and skeletal muscles, which receive a high proportion of the cardiac output. Such anticontractile effect of NO can be an important mechanism responsible for the blood pressure reduction in immature circulatory system.

The acute prothrombotic effect of aldosterone in rats is partially mediated via angiotensin II receptor type 1

IntroductionWe showed previously that the prothrombotic effect of one hour aldosterone (ALDO) infusion in rats was only partially mediated by the mineralocorticoid receptor (MR). Bearing in mind that ALDO potentiates the effects of angiotensin II (Ang II), in the present study we investigated the role of Ang II receptor type 1 — AT1 in acute ALDO prothrombotic action. Materials and methodsThe experiments were performed in a stasis-induced venous thrombosis model in male Wistar, normotensive rats. ALDO (30μg/kg) was infused for 1h. Valsartan (VAL; 10mg/kg), a selective AT1 receptor antagonist, was administered in a single bolus injection before ALDO infusion. Eplerenone (EPL, 100mg/kg), a selective MR receptor antagonist, was administered per os before ALDO. Thrombus weight and incidences of thrombosis were assayed. Bleeding time and platelet adhesion to collagen were evaluated as primary hemostasis parameters. The plasma levels of some coagulation and fibrinolysis parameters, and plasma NO metabolite levels were assayed. ResultsAT1 blockade with valsartan significantly reduced ALDO-induced thrombosis expressed as a reduced thrombus mass (p<0.05 vs ALDO) and diminished the incidence of thrombosis. Valsartan reduced the ALDO-induced changes in bleeding time and platelet adhesion, as well as in coagulation, fibrinolysis, and NO metabolite levels. The effect of AT1 blockade in ALDO-induced thrombosis was similar to the effect of MR blockade. However, dual blockade of AT1 and MR showed no additional benefit. ConclusionsALDO prothrombotic action is partially mediated via AT1 receptor in the mechanism involving enhanced platelet activation, induced coagulation, impaired fibrinolysis and reduced NO bioavailability.

Effects of amlodipine and atorvastatin on endothelial vasoactive mediators in patients with metabolic syndrome

Aims: to study the effects of the amlodipine and atorvastatin on the blood levels of vasoactive mediators in patients with metabolic syndrome (MS). Design and methods. There were included 60 patients with MS, hypertension and dyslipidemia who were randomized into three treatment groups: monotherapy with amlodipine, atorvastatin monotherapy and a combination therapy with amlodipine and atorvastatin. Office blood pressure, 24-hour ambulatory blood pressure monitoring, measurements of the NO metabolite levels, endothelin-1, thromboxane B2 (TxB2) and 6-keto-prostaglandin F1α (6-keto-PGF1α) were performed at baseline and after 24 weeks of the therapy.Results. Amlodipine and atorvastatin in monotherapy or in a combination were associated with the significant improvement of certain studied parameters. Amlodipine treatment significantly decreased TxB2 and 6-keto-PGF1α levels. There was a significant reduction of TxB2, 6-keto-PGF1a levels and increase of NO metabolite in atorvastatin group. Treatment with combination of amlodipine and atorvastatin was characterized by significant decrease of TxB2 and endothelin-1 and increase of NO metabolite.Conclusion. Amlodipine and atorvastatin treatment showed positive effects on the levels of vasoactive mediators thereby leading to the improvementof endothelial function in patients with MS.

Влияние амлодипина и аторвастатина на вазоактивные медиаторы эндотелия у больных с метаболическим синдромом

Aims: to study the effects of the amlodipine and atorvastatin on the blood levels of vasoactive mediators in patients with metabolic syndrome (MS). Design and methods. There were included 60 patients with MS, hypertension and dyslipidemia who were randomized into three treatment groups: monotherapy with amlodipine, atorvastatin monotherapy and a combination therapy with amlodipine and atorvastatin. Office blood pressure, 24-hour ambulatory blood pressure monitoring, measurements of the NO metabolite levels, endothelin-1, thromboxane B2 (TxB2) and 6-keto-prostaglandin F1α (6-keto-PGF1α) were performed at baseline and after 24 weeks of the therapy.Results. Amlodipine and atorvastatin in monotherapy or in a combination were associated with the significant improvement of certain studied parameters. Amlodipine treatment significantly decreased TxB2 and 6-keto-PGF1α levels. There was a significant reduction of TxB2, 6-keto-PGF1a levels and increase of NO metabolite in atorvastatin group. Treatment with combination of amlodipine and atorvastatin was characterized by significant decrease of TxB2 and endothelin-1 and increase of NO metabolite.Conclusion. Amlodipine and atorvastatin treatment showed positive effects on the levels of vasoactive mediators thereby leading to the improvementof endothelial function in patients with MS.

PS-205 Inhaled Nitric Oxide Increases Urinary Nitric Oxide Metabolites And Cgmp In Premature Infants: Relationship To Pulmonary Outcome

Background/aims Inhaled NO (iNO) has been tested for prevention of bronchopulmonary dysplasia in premature infants, however the role of cGMP is not known. We hypothesised that levels of NO metabolites (NOx) and cGMP in urine, as a non-invasive source for biospecimen collection, would reflect the dose of iNO and relate to pulmonary outcome. Methods Studies were performed on 125 infants Results In NO-treated infants there was a significant dose-dependent increase of both urinary NOx and cGMP per creatinine (maximal 3.1- and 2-fold, respectively, at 10–20 ppm iNO) compared to off iNO. The ratio of cGMP to NOx, which may reflect efficiency of NO signalling via guanylate cyclase, was lower (mean 38%) at all doses of iNO compared to off NO. NOx and cGMP concentrations at both 2 ppm and off iNO were inversely related to severity of lung disease (Respiratory Severity Score) during the first month, and the NOx levels were lower in infants who died or developed BPD at term. NOx was higher in Caucasian compared to other infants at all iNO doses. Conclusions Urinary NOx and cGMP are biomarkers of endogenous NO production and lung uptake of iNO, and levels at some doses reflect the severity of lung disease in infants. These results support a role of the NO-cGMP pathway in lung development and repair from injury.

Inhaled nitric oxide increases urinary nitric oxide metabolites and cyclic guanosine monophosphate in premature infants: relationship to pulmonary outcome.

Inhaled nitric oxide (iNO) has been tested to prevent bronchopulmonary dysplasia (BPD) in premature infants, however, the role of cyclic guanosine monophosphate (cGMP) is not known. We hypothesized that levels of NO metabolites (NOx) and cGMP in urine, as a noninvasive source for biospecimen collection, would reflect the dose of iNO and relate to pulmonary outcome. Studies were performed on 125 infants who required mechanical ventilation at 7 to 14 days and received 24 days of iNO at 20-2 ppm. A control group of 19 infants did not receive iNO. In NO-treated infants there was a dose-dependent increase of both NOx and cGMP per creatinine (maximal 3.1- and 2-fold, respectively, at 10-20 ppm iNO) compared with off iNO. NOx and cGMP concentrations at both 2 ppm and off iNO were inversely related to severity of lung disease during the 1st month, and the NOx levels were lower in infants who died or developed BPD at term. NOx was higher in Caucasian compared with other infants at all iNO doses. Urinary NOx and cGMP are biomarkers of endogenous NO production and lung uptake of iNO, and some levels reflect the severity of lung disease. These results support a role of the NO-cGMP pathway in lung development.

Asiatic acid reduces blood pressure by enhancing nitric oxide bioavailability with modulation of eNOS and p47phox expression in L-NAME-induced hypertensive rats.

We investigated the effect of asiatic acid (AA) on hemodynamic status, vascular function, oxidative stress markers, endothelial nitric oxide synthase (eNOS), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit expression in Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats treated with L-NAME (40 mg/kg/day) in drinking water for 5 weeks showed significant increases in mean arterial pressure, heart rate, hindlimb vascular resistance, vascular dysfunction, superoxide anion (O2(•-)) production, and plasma malondialdehyde. Moreover, NO metabolite (NOx) levels were reduced, aortic eNOS expression was downregulated, and NADPH oxidase subunit p47(phox) was upregulated in hypertensive rats (p < 0.05). Hypertensive rats that were administered AA (10 or 20 mg/kg/day) for the last 2 weeks of the study showed significant improvement in hemodynamic status and vascular function. The antihypertensive effects of AA were associated with elevated plasma NOx levels, together with upregulation of eNOS expression. Decreased vascular O2(•-) production, consistent with downregulation of p47(phox) expression, was also observed after AA treatment. Our results are therefore consistent with a model whereby AA reduces blood pressure by enhancing NO bioavailability.

Effects of Acute and Chronic Stress on the L-Arginine Nitric Oxide Pathway in Black and White South Africans

This study investigated the impact of stress on effectors of the L-arginine/nitric oxide (NO) system including the endogenous inhibitor asymmetric dimethylarginine (ADMA). Black (n = 168) and white (n = 206) South African teachers were exposed to a mental and a physical stressor for 1 minute, respectively. Serum samples for determination of l-arginine, NO metabolites, ADMA, and symmetric dimethylarginine (SDMA) were obtained at rest and during stress exposure. Perception of task stressfulness was assessed on a 7-point Likert scale, and psychological distress was estimated by the General Health Questionnaire. Black South Africans exhibited higher resting levels of NO metabolites (adjusted mean [standard error of the mean] = 11.3 [1.3] versus 3.9 [1.1] μmol/l, p < .001) but lower circulating ADMA (0.62 [0.02] versus 0.70 [0.02] μmol/l, p = .004) and SDMA (0.41 [0.01] versus 0.53 [0.01] μmol/l, p < .001) than did white South Africans. Ethnicity-by-psychological distress interaction was observed for resting levels of ADMA (p = .002), SDMA (p = .038), and L-arginine (p = .048). Ethnic differences in responses to experimental stress were evident for NO metabolites (blacks versus whites: 5.94 [1.55] versus -0.74 [1.25] μmol/l, p = .004) and SDMA (blacks versus whites: -0.02 [0.01] versus 0.02 [0.01] μmol/l, p = .004). Ethnicity-by-psychological distress interaction for stress responses was found for l-arginine/ADMA ratio (p = .027). The l-arginine/NO system is affected by psychosocial distress with higher susceptibility in black South Africans. This interaction may contribute to the higher cardiovascular disease risk in black South Africans.

Letter by Tsuda Regarding Article, “Low Plasma Arginine:Asymmetric Dimethyl Arginine Ratios Predict Mortality After Intracranial Aneurysm Rupture”

To the Editor: We read with great interest the article by Staalso et al1 pertaining to the relationship between asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, and survival in patients with aneurysmal subarachnoid hemorrhage. The results of their study demonstrated that a low arginine:ADMA ratio in the first week after subarachnoid hemorrhage predicted mortality rate in the first 30 days. The arginine:ADMA ratio was negatively correlated with the serum NO-metabolite levels. In addition, the arginine:ADMA ratio was higher in good grade patients, but did not change significantly overtime. The authors proposed that plasma arginine:ADMA ratio might be associated with the pathophysiology …

Roles of Sex Steroid Hormones and Nitric Oxide in the Regulation of Sympathetic Nerve Activity in Women

HomeHypertensionVol. 61, No. 4Roles of Sex Steroid Hormones and Nitric Oxide in the Regulation of Sympathetic Nerve Activity in Women Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBRoles of Sex Steroid Hormones and Nitric Oxide in the Regulation of Sympathetic Nerve Activity in Women Kazushi Tsuda Kazushi TsudaKazushi Tsuda Cardiovascular and Metabolic Research CenterKansai University of Health SciencesOsaka, Japan Search for more papers by this author Originally published4 Mar 2013https://doi.org/10.1161/HYPERTENSIONAHA.111.01075Hypertension. 2013;61:e36Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 To the Editor:We read with great interest the article by Dr Carter et al1 dealing with the relationship between ovarian cycle and sympathoexcitation in premenopausal women. The results of their study demonstrated that the mid luteal phase of the ovarian cycle was characterized by sympathoexcitation, and that the degree of sympathoexcitation might be partially dependent on the degree of sex steroid surges. The authors indicated that increases in estradiol were associated with decreases in muscle sympathetic nerve activity during the the mid luteal phase, suggesting that estradiol might be sympathoinhibitory. In addition, the strong inverse association between muscle sympathetic nerve activity and changes in estradiol/progesterone ratio was observed. The authors proposed that a dynamic interaction among estradiol, progesterone, and muscle sympathetic nerve activity may be related to the cardiovascular risk in postmenopausal women.Evidence indicates that one of the mechanisms underlying the cardiovascular protective effects of estrogen may be the enhancement of NO production. In an in vitro study presented earlier, we demonstrated that 17β-estradiol significantly improved membrane microviscosity of red blood cells through the NO-dependent mechanism in postmenopausal women.2 It was also shown that hormone replacement therapy ameliorated membrane microviscosity of red blood cells with a concomitant increase in plasma NO-metabolite levels in postmenopausal women.3 In this context, it is strongly suggested that estrogen-induced NO might have a beneficial effect on the rheological behavior and the microcirculation in postmenopausal women. Vongpatanasin et al4 have reported that transdermal estrogen replacement therapy decreased muscle sympathetic nerve activity at rest in postmenopausal women. On the contrary, it was demonstrated that acute intravenous administration of NO synthase inhibitors might increase blood pressure and activate sympathetic nerve activity,5 suggesting that NO might act as a sympathoinhibitory substance. Therefore, we would like to know whether the degree of estradiol and estradiol/progesterone ratio during the ovarian cycle might be correlated with the endothelial function, such as plasma and urinary NO-metabolite levels or flow-mediated dilatation of the brachial artery, in the study of Dr Carter et al. It would be important to assess more precisely the relationships among estrogen, progesterone, and NO, and their role in the regulation of sympathetic nerve activity during sex steroid surges.Kazushi TsudaCardiovascular and Metabolic Research CenterKansai University of Health SciencesOsaka, JapanDisclosuresNone.FootnotesLetters to the Editor will be published, if suitable, as space permits. They should not exceed 500 words (typed double-spaced) plus 5 references in length and may be subject to editing or abridgment.

Hyperhomocysteinemia and Increased Oxidative Stress Levels Are Associated with Impaired Membrane Fluidity of Red Blood Cells in Hypertensive and Normotensive Men: An Electron Spin Resonance Investigation

Hyperhomocysteinemia and oxidative stress may be strongly linked to hypertension, atherosclerosis and other cardiovascular diseases. The present study was performed to investigate possible relationships among plasma total homocysteine, plasma 8-iso-prostaglandin F2α (8-isoPG F2α: an index of oxidative stress), and membrane fluidity (a reciprocal value of membrane microviscosity) in hypertension. We measured the membrane fluidity of red blood cells (RBCs) in hypertensive and normotensive men using an electron spin resonance (ESR) and spin-labeling method. Membrane fluidity of RBCs was significantly decreased in hypertensive men compared with normotensive men. Plasma total homocysteine levels were significantly higher in hypertensive men than in normotensive men, and correlated with plasma 8-isoPG F2α. In contrast, plasma nitric oxide (NO)-metabolites (an index of endothelial function) were lower in hypertensive men than in normotensive men. The reduced membrane fluidity of RBCs was associated with increased total homocysteine and plasma 8-isoPG F2α levels and decreased plasma NO-metabolite levels. Multivariate regression analysis showed that, after adjusting for general risk factors, plasma total homocysteine and 8-isoPG F2α were significant determinants of membrane fluidity of RBCs, respectively. These results suggest that hyperhomocysteinemia and oxidative stress with endothelial dysfunction might have a close correlation with impaired rheologic behavior of RBCs and circulatory disorders in hypertensive men.

Contractile, but not endothelial, dysfunction in early inflammatory arthritis: a possible role for matrix metalloproteinase‐9

BACKGROUND AND PURPOSEExcess morbidity/mortality in rheumatoid arthritis (RA) is associated with increased incidence of cardiovascular disease. In this ‘proof-of-concept’ study, vascular function was characterized in the murine collagen-induced arthritis (mCIA) model, the benchmark choice for evaluation of the pathological processes and assessment of new therapies.EXPERIMENTAL APPROACHMice in the very early stages of arthritis development [and appropriate naïve (non-immunized) age-matched controls] were used in the study. Blood pressure was measured using tail cuff plethysmography. Vascular function in rings of isolated aorta was studied with isometric tension myography. Levels of NO metabolites (NOx), MMP-9 protein and IL-1β in plasma and MMP-9 protein in aortic homogenates were quantified.KEY RESULTSImpaired vascular contractile responses in arthritis were unaffected by ex vivo inhibition of NOS (endothelial/neuronal and inducible) or COX activities. Endothelium-dependent and -independent relaxation, plasma NOx and blood pressure were unaffected by arthritis. Plasma and aortic homogenate MMP-9 protein levels were increased significantly in arthritis. Incubation of aortic tissues from naïve control animals with exogenous MMP-9 impaired subsequent contractile responses, mirroring that observed in arthritis. A role for IL-1β in perpetuating contractile dysfunction and increasing aortic MMP-9 was excluded.CONCLUSIONS AND IMPLICATIONSThese data identify for the first time a relationship between early arthritis and contractile dysfunction and a possible role for MMP-9 therein, in the absence of overt endothelial dysfunction or increased NO production. As such, MMP-9 may constitute a significant target for early intervention in RA patients with a view to decreasing risk of cardiovascular disease.