Baseline left ventricular ejection fraction associated with symptom improvements in both children and adolescents with postural tachycardia syndrome under metoprolol therapy / 中华医学杂志(英文版)

BACKGROUND@#Postural tachycardia syndrome (POTS) is a common childhood disease that seriously affects the patient's physical and mental health. This study aimed to investigate whether pre-treatment baseline left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) values were associated with symptom improvement after metoprolol therapy for children and adolescents with POTS.@*METHODS@#This retrospective study evaluated 51 children and adolescents with POTS who received metoprolol therapy at the Peking University First Hospital between November 2010 and July 2019. All patients had completed a standing test or basic head-up tilt test and cardiac echocardiography before treatment. Treatment response was evaluated 3 months after starting metoprolol therapy. The pre-treatment baseline LVEF and LVFS values were evaluated for correlations with decreases in the symptom score after treatment (ΔSS). Multivariable analysis was performed using factors with a P value of  0.050). However, responders had significantly higher baseline LVEF (71.09% ± 4.44% vs. 67.17% ± 4.88%, t = -2.789, P = 0.008) and LVFS values (40.00 [38.00, 42.00]% vs. 36.79% ± 4.11%, Z = -2.542, P = 0.010) than the non-responders. The baseline LVEF and LVFS were positively correlated with ΔSS (r = 0.378, P = 0.006; r = 0.363, P = 0.009), respectively. Logistic regression analysis revealed that LVEF was independently associated with the response to metoprolol therapy in children and adolescents with POTS (odds ratio: 1.201, 95% confidence interval: 1.039-1.387, P = 0.013).@*CONCLUSIONS@#Pre-treatment baseline LVEF was associated with symptom improvement after metoprolol treatment for children and adolescents with POTS.

Body mass index is a promising predictor of response to oral rehydration saline in children with vasovagal syncope / 中华医学杂志(英文版)

BACKGROUND@#Vasovagal syncope (VVS) greatly impairs quality of life. The therapeutic efficacy of oral rehydration saline (ORS) for unselected VVS patients is not satisfactory due to the diverse mechanisms of the disease. Body mass index (BMI) was demonstrated to reflect blood volume to a certain extent. Therefore, the present study explored the capability of BMI to predict the therapeutic response of children with VVS to ORS treatment.@*METHODS@#Seventy-four children with VVS who visited the Syncope Unit of Pediatrics at Peking University First Hospital from November 2010 to June 2019 receiving ORS treatment were enrolled for this retrospective case-control study. A comparison of demographic, clinical, and hemodynamic characteristics was performed between responders and non-responders. The correlation between baseline BMI and response time was analyzed. To determine the value of baseline BMI in predicting the therapeutic efficacy of ORS in children with VVS, a receiver operating characteristic curve analysis was performed.@*RESULTS@#Fifty-two children were identified as responders, and the remaining 22 children were identified as non-responders. The baseline BMI of the responders was much lower than that of the non-responders (16.4 [15.5, 17.8] kg/m2vs. 20.7 ±e6 kg/m2, P < 0.001), and baseline BMI was positively correlated with response time in the head-up tilt test after adjusting for sex (r = 0.256, 95% confidence interval [CI]: 0.067-0.439, P = 0.029). The area under the receiver operating characteristic curve of baseline BMI was 0.818 (95% CI: 0.704-0.932, P < 0.001), and an optimal cut-off value of 18.9 kg/m2 yielded a sensitivity of 83% and a specificity of 73% to predict the efficacy of ORS in VVS.@*CONCLUSION@#Prior to treatment, baseline BMI is a promising predictor of response to ORS in children with VVS.

Hemodynamic changes in standing-up test of children and adolescents with postural tachycardia syndrome / 北京大学学报(医学版)

OBJECTIVE@#To explore the hemodynamic changes in standing-up test of children and adolescents with postural tachycardia syndrome (POTS) and to compare hemodynamic parameters of POTS patients with decreased cardiac index (CI) and those with not-decreased CI.@*METHODS@#A retrospective study was conducted to show the trends of CI, total peripheral vascular resistance index (TPVRI), heart rate and blood pressure in standing-up test of 26 POTS patients and 12 healthy controls, and to compare them between the two groups. The POTS patients were divided into two groups based on CI decreasing or not in standing-up test, namely decreased CI group (14 cases) and not-decreased CI group (12 cases). The trends of the above mentioned hemodynamic parameters in standing-up test were observed and compared between decreased CI group and not-decreased CI group.@*RESULTS@#In standing-up test for all the POTS patients, CI (F=6.936, P=0.001) and systolic blood pressure (F=6.049, P<0.001) both decreased significantly, and heart rate increased obviously (F=113.926, P<0.001). However, TPVRI (F=2.031, P=0.138) and diastolic blood pressure (F=2.018, P=0.113) had no significant changes. For healthy controls, CI (F=3.646, P=0.016), heart rate (F=43.970, P<0.001), systolic blood pressure (F=4.043, P=0.020) and diastolic blood pressure (F=8.627, P<0.001) all increased significantly in standing-up test. TPVRI (F=1.688, P=0.190) did not change obviously. The changing trends of CI (F=6.221, P=0.001), heart rate (F=6.203, P<0.001) and systolic blood pressure (F=7.946, P<0.001) over time were significantly different between the patients and healthy controls, however, no difference was found in TPVRI and diastolic blood pressure (P > 0.05). Among the POTS patients, CI was significantly different between decreased CI group and not-decreased CI group (F=14.723, P<0.001). Systolic blood pressure of the former decreased obviously (F=8.010, P<0.001), but it did not change obviously in the latter (F=0.612, P=0.639). Furthermore, none of the changes of TPVRI, heart rate and diastolic blood pressure in standing-up test were significantly different between the two groups (P > 0.05). Age was an independent factor for decreased CI patients (P=0.013, OR=2.233; 95% CI, 1.183 to 4.216).@*CONCLUSION@#POTS patients experience vital hemodynamic changes in standing-up test, part of them suffering from decreased CI, but others from not-decreased CI. Age is an independent factor for patients suffering from decreased CI.

Gut microbiota analysis and its significance in vasovagal syncope in children / 中华医学杂志(英文版)

BACKGROUND@#Vasovagal syncope (VVS) is common in children and greatly affect both physical and mental health. But the mechanisms have not been completely explained. This study was designed to analyze the gut microbiota in children with VVS and explore its clinical significance.@*METHODS@#Fecal samples from 20 VVS children and 20 matched controls were collected, and the microbiota were analyzed by 16S rRNA gene sequencing. The diversity and microbiota compositions of the VVS cases and controls were compared with the independent sample t test or Mann-Whitney U test. The correlation between the predominant bacteria and clinical symptoms was analyzed using Pearson or Spearman correlation test.@*RESULTS@#No significant differences in diversity were evident between VVS and controls (P > 0.05). At the family level, the relative abundance of Ruminococcaceae was significantly higher in VVS children than in controls (median [Q1, Q3]: 22.10% [16.89%, 27.36%] vs. 13.92% [10.31%, 20.18%], Z = -2.40, P  4, P < 0.05). The relative abundance of Ruminococcaceae in VVS patients was positively correlated with the frequency of syncope (r = 0.616, P < 0.01). In terms of its correlation with hemodynamics, we showed that relative abundance of Ruminococcaceae was negatively correlated with the systolic and diastolic pressure reduction at the positive response in head-up tilt test (HUTT; r = -0.489 and -0.448, all P < 0.05), but was positively correlated with the mean pressure drop and decline rate (r = 0.489 and 0.467, all P < 0.05) as well as diastolic pressure drop and decline rate at the HUTT positive response (r = 0.579 and 0.589, all P < 0.01) in VVS patients.@*CONCLUSION@#Ruminococcaceae was the predominant gut bacteria and was associated with the clinical symptoms and hemodynamics of VVS, suggesting that gut microbiota might be involved in the development of VVS.

Increased Endogenous Sulfur Dioxide Involved in the Pathogenesis of Postural Tachycardia Syndrome in Children: A Case-Control Study / 中华医学杂志(英文版)

<p><b>Background</b>The pathogenesis of postural tachycardia syndrome (POTS) remains unclear. This study aimed to explore the changes and significance of sulfur dioxide (SO) in patients with POTS.</p><p><b>Methods</b>The study included 31 children with POTS and 27 healthy children from Peking University First Hospital between December 2013 and October 2015. A detailed medical history, physical examination results, and demographic characteristics were collected. Hemodynamics was recorded and the plasma SOwas determined.</p><p><b>Results</b>The plasma SOwas significantly higher in POTS children compared to healthy children (64.0 ± 20.8 μmol/L vs. 27.2 ± 9.6 μmol/L, respectively, P < 0.05). The symptom scores in POTS were positively correlated with plasma SOlevels (r = 0.398, P < 0.05). In all the study participants, the maximum heart rate (HR) was positively correlated with plasma levels of SO(r = 0.679, P < 0.01). The change in systolic blood pressure from the supine to upright (ΔSBP) in POTS group was smaller than that in the control group (P < 0.05). The ΔSBP was negatively correlated with baseline plasma SOlevels in all participants (r = -0.28, P < 0.05). In the control group, ΔSBP was positively correlated with the plasma levels of SO(r = 0.487, P < 0.01). The change in HR from the supine to upright in POTS was obvious compared to that of the control group. The area under curve was 0.967 (95% confidence interval: 0.928-1.000), and the cutoff value of plasma SOlevel >38.17 μmol/L yielded a sensitivity of 90.3% and a specificity of 92.6% for predicting the diagnosis of POTS.</p><p><b>Conclusions</b>Increased endogenous SOlevels might be involved in the pathogenesis of POTS.</p>

Inhibitory Effects of Sulfur Dioxide on Rat Myocardial Fibroblast Proliferation and Migration / 中华医学杂志(英文版)

<p><b>Background</b>Myocardial fibrosis is an important pathological change in many heart diseases, but its pathogenesis is very complex and has not yet been fully elucidated. The study was designed to examine whether endogenous sulfur dioxide (SO) is a novel myocardial fibroblast proliferation and migration inhibitor.</p><p><b>Methods</b>Primary rat myocardial fibroblasts were isolated and transfected with aspartate aminotransferase (AAT1 and AAT2) knockdown lentivirus or empty lentivirus. SO content in the supernatant was determined with high-performance liquid chromatography, and the expressions of AAT1, AAT2, proliferating cell nuclear antigen (PCNA), phosphorylated extracellular signal-regulated protein kinase (p-ERK), and total ERK (T-ERK) in the cells were detected. Cell migration was detected by wound healing test. Independent sample t-test (for two groups) and one-way analysis of variance (three or more groups) were used to analyze the results.</p><p><b>Results</b>Both AAT1 and AAT2 knockdown significantly reduced SOlevels (F = 31.46, P < 0.01) and AAT1/2 protein expression (AAT1, t = 12.67, P < 0.01; AAT2, t = 9.61, P < 0.01), but increased PCNA expression and Cell Counting Kit-8 (CCK-8) activity as well as the migration in rat primary myocardial fibroblasts (P < 0.01). Supplementation of SOrather than pyruvate significantly inhibited the increase in proliferation and migration caused by AAT knockdown (P < 0.01). Mechanistically, the ratio of p-ERK to T-ERK was significantly increased in the AAT1/2 knockdown groups compared with that in the empty lentivirus group (AAT1, t = -7.36, P < 0.01; AAT2, t = -10.97, P < 0.01). Whereas PD98059, an inhibitor of ERK activation, successfully blocked AAT knockdown-induced PCNA upregulation (F = 74.01, P > 0.05), CCK-8 activation (F = 50.14, P > 0.05), and migration augmentation in myocardial fibroblasts (24 h, F = 37.08, P > 0.05; 48 h, F = 58.60, P > 0.05).</p><p><b>Conclusion</b>Endogenous SOmight be a novel myocardial fibroblast proliferation and migration inhibitor via inhibiting the ERK signaling pathway.</p>

Hydrogen Sulfide Regulating Myocardial Structure and Function by Targeting Cardiomyocyte Autophagy / 中华医学杂志(英文版)

<p><b>Objective</b>Hydrogen sulfide (HS), a gaseous signal molecule, plays a crucial role in many pathophysiologic processes in the cardiovascular system. Autophagy has been shown to participate in the occurrence of many cardiac diseases. Increasing evidences indicated that HS regulates myocardial structure and function in association with the altered autophagy and plays a "switcher" role in the autophagy of myocardial diseases. The aim of this review was to summarize these insights and provide the experimental evidence that HS targets cardiomyocyte autophagy to regulate cardiovascular function.</p><p><b>Data Sources</b>This review was based on data in articles published in the PubMed databases up to October 30, 2017, with the following keywords: "hydrogen sulfide," "autophagy," and "cardiovascular diseases."</p><p><b>Study Selection</b>Original articles and critical reviews on HS and autophagy were selected for this review.</p><p><b>Results</b>When autophagy plays an adaptive role in the pathogenesis of diseases, HS restores autophagy; otherwise, when autophagy plays a detrimental role, HS downregulates autophagy to exert a cardioprotective function. For example, HS has beneficial effects by regulating autophagy in myocardial ischemia/reperfusion and plays a protective role by inhibiting autophagy during the operation of cardioplegia and cardiopulmonary bypass. HS postpones cardiac aging associated with the upregulation of autophagy but improves the left ventricular function of smoking rats by lowering autophagy.</p><p><b>Conclusions</b>HS exerts cardiovascular protection by regulating autophagy. Cardiovascular autophagy would likely become a potential target of HS therapy for cardiovascular diseases.</p>

Plasma Neuropeptide Y Levels in Vasovagal Syncope in Children / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Vasovagal syncope (VVS) is the most common cause of syncope in children. Neuropeptide Y (NPY) plays an important role in the regulation of blood pressure (BP), as well as myocardial contractility. This study aimed to explore the role of plasma NPY in VVS in children.</p><p><b>METHODS</b>Fifty-six children who were diagnosed with VVS (VVS group) using head-up tilt test (HUT) and 31 healthy children who were selected as controls (control group) were enrolled. Plasma NPY concentrations were detected. The independent t-test was used to compare the data of the VVS group with those of the control group. The changes in plasma NPY levels in the VVS group during the HUT, as well as hemodynamic parameters, such as heart rate (HR), BP, total peripheral vascular resistance (TPVR), and cardiac output (CO), were evaluated using the paired t-test. Furthermore, the correlations between plasma NPY levels and hemodynamic parameters were analyzed using bivariate correlation analysis.</p><p><b>RESULTS</b>The BP, HR, and plasma NPY (0.34 ± 0.12 pg/ml vs. 0.46 ± 0.13 pg/ml) levels in the supine position were statistically low in the VVS group compared to levels in the control group (all P < 0.05). Plasma NPY levels were positively correlated with the HR (Pearson, R = 0.395, P < 0.001) and diastolic BP (Pearson, R = 0.311, P = 0.003) when patients were in the supine position. When patients in the VVS group were in the supine position, elevated TPVR (4.6 ± 3.7 mmHg·min-1·L-1 vs. 2.5 ± 1.0 mmHg·min-1·L-1, respectively, P < 0.001; 1 mmHg = 0.133 kPa) and reduced CO (1.0 ± 0.7 L/min vs. 2.4 ± 1.3 L/min, respectively, P < 0.001) were observed in the positive-response period compared with baseline values. The plasma NPY levels were positively correlated with TPVR (Spearman, R = 0.294, P = 0.028) but negatively correlated with CO in the positive-response period during HUT (Spearman, R = -0.318, P = 0.017).</p><p><b>CONCLUSIONS</b>Plasma NPY may contribute to the pathogenesis of VVS by increasing the TPVR and decreasing the CO during orthostatic regulation.</p>

Sulfur Dioxide Inhibits Extracellular Signal-regulated Kinase Signaling to Attenuate Vascular Smooth Muscle Cell Proliferation in Angiotensin II-induced Hypertensive Mice / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Clarifying the mechanisms underlying vascular smooth muscle cell (VSMC) proliferation is important for the prevention and treatment of vascular remodeling and the reverse of hyperplastic lesions. Previous research has shown that the gaseous signaling molecule sulfur dioxide (SO2) inhibits VSMC proliferation, but the mechanism for the inhibition of the angiotensin II (AngII)-induced VSMC proliferation by SO2has not been fully elucidated. This study was designed to investigate if SO2inhibited VSMC proliferation in mice with hypertension induced by AngII.</p><p><b>METHODS</b>Thirty-six male C57 mice were randomly divided into control, AngII, and AngII + SO2groups. Mice in AngII group and AngII + SO2group received a capsule-type AngII pump implanted under the skin of the back at a slow-release dose of 1000 ng·kg-1·min-1. In addition, mice in AngII + SO2received intraperitoneal injections of SO2donor. Arterial blood pressure of tail artery was determined. The thickness of the aorta was measured by elastic fiber staining, and proliferating cell nuclear antigen (PCNA) and phosphorylated-extracellular signal-regulated kinase (P-ERK) were detected in aortic tissues. The concentration of SO2 in serum and aortic tissue homogenate supernatant was measured using high-performance liquid chromatography with fluorescence determination. In the in vitro study, VSMC of A7R5 cell lines was divided into six groups: control, AngII, AngII + SO2, PD98059 (an inhibitor of ERK phosphorylation), AngII + PD98059, and AngII + SO2 + PD98059. Expression of PCNA, ERK, and P-ERK was determined by Western blotting.</p><p><b>RESULTS</b>In animal experiment, compared with the control group, AngII markedly increased blood pressure (P < 0.01) and thickened the aortic wall in mice (P < 0.05) with an increase in the expression of PCNA (P < 0.05). SO2, however, reduced the systemic hypertension and the wall thickness induced by AngII (P < 0.05). It inhibited the increased expression of PCNA and P-ERK induced by AngII (P < 0.05). In cell experiment, PD98059, an ERK phosphorylation inhibitor, blocked the inhibitory effect of SO2on VSMC proliferation (P < 0.05).</p><p><b>CONCLUSIONS</b>ERK signaling is involved in the mechanisms by which SO2inhibits VSMC proliferation in AngII-induced hypertensive mice via ERK signaling.</p>

The antihypertensive effect of adrenomedullin 2 and related mechanism / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To observe the vasodilating effect of adrenomedullin 2 (ADM2) by antagonizing angiotensin 1 (Ang II), and to explore its mechanism.</p><p><b>METHODS</b>Eighteen male, 180-200 g SD rats were randomly divided into 3 groups (n = 6): control group, Ang II (150 ng/(kg x min)) group and Ang II (150 ng/(kg x min)) + ADM2(500 ng/(kg x h)) group. Mini-osmotic pumps filled with peptide were implanted in the back of rats subcutaneously. After two weeks, the blood pressure was measured by the way of carotid intubation. The plasma was collected for the detection of nitric oxide (NO) content and the activity of endothelial nitric oxide synthase (eNOS). The in situ oxidation of fluorescent dye dihydroethidium (DHE) was used for detecting superoxide in rat arteries. The rat isolated arterial rings were made for studying the vasodilating effect of ADM2. Human umbilical vein endothelial cell line EA. hy 926 cells were cultured and their intracellular reactive oxygen species (ROS) were evaluated by probe DCFH-DA.</p><p><b>RESULTS</b>ADM2 dramatically decreased the blood pressure in angiotensin II-induced hypertension rat model, enhanced plasma NO content and the activity of eNOS and reduced superoxide formation in vessel walls. ADM2 also induced relaxation of the vascular rings preconstricted by Ang II in a concentration-dependent and endothelium-dependent manner. In cultured vascular endothelium, ADM2 ameliorated the ROS generation induced by Ang II.</p><p><b>CONCLUSION</b>Adrenomedullin 2 relaxed blood vessels by antagonizing angiotensin II-induced oxidative stress and improving the vascular endothelial function.</p>

Hydrogen sulfide is endogenously generated in rat skeletal muscle and exerts a protective effect against oxidative stress / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Skeletal muscle has recently been recognized as an endocrine organ that can express, synthesize and secrete a variety of bioactive molecules which exert significant regulatory effects. Hydrogen sulfide (H2S) is endogenously produced in mammalian tissues and participates in a number of physiological and pathophysiological processes. We aimed to verify whether H2S could be endogenously generated and released by rat skeletal muscle, and determine the biological effects of H2S in rat skeletal muscle.</p><p><b>METHODS</b>The study was divided into two parts: detection of endogenous H2S generation and release in rat skeletal muscle and determination of antioxidative activity of skeletal muscle-derived H2S. H2S content and production in tissues were detected by sensitive sulfur electrode method. The expressions of H2S producing enzymes cystathionine β-synthase, cystathionine γ-lyase and mercaptopyruvate sulfurtransferase were detected by real-time PCR and western blotting and their tissue distributions were observed by immunohistochemical and immunofluorescent analysis. Rat skeletal muscular ischemia-reperfusion (I-R) injury model was created and evaluated by histological analysis under microscope. The malondialdehyde (MDA) contents, hydrogen peroxide levels, superoxide anion and superoxide dismutase (SOD) activities were detected using spectrophotometer.</p><p><b>RESULTS</b>H2S could be endogenously generated and released by skeletal muscle of Sprague-Dawley rats (H2S content: (2.06 ± 0.43) nmol/mg; H2S production: (0.17 ± 0.06) nmol×min(-1)×mg(-1)). Gene and protein expressions of the three H2S producing enzymes were detected in skeletal muscle, as well as the liver and kidney. Endogenous H2S content and production were decreased in skeletal muscles of rats with I-R skeletal muscle injury (P < 0.05). Furthermore, H2S significantly protected rat skeletal muscle against I-R injury and resulted in decreased MDA content, reduced hydrogen peroxide and superoxide anion levels, but increased SOD activity and protein expression in skeletal muscles (all P < 0.01).</p><p><b>CONCLUSION</b>H2S generation pathway exists in rat skeletal muscle and it acts as an antioxidant in skeletal muscle.</p>

Modified methylene blue method for measurement of hydrogen sulfide level in plasma / 生理学报

In past decade, hydrogen sulfide (H₂S) as a novel gasotransmitter, covered many fields in biological and medical research. However, there is no effective, convenient and high-throughput method for determination of circulatory H₂S until now. Here, we aim to develop an easy method for measurement of circulatory H₂S by modified methylene blue method. In the present study, we added Zn²⁺ to plasma sample to deposit H₂S, HS⁻ and S²⁻, as well as plasma protein, then used NaOH to re-dissolve plasma protein. ZnS deposition was re-dissolved by the addition of N, N-dimethyl-p-phenylenediamine, and the remnant protein was deposited by trichloroacetic acid. After centrifugation, ferriammonium sulfate was added to the supernatant fluid to generate methylene blue, which was analyzed by spectrophotometer at 665 nm. Using the present method, we found that most ions including sulfate and thiosulfate did not affect detection of H₂S concentration, but albumin (physiological concentration) reduced the detection value, which suggested the binding of serum albumin and a certain amount of H₂S. The relative recovery ratio of present method is 81.9%, which implies that the method is relative accurate for the determination of H₂S concentration in plasma or serum. H₂S levels of frozen plasma samples from 65 healthy volunteers detected by the present method were (13.93 ± 4.98) µmol/L. There was no obvious difference between the detection values of fresh and frozen samples from the same SD rats. These results suggest the modified methylene blue assay is stable, sensitive, convenient and high-throughput. The method can be used to analyze the circulatory H₂S in clinical and basic research.

Hydrogen sulfide and vascular relaxation / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To review the vasorelaxant effects of hydrogen sulfide (H(2)S) in arterial rings in the cardiovascular system under both physiological and pathophysiological conditions and the possible mechanisms involved.</p><p><b>DATA SOURCES</b>The data in this review were obtained from Medline and Pubmed sources from 1997 to 2011 using the search terms "hydrogen sulfide" and "vascular relaxation".</p><p><b>STUDY SELECTION</b>Articles describing the role of hydrogen sulfide in the regulation of vascular activity and its vasorelaxant effects were selected.</p><p><b>RESULTS</b>H(2)S plays an important role in the regulation of cardiovascular tone. The vasomodulatory effects of H(2)S depend on factors including concentration, species and tissue type. The H(2)S donor, sodium hydrosulfide (NaHS), causes vasorelaxation of rat isolated aortic rings in a dose-dependent manner. This effect was more pronounced than that observed in pulmonary arterial rings. The expression of K(ATP) channel proteins and mRNA in the aortic rings was increased compared with pulmonary artery rings. H(2)S is involved in the pathogenesis of a variety of cardiovascular diseases. Downregulation of the endogenous H(2)S pathway is an important factor in the pathogenesis of cardiovascular diseases. The vasorelaxant effects of H(2)S have been shown to be mediated by activation of K(ATP) channels in vascular smooth muscle cells and via the induction of acidification due to activation of the Cl(-)/HCO(3)(-) exchanger. It is speculated that the mechanisms underlying the vasoconstrictive function of H(2)S in the aortic rings involves decreased NO production and inhibition of cAMP accumulation.</p><p><b>CONCLUSION</b>H(2)S is an important endogenous gasotransmitter in the cardiovascular system and acts as a modulator of vascular tone in the homeostatic regulation of blood pressure.</p>

Erythrocytic or serum hydrogen sulfide association with hypertension development in untreated essential hypertension / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Endogenous hydrogen sulfide (H(2)S) plays an important role in hypertension. The aim of this study was to investigate the role of erythrocyte and serum H(2)S in patients with untreated essential hypertension.</p><p><b>METHODS</b>We recruited 62 patients (age 22 - 74 years) with untreated prehypertension or hypertension, and 64 normotensive subjects (age 18 - 64 years). We assessed the 3-mercaptopyruvate sulphurtransferase (MPST) protein expression in erythrocytes and measured the H(2)S production from erythrocytes and serum H(2)S levels, then analyzed the association of erythrocytic or serum H(2)S content and blood pressure or cardiovascular risk factors (e.g., age, body mass index (BMI) and dyslipidemia). A stepwise regression analysis was used to evaluate the possible relationship of erythrocytic H(2)S in hypertension.</p><p><b>RESULTS</b>In hypertensive patients, erythrocyte H(2)S production ((111.04 ± 29.20) nmol/min per 10(8) erythrocytes) was higher than that in controls ((78.85 ± 19.38) nmol/min per 10(8) erythrocytes), and serum H(2)S was also higher. The erythrocytic H(2)S production was associated with increased systolic blood pressure (sBP), diastolic blood pressure (dBP), age, BMI, level of C-reactive protein (CRP), as well as triglycerides (TG) and high density lipoprotein cholesterol (HDL-C). Serum H(2)S was not associated with age or CRP. Stepwise regression analysis showed that erythrocytic H(2)S production was correlated with sBP, TG, HDL-C, low density lipoprotein cholesterol (LDL-C) and blood urea nitrogen (BUN) and serum H(2)S was correlated with dBP and TG. Results of receiver-operating characteristic curve analysis suggested that erythrocytic H(2)S production was a more sensitive predictor of hypertension development than serum H(2)S.</p><p><b>CONCLUSION</b>Erythrocytic or serum H(2)S production is sensitive predictor of hypertension.</p>

Sulfur dioxide acts as a novel endogenous gaseous signaling molecule in the cardiovascular system / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>Sulfur dioxide was considered to be toxic and detrimental to human health. However, this review highlights recent advances that suggest sulfur dioxide might be a novel endogenous gaseous signaling molecule involved in the regulation of cardiovascular functions.</p><p><b>DATA SOURCES</b>The data used in this review were mainly from the studies reported in Medline and PubMed published from 1986 to 2010.</p><p><b>STUDY SELECTION</b>Original articles and critical reviews selected were relevant to exogenous and endogenous sulfur dioxide.</p><p><b>RESULTS</b>The sulfur dioxide/aspartate amino transferase pathway is endogenously generated in the cardiovascular system, and sulfur dioxide shows broad bioactive effects, such as antihypertension, vasodilation, and amelioration of vascular remodeling. A disturbed sulfur dioxide/aspartate amino transferase pathway is known to be involved in the pathogenesis of many cardiovascular diseases, such as ischemia-reperfusion injury, monocrotaline-induced pulmonary hypertension, athrosclerosis, spontaneous hypertension and hypoxic pulmonary hypertension. Furthermore, in experimental studies the prognosis of these cardiovascular diseases can be improved by targeting endogenous sulfur dioxide.</p><p><b>CONCLUSION</b>The findings suggest that sulfur dioxide is a novel endogenous gaseous signaling molecule involved in the regulation of cardiovascular functions.</p>

Multiple hemodynamic effects of endogenous hydrogen sulfide on central nervous system in rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Endogenous hydrogen sulfide is a new neuromodulator which takes part in the regulation of central nervous system physiology and diseases. Whether endogenous hydrogen sulfide in the central nervous system regulates cardiovascular activity is not known. In the present study, we observed the hemodynamic changes of hydrogen sulfide or its precursor by intracerebroventricular injection, and investigate the possible roles of endogenous digitalis like factors and sympathetic activity in the regulation.</p><p><b>METHODS</b>Ninety-four Sprague-Dawley rats underwent a right cerebroventricular puncture, then the hydrogen sulfide saturation buffer or its precursor injected by intrcerebroventricular catheter. A heperin-filled catheter was inserted into the right femoral artery or into the left ventricle, and changes of blood pressure or cardiac function recorded by a Powerlab/4S instrument. Phentolamine or metoprolol were pre-injected to observe the possible role in autonomic nerve activity. After rats were sacrificed, plasma was collected and endogenous digitalis-like factors were measured with a commercial radioimmunoassay kit. The aortic, cardiac sarcolemmal vesicles were isolated and the activity of Na(+)-K(+)-ATPase was measured as ouabain-sensitive ATP hydrolysis under maximal velocity conditions by measuring the release of inorganic phosphate from ATP. Unpaired Student's t test for two groups or analysis of variances (ANOVA) for multiple groups were used to compare the differences of the changes.</p><p><b>RESULTS</b>Intracerebroventricular injection of hydrogen sulfide induced a transient hypotension, then dramatic hypertenive effects in a dose-dependent manner. Bolus injection of L-cysteine or beta- mercaptopyruvate also increased mean arterial pressure (P < 0.01), whereas hydroxylamine-a cystathionine beta synthase inhibitor decreased the arterial pressure (P < 0.01). Hydrogen sulfide and L-cysteine increased mean arterial pressure, left ventricular develop pressure and left-ventricle maximal rate of systolic and diastolic pressure; these functions were decreased by hydroxylamine (P < 0.01). Glibenclamide (a K(ATP) channel blocker) blocked the transient hypotensive effect, phentolamine (an alpha-adrenergic receptor blocker) blocked the hypertensive effect, and metoprolol (a selective beta 1 receptor blocker) blocked the positive inoptropic effect of central nervous system hydrogen sulfide. The endogenous digitalis-like factors in plasma were elevated (P < 0.01) after treatment with L-cysteine, association with decreasing Na(+)-K(+)-ATPase activity in cardiac or aortic sarcolemmal vesicles (P < 0.01). Hydroxylamine injection reduced the endogenous digitalis-like factors level in plasma association with increasing Na(+)-K(+)-ATPase activity in cardiac and aortic sarcolemmal vesicles.</p><p><b>CONCLUSION</b>Central nervous system endogenous hydrogen sulfide upregulated mean arterial pressure and cardiac systolic function by activation of sympathetic nerves or release of endogenous digitalis-like factors.</p>

Hydrogen sulfide regulates vascular endoplasmic reticulum stress in apolipoprotein E knockout mice / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Atherosclerosis is an important cardiovascular disease, becoming a major and increasing health problem in developed countries. However, the possible underlying mechanisms were not completely clear. In 2009, our research group first discovered that hydrogen sulfide (H(2)S) as a novel gastrotransmitter played an important anti-atherosclerotic role. The study was designed to examine the regulatory effect of hydrogen sulfide (H(2)S) on endoplasmic reticulum stress (ERS) in apolipoprotein E knockout (apoE(-/-)) mice fed a Western type diet.</p><p><b>METHODS</b>C57BL/6 mice and homozygous apoE(-/-) mice were fed a Western type diet. C57BL/6 mice were injected intraperitoneally with normal saline (5 ml/kg per day) as control group. The apoE(-/-) mice were treated with the same dose of normal saline as the apoE(-/-) group, injected intraperitoneally with sodium hydrosulfide (NaHS, an H(2)S donor, 56 µmol/kg per day) as the apoE(-/-) + NaHS group and injected intraperitoneally with DL-propargylglycine (PPG, a cystathionine-γ-lyase inhibitor, 50 mg/kg, per day) as the apoE(-/-) + PPG group. After 10 weeks, the mice were sacrificed and the plasma lipids were detected. Sections of aortic root from these animals were examined for atherosclerotic lesions by HE and oil red O staining. The aortic ultrastructure and microstructure were analyzed with the help of light and electronic microscope. Glucose-regulated protein 78 (GRP78), caspase-12, copper-andzinc-containing superoxide dismutase (Cu/ZnSOD) and Mn-containing superoxide dismutase (MnSOD) protein expression in aortic tissues were detected with immunohistochemistry. The level of intracellular reactive oxygen species (ROS) were measured by using a commercial assay kit.</p><p><b>RESULTS</b>Compared with control mice, apoE(-/-) mice showed increased plasma levels of total cholesterol (TC), triglyceride (TG) and low density lipoprotein (LDL), decreased high density lipoprotein (HDL), increased aortic plaque size, destroyed ultra-structure of aortic tissue, and increased expression of GRP78 and caspase-12 proteins. Compared with apoE(-/-) mice, H(2)S donor-treated apoE(-/-) mice showed a decreased plasma LDL level, lessened plaque necrosis and attenuated aortic ultra-structural disorder. H(2)S donor-treatment induced GRP78 expression but suppressed caspase-12 expression in aortic lesions. However, compared with apoE(-/-) mice, PPG treated apoE(-/-) mice showed enlarged plaque size, more severe ultrastructural disorder of the aortic tissue and reduced GRP78 staining in aortic lesions. The plasma lipids and the staining of caspase-12 in apoE(-/-) + PPG rats did not significantly differ from those in the apoE-/-mice. Consistently, H(2)S induced SOD expression, accompanied by a reduced level of ROS.</p><p><b>CONCLUSION</b>H(2)S plays a regulatory role in aortic ERS and reduces atherosclerotic lesions in apoE(-/-) mice fed with a Western type diet.</p>

Predictive role of cerebrospinal fluid hydrogen sulfide in central nervous system leukemia / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Central nervous system leukemia (CNSL) is an important relapse in children with acute lymphoblastic leukemia (ALL). We investigated the possible role of endogenous hydrogen sulfide (H(2)S) of cerebrospinal fluid (CSF) in predicting CNSL.</p><p><b>METHODS</b>From August 2008 to December 2010, 380 children were enrolled in this study at Shijitan Hospital, China. These children were from 2 to 16 years old, and the median age was 6.5 years. They were divided into a CNSL group (7 cases), a leukemia group (307 cases), a non-leukemia group (26 cases) and a healthy group (40 children). CSF specimens were obtained from conventional lumbar punctured, then centrifuged and supernatants preserved for H(2)S detection. Leukemic cells precipitates from CSF were found in three cases, the hCSE and hCBS mRNA expression was detected by reverse transcription polymerase chain reaction (RT-PCR), and H(2)S levels in serum were also measured. The receiver operating characteristic (ROC) curve and area under curve (AUC) were used to assess the predictive diagnosis role of CSF H(2)S in children with ALL and CNSL.</p><p><b>RESULTS</b>The serum H(2)S contents of the CNSL and leukemia groups were (96.98 ± 15.77) µmol/L and (93.35 ± 17.16) µmol/L respectively, much higher than those of healthy, (44.29 ± 2.15) µmol/L, and non-leukemia, (46.32 ± 6.54) µmol/L, groups (P < 0.01). Compared with the leukemia group, CSF H(2)S content of the CNSL group was significantly high (P < 0.01). Meanwhile, in contrast to the non-leukemia group, CSF H(2)S contents of the CNSL and leukemia groups were both significantly increased (P < 0.01). In addition, leukemic cells from CSF precipitations could express CBS and CSE mRNA. Furthermore, the ROC analysis showed the UAC was 0.929 (95%CI: 0.857 - 1.000), and the optimum cut-off value of CSF H(2)S was 12.08 µ mol/L, and the sensitivity and specificity were 83.3% and 97.2% respectively.</p><p><b>CONCLUSIONS</b>CSF H(2)S contents were significantly increased in children with CNSL. After treatment, H(2)S contents were decreased subsequently. Therefore, we speculated that H(2)S levels of CSF would predict CNSL in ALL children.</p>

Impact of sulfur dioxide on hydrogen sulfide/cystathionine-γ-lyase and hydrogen sulfide/mercaptopyruvate sulfurtransferase pathways in the pathogenesis of hypoxic pulmonary hypertension in rats / 中华儿科杂志

<p><b>OBJECTIVE</b>To explore the impact of sulfur dioxide (SO(2)) on hydrogen sulfide (H(2)S)/cystathionine-γ-lyase (CSE) and H(2)S/mercaptopyruvate sulfurtransferase (MPST) pathways in the pathogenesis of hypoxic pulmonary hypertension.</p><p><b>METHODS</b>Thirty-two male Wistar rats were randomly divided into four groups: control group (n = 8), hypoxic group (n = 8), hypoxic + SO(2) group (n = 8) and hypoxic + hydroxamate (HDX) group (n = 8). After 21 days of experiment, the concentration and production of H(2)S in lung tissues were measured respectively for each rat. The protein expression of CSE and MPST in intima and media of small pulmonary arteries in rats was detected with immunohistochemical method.</p><p><b>RESULTS</b>Compared with control group, the mean pulmonary artery pressure (mPAP) in rats of hypoxic group was increased significantly [(33.38 ± 6.32) mm Hg vs. (16.74 ± 3.81) mm Hg, P < 0.01]. Compared with hypoxic group, the mPAP in rats of hypoxic + SO(2) group was decreased significantly [(29.65 ± 2.53) mm Hg vs. (33.38 ± 6.32) mm Hg, P < 0.01]. However, compared with hypoxic group, the mPAP in rats of hypoxic + HDX group was increased significantly [(39.44 ± 6.26) mm Hg vs. (33.38 ± 6.32) mm Hg, P < 0.01]. Compared with control group, the concentration [(2.02 ± 0.43) µmol/g vs. (3.11 ± 0.42) µmol/g, P < 0.01] and production [(19.64 ± 3.48) nmol/(g·min)vs. (28.20 ± 5.95) nmol/(g·min), P < 0.05] of H(2)S were decreased significantly in rats of hypoxic group, respectively. When treated with SO(2), hypoxic rats showed an increased concentration [(2.73 ± 0.20) µmol/g vs. (2.02 ± 0.43) µmol/g, P < 0.01] and production [(26.24 ± 1.92) nmol/(g·min) vs. (19.64 ± 3.48) nmol/(g·min), P < 0.01] of H(2)S in lung tissue compared with those without receiving SO(2) treatment. When treated with HDX, hypoxic rats showed a significant decrease in concentration [(1.64 ± 0.23) µmol/g vs. (2.02 ± 0.43) µmol/g, P < 0.05] and production [(13.94 ± 3.63) nmol/(g·min) vs. (19.64 ± 3.48) nmol/(g·min), P < 0.05] of H(2)S in lung tissue compared with those without receiving HDX treatment. As for the expression of CSE in small pulmonary arteries (SPAs), compared with control group, the expression of CSE in intima [(0.31 ± 0.02) vs. (0.36 ± 0.01), P < 0.01] and media [(0.27 ± 0.01) vs. (0.30 ± 0.01), P < 0.01] in rats of hypoxic group was decreased significantly. While compared with hypoxic group, the expression of CSE in intima [(0.35 ± 0.02) vs. (0.31 ± 0.02), P < 0.01] in SPAs of hypoxic + SO(2) group was increased significantly. With HDX treatment, the expression of CSE in intima [(0.26 ± 0.01) vs. (0.31 ± 0.02), P < 0.01] in SPAs of hypoxic group was lower than that without HDX treatment. As for the expression of MPST in SPAs, compared with hypoxic group, the expression of MPST in media [(0.32 ± 0.02) vs. (0.29 ± 0.01), P < 0.01] in SPAs of hypoxic + SO(2) group was increased significantly.</p><p><b>CONCLUSION</b>SO(2) might upregulate H(2)S/CSE and H(2)S/MPST pathways in pulmonary arteries of hypoxic rats.</p>

"Waste gas is not waste": advance in the research of hydrogen sulfide / 生理学报

The discovery of endogenous gasotransmitters puts forwards a new concept, "waste gas is not waste". Hydrogen sulfide (H(2)S) is considered as a new member of gasotransmitter family, following nitric oxide (NO) and carbon monoxide (CO). Recently, the understanding of H(2)S biological effect and its mechanisms has been deepened, especially the pathophysiological significance of H(2)S in the various diseases such as cardiovascular diseases, neurological diseases, respiratory diseases, endocrine diseases, etc. This article reviews recent progress of basic, clinical and pharmacological researches related to endogenous H(2)S, including the regulatory effects of H(2)S on the cell proliferation, apoptosis, inflammation, angiogenesis and ion channels, the role of endogenous H(2)S pathway in the pathogenesis of various diseases, as well as the study of the H(2)S donor and H(2)S-related drugs.