Simulated sleep apnea alters hydrogen sulfide regulation of blood flow and pressure.

In sleep apnea, airway obstruction causes intermittent hypoxia (IH). In animal studies, IH-dependent hypertension is associated with loss of vasodilator hydrogen sulfide (H2S), and increased H2S activation of sympathetic nervous system (SNS) activity in the carotid body. We previously reported that inhibiting cystathionine γ-lyase (CSE) to prevent H2S synthesis augments vascular resistance in control rats. The goal of this study was to evaluate the contribution of IH-induced changes in CSE signaling to increased blood pressure and vascular resistance. We hypothesized that chronic IH exposure eliminates CSE regulation of blood pressure (BP) and vascular resistance. In rats instrumented with venous catheters, arterial telemeters, and flow probes on the main mesenteric artery, the CSE inhibitor dl-propargylglycine (PAG, 50 mg/kg/day i.v. for 5 days) increased BP in Sham rats but decreased BP in IH rats [in mmHg, Sham (n = 11): 114 ± 4 to 131 ± 6; IH (n = 8): 131 ± 8 to 115 ± 7 mmHg, P < 0.05]. PAG treatment increased mesenteric vascular resistance in Sham rats but decreased it in IH rats (day 5/day 1: Sham: 1.50 ± 0.07; IH: 0.85 ± 0.19, P < 0.05). Administration of the ganglionic blocker hexamethonium (to evaluate SNS activity) decreased mesenteric resistance in PAG-treated Sham rats more than in saline-treated Sham rats or PAG-treated IH rats. CSE immunoreactivity in IH carotid bodies compared with those from Sham rats. However, CSE staining in small mesenteric arteries was less in arteries from IH than in Sham rats but not different in larger arteries (inner diameter > 200 µm). These results suggest endogenous H2S regulates blood pressure and vascular resistance, but this control is lost after IH exposure with decreased CSE expression in resistance size arteries. IH exposure concurrently increases carotid body CSE expression and relative SNS control of blood pressure, suggesting both vascular and carotid body H2S generation contribute to blood pressure regulation.NEW & NOTEWORTHY These results suggest that CSE's protective role in the vasculature is impaired by simulated sleep apnea, which also upregulates CSE in the carotid body. Thus, this enzyme system can exert both pro- and antihypertensive effects and may contribute to elevated SNS outflow in sleep apnea.

Decreased plasma levels of gasotransmitter hydrogen sulfide in patients with schizophrenia: correlation with psychopathology and cognition.

OBJECTIVE: Aberrant N-methyl-D-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. Hydrogen sulfide (H2S) is an endogenous gasotransmitter that regulates NMDAR function. The current study investigated the relationship between plasma H2S levels and both psychopathological and cognitive symptoms in schizophrenia. MATERIALS AND METHODS: Forty-one patients with schizophrenia and 40 healthy control subjects were recruited in present study. Schizophrenic symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive function was evaluated with a neuropsychological battery including seven neurocognitive tests. Plasma H2S levels were measured by reversed-phase high-performance liquid chromatography (RP-HPLC). RESULTS: Patients with schizophrenia performed worse in all of the cognitive tests than the healthy controls except for the visual memory. Plasma H2S levels were significantly lower in patients with schizophrenia relative to healthy control subjects (F = 3.821, p = 0.007). Correlation analysis revealed a significant negative correlation between the H2S levels and the PANSS general scores (r = - 0.413, p = 0.007). Additionally, a positive association was observed between plasma H2S levels and working memory (r = 0.416, p = 0.007), visual memory (r = 0.363, p = 0.020), or executive function (r = 0.344, p = 0.028) in patients. Partial correlation analysis showed that the correlations between the H2S levels and the PANSS general scores, working memory, visual memory, or executive function were still significant when controlling for age, gender, years of education, BMI, duration of illness, and age of onset. CONCLUSION: The significant relations observed in the current study between H2S and the general psychopathological as well as cognitive symptoms suggest that decreased H2S is involved in the psychopathology and cognitive deficits of schizophrenia, and it might be a promising peripheral biomarker of schizophrenia.

The analysis on the expression of gasotransmitters in early trauma patients

Summary Objective: Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) were endogenously-generated molecules gas. They owned important biological activity and participated in many pathophysiological processes. This study aimed to examine the levels of three gasotransmitters in the early phase of trauma patients. Method: Blood samples were collected from 60 trauma patients and ten healthy volunteers. Concentration of serum iNOS and HO-1 were analyzed by enzyme linked immunosorbent assay and plasma H2S was determined by colorimetric method. Meanwhile, the occurrence of multiple organ dysfunction syndrome (MODS) was also monitored. Results: The levels of iNOS, HO-1 and endogenous H2S in the patients group were significantly different from the healthy control group, and the difference was more obvious with the increase of ISS score. iNOS levels were positively correlated with ISS scores and blood lactic acid values, and HO-1 and endogenous H2S were negatively correlated with ISS scores and blood lactic acid values. Of 60 trauma patients, eight (13.33%) developed MODS. The level of iNOS in the MODS group was higher than that in non-MODS group, while HO-1 and H2S were significant lower in the MODS group. Conclusion: The three gasotransmitters participated in systemic inflammatory responses during early trauma and could be used as important indicators for trauma severity. Their measurements were meaningful for evaluating the severity and prognosis of trauma.

The analysis on the expression of gasotransmitters in early trauma patients.

OBJECTIVE: Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) were endogenously-generated molecules gas. They owned important biological activity and participated in many pathophysiological processes. This study aimed to examine the levels of three gasotransmitters in the early phase of trauma patients. METHOD: Blood samples were collected from 60 trauma patients and ten healthy volunteers. Concentration of serum iNOS and HO-1 were analyzed by enzyme linked immunosorbent assay and plasma H2S was determined by colorimetric method. Meanwhile, the occurrence of multiple organ dysfunction syndrome (MODS) was also monitored. RESULTS: The levels of iNOS, HO-1 and endogenous H2S in the patients group were significantly different from the healthy control group, and the difference was more obvious with the increase of ISS score. iNOS levels were positively correlated with ISS scores and blood lactic acid values, and HO-1 and endogenous H2S were negatively correlated with ISS scores and blood lactic acid values. Of 60 trauma patients, eight (13.33%) developed MODS. The level of iNOS in the MODS group was higher than that in non-MODS group, while HO-1 and H2S were significant lower in the MODS group. CONCLUSION: The three gasotransmitters participated in systemic inflammatory responses during early trauma and could be used as important indicators for trauma severity. Their measurements were meaningful for evaluating the severity and prognosis of trauma.

[PARTICIPATION OF GASEOUS TRANSMITTERS IN BLOOD OXYGEN TRANSPORT FUNCTION MODIFICATION UNDER THE INFLUENCE OF MAGNETIC FIELD].

Gaseous transmitters contribution in blood oxygen transport function modification under the influence of the magnetic field was studied. It is found, that irradiation of the tail artery of rats for 10 days during 10 minutes increases p50 value, indicating a decrease in the hemoglobin affinity for oxygen and is accompanied by increased concentrations of nitrate/nitrite, and hydrogen sulfide. Administration of L-arginine and nitroglycerin during magnetic field action is accompanied by a decrease of hemoglobin affinity for oxygen, which is absent when NO-synthase enzyme inhibitor (L-NAME) is added. These data suggest an important role in the formation of blood oxygen transport function such gaseous transmitters as nitrogen monoxide and hydrogen sulfide.

Hydrogen sulfide upregulates KATP channel expression in vascular smooth muscle cells of spontaneously hypertensive rats.

UNLABELLED: The study was designed to investigate whether H2S could upregulate expression of KATP channels in vascular smooth muscle cells (VSMCs), and by this mechanism enhances vasorelaxation in spontaneously hypertensive rats (SHR). Blood pressure, vascular structure, and vasorelaxation were analyzed. Plasma H2S was detected using polarographic sensor. SUR2B and Kir6.1 expressions were detected in VSMCs of SHR and in A7r5 cells as well as primarily cultured ASMCs using real-time PCR, western blot, immunofluorescence, and confocal imaging. Nuclear translocation of forkhead transcription factors FOXO1 and FOXO3a in ASMCs was detected using laser confocal microscopy, and their binding activity with SUR2B and Kir6.1 promoters was examined by chromatin immunoprecipitation. SHR developed hypertension at 18 weeks. They showed downregulated vascular SUR2B and Kir6.1 expressions in association with a decreased plasma H2S level. H2S donor, however, could upregulate vascular SUR2B and Kir6.1 expressions, causing a left shift of the vasorelaxation curve to pinacidil and lowered tail artery pressure in the SHR. Also, H2S antagonized endothelin-1 (ET-1)-inhibited KATP expression in A7r5 cells and cultured ASMCs. Mechanistically, H2S inhibited ET-1-stimulated p-FOXO1 and p-FOXO3a expressions (inactivated forms), but increased their nuclear translocation and the ET-1-inhibited binding of FOXO1 and FOXO3a with Kir6.1 and SUR2B promoters in ASMCs. Hence, H2S promotes vasorelaxation of SHR, at least in part, through upregulating the expression of KATP subunits by inhibiting phosphorylation of FOXO1 and FOXO3a, and stimulating FOXO1 and FOXO3a nuclear translocation and their binding activity with SUR2B and Kir6.1 promoters. KEY MESSAGES: H2S increased vascular SUR2B and Kir6.1 expression of SHR, promoting vasorelaxation. H2S antagonized ET-1-inhibited KATP expression in A7r5 cells and cultured ASMCs. H2S inhibited ET-1-induced FOXO1 and FOXO3a phosphorylation in ASMCs. H2S promoted FOXO1 and FOXO3a nuclear translocation and binding with target gene promoters.

Development of a Clinically Applicable Protocol for Assessment of Hypoxic Response Through Measurement of the Endogenous Gasotransmitter Hydrogen Sulfide in Human Plasma.

BACKGROUND: Gasotransmitters are endogenously made, biologically active gases with unique physiological properties. In addition to participation in the hypoxic respiratory reflex of the carotid body, the gasotransmitter hydrogen sulfide (H(2)S) is thought to play a role in more localized vasodilatory hypoxic tissue responses. This pilot project describes a methodology suitable to the clinical environment that allows for H(2)S gas capture in human plasma utilizing the fluorescent trapping agent dansyl azide. METHODS: Under an IRB-approved pilot project, 10 healthy male volunteers were spontaneously ventilated on room air, hypoxic (15% oxygen, 85% nitrogen), and hyperoxic (100%) gas mixtures through a nonrebreather system. Venous whole-blood samples were collected at both internal jugular and antecubital sites following 7 minutes of exposure to the tested oxygen environments. Resultant plasma aliquots were treated with dansyl azide and submitted to fluorescence reading (excitation 340 nm, emission 517 nm). RESULTS: Compiled mean data from volunteer plasma samples demonstrated statistically significant findings (P<0.05) in measurement of increased fluorescent intensity between those samples collected under mildly hypoxic conditions compared with normoxic and hyperoxic samples submitted to the same laboratory criteria. CONCLUSIONS: To study the role of H(2)S as a marker of hypoxic response in humans, a reliable, robust, and safe protocol amenable to standard hospital laboratory procedures is needed. Through modification to methodologies described in the biochemistry literature, this pilot project demonstrates the feasibility of utilizing a fluorescent H2S gas trapping agent for assessment of hypoxic response in humans within the confines of a typical clinical collection and analysis environment.