Interaction among Hydrogen Sulfide and Other Gasotransmitters in Mammalian Physiology and Pathophysiology.

Hydrogen sulfide (H2S), nitric oxide (NO), carbon monoxide (CO), and sulfur dioxide (SO2) were previously considered as toxic gases, but now they are found to be members of mammalian gasotransmitters family. Both H2S and SO2 are endogenously produced in sulfur-containing amino acid metabolic pathway in vivo. The enzymes catalyzing the formation of H2S are mainly CBS, CSE, and 3-MST, and the key enzymes for SO2 production are AAT1 and AAT2. Endogenous NO is produced from L-arginine under catalysis of three isoforms of NOS (eNOS, iNOS, and nNOS). HO-mediated heme catabolism is the main source of endogenous CO. These four gasotransmitters play important physiological and pathophysiological roles in mammalian cardiovascular, nervous, gastrointestinal, respiratory, and immune systems. The similarity among these four gasotransmitters can be seen from the same and/or shared signals. With many studies on the biological effects of gasotransmitters on multiple systems, the interaction among H2S and other gasotransmitters has been gradually explored. H2S not only interacts with NO to form nitroxyl (HNO), but also regulates the HO/CO and AAT/SO2 pathways. Here, we review the biosynthesis and metabolism of the gasotransmitters in mammals, as well as the known complicated interactions among H2S and other gasotransmitters (NO, CO, and SO2) and their effects on various aspects of cardiovascular physiology and pathophysiology, such as vascular tension, angiogenesis, heart contractility, and cardiac protection.

[Cardiovascular Regulation by Sulfur-containing Gaseous Signaling Molecules and the Underlying Mechanisms:Updated Research Evidence].

The sulfur-containing gases hydrogen sulfide (H2S)and sulfur dioxide (SO2 )were previously considered to be waste gases. Recent studies showed that they could be endogenously generated from metabolism of the sulfur-containing amino acids in mammals. Endogenous H2S and SO2 generation pathways also existed in the cardiovascular system.H2S and SO2 had important physiological effects in the cardio-vascular system including vasorelaxation and myocardial negative inotropic effect. The pathophysiological effects of H2S and SO2 in the cardiovascular system have been recognized, such as alleviating hypertension and pulmonary hypertension, inhibiting the development of atherosclerosis, and protecting against myocardial ischemia-reperfusion (I /R)injury and isoproterenol-induced myocardial injury. Adenosine triphosphate-sensitive potassium (KATP )channel, L-type calcium (L-Ca2 +) channel, cGMP, NF-κB signaling pathway and MAPK signaling pathway and so on participated in the biological effects of H2S and SO2 .The above findings suggested that H2S and SO2 were important endogenous gaseous signaling molecules in the cardiovascular system, which provided a new way to elucidate the pathogenesis and therapeutic targets of cardiovascular diseases.

[Effects of hydrogen sulfide donor on production of adrenomedullin and atrial natriuretic peptide in rats with atherosclerosis].

OBJECTIVE: Endogenous hydrogen sulfide (H2S), a novel gasotransmitter in cardiovascular regulation, plays an important protective role in the development and progression of atherosclerosis (AS). This study was designed to explore the effects of H2S donor on the production of adrenomedullin (ADM) and atrial natriuretic peptide (ANP) in AS rats. METHODS: Male Sprague-Dawley rats were randomly divided into control group (n=10), AS group (n=10), and AS+NaHS group (n=10). Rats in the AS and AS+NaHS groups were given 3-day intraperitoneal injections of vitamin D3 and 8-week high-fat diet to induce AS, and the rats in the AS+NaHS group were intraperitoneally injected with H2S donor NaHS. Oil red O staining was applied to detect changes in the areas of the atherosclerotic plaques in the aortic root and the coronary artery; sulfide-sensitive electrode method was used to measure the plasma concentration of H2S. ADM and ANP levels in plasma were determined by radioimmunoassay. RESULTS: Compared with the control group, marked atherosclerotic plaques were observed in the aortic root and the coronary artery in AS rats. Moreover, plasma H2S level decreased significantly, ADM level increased, and ANP level decreased significantly in AS rats (P<0.01). However, after the treatment with H2S donor NaHS for 8 weeks, the above changes in AS rats were reversed, demonstrated by significantly reduced areas of the atherosclerotic plaques in both the aortic root and the coronary artery, significantly increased plasma H2S level, significantly decreased plasma ADM level, and significantly increased plasma ANP level (P<0.01). CONCLUSIONS: H2S plays an important regulatory effect on vasoactive peptides ADM and ANP in AS rats.

Age and mean platelet volume-based nomogram for predicting the therapeutic efficacy of metoprolol in Chinese pediatric patients with vasovagal syncope.

BACKGROUND: Vasovagal syncope (VVS) is the most common type of orthostatic intolerance in children. We investigated whether platelet-related factors related to treatment efficacy in children suffering from VVS treated with metoprolol. METHODS: Metoprolol-treated VVS patients were recruited. The median duration of therapy was three months. Patients were followed and divided into two groups, treament-effective group and treatment-ineffective group. Logistic and least absolute shrinkage selection operator regressions were used to examine treatment outcome variables. Receiver-operating characteristic (ROC) curves, precision-recall (PR) curves, calibration plots, and decision curve analyses were used to evaluate the nomogram model. RESULTS: Among the 72 patients who complete the follow-up, treatment-effective group and treatment-ineffective group included 42 (58.3%) and 30 (41.7%) cases, respectively. The patients in the treatment-effective group exhibited higher mean platelet volume (MPV) [(11.0 ± 1.0) fl vs. (9.8 ± 1.0) fl, P < 0.01] and platelet distribution width [12.7% (12.3%, 14.3%) vs. 11.3% (10.2%, 12.2%), P < 0.01] than those in the treatment-ineffective group. The sex ratio was significantly different (P = 0.046). A fit model comprising age [odds ratio (OR) = 0.766, 95% confidence interval (CI) = 0.594-0.987] and MPV (OR = 5.613, 95% CI = 2.297-13.711) might predict therapeutic efficacy. The area under the curve of the ROC and PR curves was computed to be 0.85 and 0.9, respectively. The P value of the Hosmer-Lemeshow test was 0.27. The decision curve analysis confirmed that managing children with VVS based on the predictive model led to a net advantage ranging from 0.01 to 0.58. The nomogram is convenient for clinical applications. CONCLUSION: A novel nomogram based on age and MPV can predict the therapeutic benefits of metoprolol in children with VVS.

Sulfur dioxide preconditioning increases antioxidative capacity in rat with myocardial ischemia reperfusion (I/R) injury.

BACKGROUND: The study was designed to explore if sulfur dioxide (SO2) preconditioning increased antioxidative capacity in rat with myocardial ischemia reperfusion (I/R) injury. METHODS: The myocardial I/R model was made by left coronary artery ligation for 30min and reperfusion for 120min in rats. Myocardial infarct size and plasma lactate dehydrogenase (LDH) and creatine kinase (CK) activities, plasma superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and glutathione (GSH) changes were detected for the rats. The contents of myocardial hydrogen sulfide (H2S) and nitric oxide (NO) were measured. Myocardial protein expressions of SOD1, SOD2, cystathionine γ-lyase (CSE) and iNOS were tested using Western blot. RESULTS: Myocardial infarction developed and plasma CK and LDH activities were significantly increased in I/R group compared with those in control group, but SO2 preconditioning significantly reduced myocardial infarct size, and plasma CK and LDH activities. SO2 preconditioning successfully increased plasma SOD, GSH and GSH-Px levels and myocardial SOD1 protein expression, but decreased MDA level in rats of I/R group. Compared with controls, the myocardial H2S level and CSE expression were decreased after I/R, but myocardial NO level and iNOS expression were increased. With the treatment of SO2, myocardial H2S level and CSE expression were increased, but myocardial NO level and iNOS expression were decreased compared with those in I/R group. CONCLUSIONS: SO2 preconditioning could significantly reduce I/R-induced myocardial injury in vivo in association with increased myocardial antioxidative capacity, upregulated myocardial H2S/CSE pathway but downregulated NO/iNOS pathway.

The PI3K/Akt pathway mediates the protection of SO(2) preconditioning against myocardial ischemia/reperfusion injury in rats.

AIM: To explore the mechanisms underlying the protection by SO2 preconditioning against rat myocardial ischemia/reperfusion (I/R) injury. METHODS: Male Wistar rats underwent 30-min left coronary artery ligation followed by 120-min reperfusion. An SO2 donor (1 µmol/kg) was intravenously injected 10 min before the ischemia, while LY294002 (0.3 mg/kg) was intravenously injected 30 min before the ischemia. Plasma activities of LDH and CK were measured with an automatic enzyme analyzer. Myocardial infarct size was detected using Evans-TTC method. The activities of caspase-3 and -9 in myocardium were assayed using a commercial kit, and the levels of p-Akt, Akt, PI3K and p-PI3K were examined with Western blotting. RESULTS: Pretreatment with SO2 significantly reduced the myocardial infarct size and plasma LDH and CK activities, as well as myocardial caspase-3 and -9 activities in the rats. Furthermore, the pretreatment significantly increased the expression levels of myocardial p-Akt and p-PI3K p85. Administration of the PI3K inhibitor LY294002 blocked all the effects induced by SO2 pretreatment. CONCLUSION: The results suggest that the PI3K/Akt pathway mediates the protective effects of SO2 preconditioning against myocardial I/R injury in rats.

[Significance of serum iron in the differential diagnosis between vasovagal syncope and postural orthostatic tachycardia syndrome in children].

OBJECTIVE: To explore the predictive value of serum iron in differentiating between vasovagal syncope (VVS) and postural orthostatic tachycardia syndrome (POTS) in children. METHODS: Totally 57 children (aged 4-17 years, POTS 40 cases, and VVS 17 cases) who were at the syncope clinic or admitted to the Department of Pediatrics, Peking University First Hospital from August 2009 to September 2012 were included in the study. The diagnoses were analyzed by the value of serum iron and receiver operating characteristic (ROC) curves used to explore the predictive value of different serum iron in differential diagnosis between VVS and POTS. RESULTS: There were significant differences in the median value of POTS [17.4 (interquartile range 13.5 -21.8) µmol/L] and VVS [8.9 (interquartile range 7.5-17.6) µmol/L] (P<0.01). When the value of serum iron was 11.8 µmol/L, the sensitivity and specificity of the differential diagnosis between VVS and POTS were 92.5% and 64.7%, respectively. CONCLUSION: The serum iron might be used as an initial diagnostic method in differential diagnosis between VVS and POTS, based on the history of the patients.

[Plasma prealbumin and C-reactive protein predicts coronary artery lesions in children with Kawasaki disease].

OBJECTIVE: To study the changes of plasma prealbumin (PA) and C-reactive protein (CRP) in children with Kawasaki disease, and to explore the importance of integral analysis of plasma PA and CRP in predicting the severity of coronary artery lesions in Kawasaki Disease. METHODS: In a retrorespective study, 108 children with Kawasaki disease admitted in our hospital were enrolled. The statistical methods included t test, Chi-square test, and ROC curve analysis. The changes of plasma PA and CRP during the disease were studied. Also, the usefulness of comprehensive analysis of PA and CRP in predicting the severity of coronary artery lesions was also evaluated. RESULTS: During the acute phase of Kawasaki disease, the plasma PA level was decreased distinctly, while the CRP level increased significantly. Among the 55 cases whose plasma PA level was <80 mg/L, setting CRP=76.5 mg/L as the cutoff value, the occurrence of coronary artery dilations for those with CRP level<76.5 mg/L was significantly higher than those with CRP level >76.5 mg/L (P<0.05). CONCLUSION: Plasma PA and CRP changed greatly during the process of Kawasaki disease. And it may be of importance in predicting the severity of coronary artery lesions, by using integrated plasma PA and CRP.

[Impact of H2S on oxidized-low density lipoprotein-stimulated nuclear factor-κB in human monocytes/macrophage and its mechanisms].

OBJECTIVE: To investigate the role of hydrogen sulfide (H2S) on oxidized-low density lipoprotein (ox-LDL)-stimulated NF-κB pathway in human monocytes/macrophages and its mechanisms. METHODS: THP-1 cells were induced to differentiate into macrophages by incubation with phorbol myristate acetate (PMA) . The human monocytes/macrophages were divided into 4 groups: control group, ox-LDL group, ox-LDL + H2S 100 µmol/L group and ox-LDL + H2S 500 µmol/L group. The expression of IκBα and phosphorylation of NF-κB p65 in the cells were detected by Western blotting. The expression of IκBα and nuclear translocation of NF-κB p65 in the cells were observed by laser confocal method. The interaction between NF-κB p65 and IκBα in the nuclear extracts was detected by coimmunoprecipitation method. RESULTS: Compared with the control group, the phosphorylation of NF-κB p65 in the human monocytes/macrophages of ox-LDL group was increased significantly (0.855 ± 0.116 vs. 0.502 ± 0.218, P=0.046), while the expression of IκBα in the cells of the ox-LDL group was decreased (0.612 ± 0.216 vs. 0.997 ± 0.167, P=0.029). Compared with the ox-LDL group, the phosphorylation of NF-κB p65 in the cells of the ox-LDL + H2S 100 µmol/L group and the ox-LDL + H2S 500 µmol/L group was decreased significantly (0.424 ± 0.225 vs. 0.855 ± 0.116, P=0.020; 0.378 ± 0.071 vs. 0.855 ± 0.116, P=0.011, respectively), while the expressions of IκBα in the cells of the ox-LDL + H2S 100 µmol/L group and the ox-LDL + H2S 500 µmol/L group were increased (1.037 ± 0.111 vs. 0.612 ± 0.216, P=0.015; 1.046 ± 0.084 vs. 0.612 ± 0.216, P=0.013, respectively). The results from laser confocal method demonstrated that the IκBα expression in the cytoplasma of cells in the ox-LDL group was lower than that in the control group, and the nuclear translocation of NF-κB p65 in the cells of the ox-LDL group was higher than that in the control group. The IκBα expression in the cytoplasma of cells in the ox-LDL+ H2S 100 µmol/L group and ox-LDL + H2S 500 µmol/L group was higher than that in the ox-LDL group, and the nuclear translocation of NF-κB p65 in the cells of ox-LDL group was lower than that in the ox-LDL group. The coimmunoprecipitation experiment showed that no IκBα integrated with NF-κB p65 was detected in the nuclear extracts of cells in the control group, a small amount of IκBα integrated with NF-κB p65 was detected in the nuclear extracts of cells in the ox-LDL group, but a large amount of IκBα integrated with NF-κB p65 was detected in the nuclear extracts of cells in the ox-LDL+H2S 100 µmol/L group and the ox-LDL + H2S 500 µmol/L group. CONCLUSION: H2S inhibited the activation of NF-κB p65 pathway in the ox-LDL-induced human monocytes/macrophages. The mechanisms might involve the prevention of the degradation of IκBα, then the inhibition of the phosphorylation and nuclear translocation of NF-κB p65, thus promoting the IκBα integrated with NF-κB p65 in the nuclei, and then inhibiting the activity of NF-κB.

A predictive model of response to metoprolol in children and adolescents with postural tachycardia syndrome.

BACKGROUND: The present work was designed to explore whether electrocardiogram (ECG) index-based models could predict the effectiveness of metoprolol therapy in pediatric patients with postural tachycardia syndrome (POTS). METHODS: This study consisted of a training set and an external validation set. Children and adolescents with POTS who were given metoprolol treatment were enrolled, and after follow-up, they were grouped into non-responders and responders depending on the efficacy of metoprolol. The difference in pre-treatment baseline ECG indicators was analyzed between the two groups in the training set. Binary logistic regression analysis was further conducted on the association between significantly different baseline variables and therapeutic efficacy. Nomogram models were established to predict therapeutic response to metoprolol. The receiver-operating characteristic curve (ROC), calibration, and internal validation were used to evaluate the prediction model. The predictive ability of the model was validated in the external validation set. RESULTS: Of the 95 enrolled patients, 65 responded to metoprolol treatment, and 30 failed to respond. In the responders, the maximum value of the P wave after correction (Pcmax), P wave dispersion (Pd), Pd after correction (Pcd), QT interval dispersion (QTd), QTd after correction (QTcd), maximum T-peak-to-T-end interval (Tpemax), and T-peak-to-T-end interval dispersion (Tped) were prolonged (all P < 0.01), and the P wave amplitude was increased (P < 0.05) compared with those of the non-responders. In contrast, the minimum value of the P wave duration after correction (Pcmin), the minimum value of the QT interval after correction (QTcmin), and the minimum T-peak-to-T-end interval (Tpemin) in the responders were shorter (P < 0.01, < 0.01 and < 0.01, respectively) than those in the non-responders. The above indicators were screened based on the clinical significance and multicollinearity analysis to construct a binary logistic regression. As a result, pre-treatment Pcmax, QTcmin, and Tped were identified as significantly associated factors that could be combined to provide an accurate prediction of the therapeutic response to metoprolol among the study subjects, yielding good discrimination [area under curve (AUC) = 0.970, 95% confidence interval (CI) 0.942-0.998] with a predictive sensitivity of 93.8%, specificity of 90.0%, good calibration, and corrected C-index of 0.961. In addition, the calibration curve and standard curve had a good fit. The accuracy of internal validation with bootstrap repeated sampling was 0.902. In contrast, the kappa value was 0.769, indicating satisfactory agreement between the predictive model and the results from the actual observations. In the external validation set, the AUC for the prediction model was 0.895, and the sensitivity and specificity were 90.9% and 95.0%, respectively. CONCLUSIONS: A high-precision predictive model was successfully developed and externally validated. It had an excellent predictive value of the therapeutic effect of metoprolol on POTS among children and adolescents.

Effect of sulfur dioxide preconditioning on rat myocardial ischemia/reperfusion injury by inducing endoplasmic reticulum stress.

Sulfur dioxide has recently been found to be produced endogenously in the cardiovascular system and have important positive biological effects. However, it is unknown whether sulfur dioxide preconditioning has a protective effect on rat myocardial ischemia/reperfusion (I/R) injury and whether this process involves endoplasmic reticulum stress (ERS). In this study, we showed that preconditioning with sulfur dioxide 10 min before ischemia (with a low concentration of sulfur dioxide of 1-10 µmol/kg) could reduce myocardial infarct size and plasma activities of lactate dehydrogenase and creatine kinase in rats with I/R in vivo. Sulfur dioxide preconditioning also reduced myocardium apoptosis induced by I/R. In addition, sulfur dioxide preconditioning increased cardiac function in vitro. Sulfur dioxide preconditioning induced expression of myocardial glucose-regulated protein 78 (GRP78) and phosphorylated eukaryotic initiation of the factor 2α-subunit (p-eIF2α) prior to myocardial I/R but suppressed expression of myocardial GRP78, C/EBP homologous protein, and p-eIF2α during myocardial I/R, in association with improved myocardial injury in vivo and in vitro. Pretreatment with dithiothreitol, an ERS stimulator mimicked the above cardioprotective effect. However, pretreatment with the ERS inhibitor 4-phenylbutyrate reversed the cardioprotection provided by sulfur dioxide preconditioning. These data indicated that sulfur dioxide preconditioning reduced I/R-induced myocardial injury in vivo and in vitro, and that augmenting ERS by sulfur dioxide preconditioning prior to I/R contributed to protection against myocardial I/R injury.

The vasorelaxing effect of hydrogen sulfide on isolated rat aortic rings versus pulmonary artery rings.

AIM: To compare the vasorelaxing effects of hydrogen sulfide (H(2)S) on isolated aortic and pulmonary artery rings and to determine their action mechanisms. METHODS: H(2)S-induced vasorelaxation of isolated rat aortic versus pulmonary artery rings under 95% O(2) and 5% CO(2) was analyzed. The expression of cystathinonine gamma-lyase (CSE), cystathionine beta synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3MST), SUR2B and Kir6.1 was examined. RESULTS: NaHS caused vasorelaxation of rat aortic and pulmonary artery rings in a dose-dependent manner. NaHS dilated aortic rings to a greater extent (16.4%, 38.4%, 64.1%, 84.3%, and 95.9% at concentrations of 50, 100, 200, 500, and 1000 µmol/L, respectively) than pulmonary artery rings (10.1%, 22.2%, 50.6%, 73.6%, and 84.6% at concentrations of 50, 100, 200, 500 and 1000 µmol/L, respectively). The EC(50) of the vasorelaxant effect for aortic rings was 152.17 µmol/L, whereas the EC(50) for pulmonary artery rings was 233.65 µmol/L. The vasorelaxing effect of H(2)S was markedly blocked b y cellular and mitochondrial membrane K(ATP) channel blockers in aortic rings (P<0.01). In contrast, only the cellular membrane K(ATP) channel blocker inhibited H(2)S-induced vasorelaxation in pulmonary artery rings. SUR2B mRNA and protein expression was higher in aortic rings than in pulmonary artery rings. Cystathinonine gamma-lyase (CSE) but not cystathionine beta synthase (CBS) expression in aortic rings was higher than in pulmonary artery rings. 3-Mercapto pyruvate sulfurtransferase (3MST) mRNA was lower in aortic rings than in pulmonary artery rings. CONCLUSION: The vasorelaxing effect of H(2)S on isolated aortic rings was more pronounced than the effect on pulmonary artery rings at specific concentrations, which might be associated with increased expression of the K(ATP) channel subunit SUR2B.

Sulfur dioxide derivatives depress L-type calcium channel in rat cardiomyocytes.

1. Sulfur dioxide (SO(2) ) has recently been found to have various biological effects on the cardiovascular system. The present study was designed to explore the effects of SO(2) derivatives on the L-type calcium current (I (Ca, L) ) in isolated rat ventricular cardiomyocytes. 2. A Langendorf system was used to dissociate single ventricular cells. SO(2) derivatives from 5 to 1000 µmol/L were incubated with cardiomyocytes. The whole-cell patch-clamp technique was used to record I (Ca, L) . The effect of SO(2) derivatives on intracellular calcium concentration ([Ca(2+) ](i) ) was detected by confocal microscopy. 3. Concentrations of 5 or 10 µmol/L SO(2) derivatives could not change I (Ca, L) evoked by a single pulse from -40 to 0 mV for 200 ms in rat ventricular cardiomyocytes; however, 50, 100, 500 or 1000 µmol/L SO(2) derivatives could depress the peak amplitudes of calcium currents in 6 min, and the I (Ca, L) was attenuated by 13.19%, 16.59%, 21.23% and 24.72%, respectively, as compared with corresponding controls (P < 0.05). The 50, 100, 500 or 1000 µmol/L SO(2) derivatives also depressed the peak I-V curves, without altering the reversal potential and the voltage dependence of the peak I (Ca, L) . Therefore, 1000 µmol/L SO(2) derivatives could reduce [Ca(2+) ](i) in cardiomyocytes. 4. The results of the present study suggest that SO(2) derivatives can depress I (Ca, L) in cardiomyocytes, which might have a protective effect in cardiovascular diseases.

[Change and significance in the levels of plasma urotensin II and catestatin in children with postural orthostatic tachycardia syndrome].

OBJECTIVE: To explore possible mechanisms by analyzing cardiovascular bioactive peptides levels in children with postural orthostatic tachycardia syndrome (POTS). METHODS: Forty-six children diagnosed as POTS (POTS group, aged 12.1±2.8 years) and 20 healthy children (control group, aged 11.5±3.6 years) were enrolled as controls in this clinical controlled study. Two kinds of cardiovascular bioactive peptides named urotensin II (UII) and catestatin (Cs) were measured by using enzyme immunoassay. The comparisons between the two groups were made by independent t test or non-parametric test. Correlation analyses between plasma levels of bioactive peptides and changes in heart rate during standing test or head-up tilt test (HUT) were conducted using bivariate correlations. RESULTS: The plasma UII levels were significantly lower in POTS group as compared with those of controls [0.41 (0.27, 0.85) µg/L in POTS group vs. 0.46 (0.35, 1.41) µg/L in control group, P<0.05]. The plasma UII level was negatively correlated with the increase in heart rate during standing test or head-up tilt test (correlation coefficient-0.363, P<0.05). No difference was found in plasma Cs levels between the two groups [ 0.48 (0.20, 1.91) µg/L in POTS group vs. 0.48 (0.20, 1.91) µg/L in control group, P>0.05]. CONCLUSION: POTS children had low levels of plasma UII, and disturbance of vascular tone regulation might play a role in POTS of children.

[Effects of hydrogen sulfide on the expressions of nuclear factor-κB and intercellular adhesion molecule 1 in pulmonary tissue of rats with acute lung injury].

OBJECTIVE: To explore the potential effects of hydrogen sulfide (H(2)S) on nuclear factor kappa B (NF-κB) and intercellular adhesion molecule 1 (ICAM-1) in lung tissue with oleic acid (OA)-induced acute lung injury (ALI) in rats. METHODS: Forty-two rats were randomly divided into 3 groups: control (n = 6), OA (n = 18) and OA + NaHS (n = 18). Rats in the OA group received an intra-tail vein injection of oleic acid 0.1 ml/kg while those in the OA + NaHS group an intraperitoneal injection of NaHS 56 µmol/kg at 30 mins before OA injection. The OA and OA + NaHS groups were subdivided into 3 subgroups depending on the therapeutic duration: 2 h (n = 6), 4 h (n = 6) and 6 h (n = 6). Rats in the control group received an intra-tail vein injection of normal saline 0.1 ml/kg. Bronchioalveolar lavage fluid (BALF) was collected and the leucocytic differential count of sediment examined. The extent of lung injury was evaluated by the index of quantitative assessment (IQA). The H(2)S level in lung tissue was measured by sensitive sulphur electrode. The nuclear translocation of NF-κB and the expression of ICAM-1 in alveolar epithelial cells were measured by immunohistochemical staining. RESULTS: Compared with the control group, the BALF percentage of polymorphonuclear (PMN) cell was significantly higher at 2, 4 and 6 h in the OA-treated rats [(74.5 ± 3.0)%, (80.2 ± 2.0)%, (87.2 ± 2.7)% vs (3.1 ± 1.6)%, all P < 0.01]. And the value of IQA increased significantly versus those at 2, 4 and 6 h in the control group (5.2 ± 0.8, 6.4 ± 0.6, 6.8 ± 0.8 vs 0.4 ± 0.6, all P < 0.01). And the levels of H(2)S in lung tissue decreased at 2, 4 and 6 h [(21.20 ± 0.38) µmol/g, (20.80 ± 0.53) µmol/g, (18.92 ± 0.75) µmol/g vs (26.81 ± 0.65) µmol/g, all P < 0.01]. Moreover, the nuclear expression of NF-κB and the membranous expression of ICAM-1 in the alveolar epithelial cells in OA group rats was significantly higher than those of the control group (all P < 0.05). After the dosing of H(2)S donor (NaHS), the BALF percentage of PMN cell and the lung IQA decreased in the three subgroup rats (2, 4 and 6 h) versus the OA group. And the concentration of H(2)S increased significantly in the 4 h and 6 h subgroups versus the OA group at the corresponding time points. Simultaneously, the nuclear expression of NF-κB and the membranous expression of ICAM-1 in alveolar epithelial cells were significantly lower than that of the OA group at 4 h and 6 h subgroups (all P < 0.05). CONCLUSION: H(2)S may play a protective role in the ALI rats through the suppression of lung inflammation. And the inhibited expression of alveolar epithelial cell NF-κB mediates the anti-inflammatory effects of H(2)S.

Baseline left ventricular ejection fraction associated with symptom improvements in both children and adolescents with postural tachycardia syndrome under metoprolol therapy.

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 <0.100 in the univariate analyses and the demographic characteristics. RESULTS: A comparison of responders and non-responders revealed no significant differences in demographic, hemodynamic characteristics, and urine specific gravity (all P > 0.050). However, responders had significantly higher baseline LVEF (71.09% ±â€Š4.44% vs. 67.17% ±â€Š4.88%, t = -2.789, P = 0.008) and LVFS values (40.00 [38.00, 42.00]% vs. 36.79% ±â€Š4.11%, 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.

Significance of endogenous sulphur-containing gases in the cardiovascular system.

1. The sulphur-containing gases hydrogen sulphide and sulphur dioxide can be generated endogenously in mammalian tissues and exert significant biological effects in the cardiovascular system. Hydrogen sulphide is considered to be the third novel gasotransmitter in addition to nitric oxide and carbon monoxide. The present review describes the effects of hydrogen sulphide on the cardiovascular system and its possible mechanisms under physiological conditions. We also discuss the pathophysiological effects of hydrogen sulphide on cardiovascular diseases. The therapeutic potential of hydrogen sulphide is summarized. 2. We recently discovered that sulphur dioxide, another endogenous sulphur-containing gas, has important physiological and pathophysiological roles in the cardiovascular system. To some extent, the effect of sulphur dioxide is similar to that of the other gasotransmitters nitric oxide, carbon monoxide and hydrogen sulphide. Sulphur dioxide may also be a novel gas mediator in the cardiovascular system.

["Waste gas is not waste": advance in the research of hydrogen sulfide].

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.

Body mass index is a promising predictor of response to oral rehydration saline in children with vasovagal syncope.

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.