Students' perceived research skills development and satisfaction after completion of a mandatory research project: results from five cohorts of the Sydney medical program.

BACKGROUND: Research activities undertaken during University studies contribute to preparation of medical students for practice of evidence-based medicine. This study aimed to understand medical students' experiences, perceived research skills development and satisfaction associated with completion of mandatory research projects. METHODS: An online survey was sent to five cohorts of students (n = 1375) from years 2017-2021 at the completion of their research projects. Univariate analysis was conducted to understand students' perception of research skills development, followed by linear regression modeling to explore factors influencing satisfaction with their research project. Manifest content analysis employing a framework approach was used to analyse qualitative data from responses to open ended questions. RESULTS: Response rate was 42%, with 513 (89%) returned surveys being complete and included in analysis. Whilst 37% of students felt they had requisite research skills before undertaking the research project, 84% reported they had these skills after completing the project (χ2 = 8.99, P = 0.02). Mean satisfaction score of the students was 5.0/10 (+/- 2.5, median = 6 (IQR = 3.0-7.0) with 59% of students reporting satisfaction scores higher than the average. Higher satisfaction scores were reported by those who perceived that: research methods and teaching was useful in preparing them for conducting research; the research project helped them acquire new skills; the project resulted in peer-reviewed publication; and, who felt supported by their supervisors. Responses to open ended questions offered important insights into student experience and emphasised the importance of supportive supervisors and the need for a dedicated research block in the busy medical program. CONCLUSIONS: The majority of students reported positive outcomes from the mandatory research project. Student satisfaction can be improved by ensuring supportive research environments and high-quality supervision, and inclusion of dedicated research time in the medical curriculum.

Research supervisors' views of barriers and enablers for research projects undertaken by medical students; a mixed methods evaluation of a post-graduate medical degree research project program.

BACKGROUND: Medical degree programs use scholarly activities to support development of basic research skills, critical evaluation of medical information and promotion of medical research. The University of Sydney Doctor of Medicine Program includes a compulsory research project. Medical student projects are supervised by academic staff and affiliates, including biomedical science researchers and clinician-academics. This study investigated research supervisors' observations of the barriers to and enablers of successful medical student research projects. METHODS: Research supervisors (n = 130) completed an anonymous, online survey after the completion of the research project. Survey questions targeted the research supervisors' perceptions of barriers to successful completion of projects and sources of support for their supervision of the student project. Data were analysed by descriptive statistics and using manifest content analysis. Further quantitative investigation was made by cross-tabulation according to prior research supervision experience. RESULTS: Research supervisors reported that students needed both generic skills (75%) and research-based skills (71%) to successfully complete the project. The major barrier to successful research projects was the lack of protected time for research activities (61%). The assessment schedule with compulsory progress milestones enabled project completion (75%), and improved scientific presentation (90%) and writing (93%) skills. Supervisors requested further support for their students for statistics (75%), scientific writing (51%), and funding for projects (52%). Prior research supervision experience influenced the responses. Compared to novice supervisors, highly experienced supervisors were significantly more likely to want students to be allocated dedicated time for the project (P < 0.01) and reported higher rates of access to expert assistance in scientific writing, preparing ethics applications and research methodology. Novice supervisors reported higher rates of unexpected project delays and data acquisition problems (P < 0.05). Co-supervision was favoured by experienced supervisors but rejected by novice supervisors. CONCLUSIONS: Both generic and research-related skills were important for medical student research project success. Overall, protected research time, financial and other academic support were identified as factors that would improve the research project program. Prior research supervision experience influences perceptions of program barriers and enablers. These findings will inform future support needs for projects and research supervisor training for the research supervision role.

An organisational participatory research study of the feasibility of the behaviour change wheel to support clinical teams implementing new models of care.

BACKGROUND: Health and social care organisations globally are moving towards prevention-focussed community-based, integrated care. The success of this depends on professionals changing practice behaviours. This study explored the feasibility of applying a behavioural science approach to help staff teams from health organisations overcome psychological barriers to change and implement new models of care. METHODS: An Organisational Participatory Research study was conducted with health organisations from North West England, health psychologists and health workforce education commissioners. The Behaviour Change Wheel (BCW) was applied with teams of professionals seeking help to overcome barriers to practice change. A mixed-methods data collection strategy was planned, including qualitative stakeholder interview and focus groups to explore feasibility factors and quantitative pre-post questionnaires and audits measuring team practice and psychological change barriers. Qualitative data were analysed with thematic analysis; pre-post quantitative data were limited and thus analysed descriptively. RESULTS: Four clinical teams from paediatrics, midwifery, heart failure and older adult mental health specialties in four organisations enrolled, seeking help to move care to the community, deliver preventative healthcare tasks, or become more integrated. Eighty-one managers, medical doctors, nurses, physiotherapists, midwives and other professionals contributed data. Three teams successfully designed a BCW intervention; two implemented and evaluated this. Five feasibility themes emerged from the thematic analysis of qualitative data. Optimising the BCW in an organisational change context meant 1) qualitative over quantitative data collection, 2) making behavioural science attractive, 3) co-development and a behavioural focus, 4) effective ongoing communication and 5) support from engaged leaders. Pre-post quantitative data collected suggested some positive changes in staff practice behaviours and psychological determinants following the intervention. CONCLUSIONS: Behavioural science approaches such as the BCW can be optimised to support teams within health and social care organisations implementing complex new models of care. The efficacy of this approach should now be trialled.

Exploring what teams perceive by 'culture' when implementing new models of care.

INTRODUCTION: Health and social care organizations continually face change to coordinate efforts, improve care quality and better meet patient needs in the context of growing pressure on services. NHS 'vanguard' teams funded to pilot organizational change in England have argued that alongside new structures, policies and governance, a shift in 'workplace culture' is needed to implement change. Although now defined in the literature and seen as an important driver of quality care, it was not clear what teams themselves meant when discussing workplace culture. METHODS: In a qualitative study nested in a wider behavioural science programme, 34 managers and frontline NHS staff took part in interviews and focus groups on the role and meaning of 'workplace culture' in their experience of change. Participants were from organizations in four NHS England vanguards implementing new models of care. Inductive thematic analysis revealed six interlinking themes: unity, emotions, support, consistency, openness to innovation and performance. RESULTS: The term 'workplace culture' was nuanced and used in various ways. It was seen as a determinant, measure and/or consequence of change and linked to workplace behaviours, emotions and cognitions. Participants agreed that imposed top-down change in new models of care was a common cause of damaged culture and had knock-on effects on care quality, despite manager accounts of the importance of staff ideas. DISCUSSION: Our findings suggest that exploring teams' own meanings of culture and behaviour change barriers, gathering ideas and co-developing tailored support would help overcome cultural challenges in implementing new models of care.

Informal peer-assisted learning amongst medical students: A qualitative perspective.

PURPOSE: Peer-assisted learning (PAL) can occur informally as part of a medical programme and complements the formal curriculum. However, little is known about the mechanisms and processes of how informal peer-assisted learning (IPAL) is enacted. MATERIALS AND METHODS: This paper presents data from an ethnographic and semi-structured interview study with Year 1 and 2 undergraduate medical students at a UK university. RESULTS: Peers were observed assisting each other informally: a process that developed as part of the integrated, group-based approach to undergraduate medical education at a UK university. IPAL took place both within and outside of formal teaching sessions and included explanation/clarification of particular points, sharing resources, guiding pronunciation and demonstrating skills. Students placed a high value on IPAL and believed that it was beneficial. When IPAL broke down, this led to negative emotions that presented obstacles to learning, such as resentment. CONCLUSIONS: IPAL is an important part of academic support for medical students, and this work shows both its scope, extending from formal to informal teaching, and how it is enacted. This understanding can help educators situate IPAL within student education.

An evaluation of pharmacology curricula in Australian science and health-related degree programs.

BACKGROUND: Pharmacology is a biomedical discipline taught in basic science and professional degree programs. In order to provide information that would facilitate pharmacology curricula to be refined and developed, and approaches to teaching to be updated, a national survey was undertaken in Australia that investigated pharmacology course content, teaching and summative assessment methods. METHODS: Twenty-two institutions participated in a purpose-built online questionnaire, which enabled an evaluation of 147 courses taught in 10 different degrees. To enable comparison, degrees were grouped into four major degree programs, namely science, pharmacy, medicine and nursing. The pharmacology content was then classified into 16 lecture themes, with 2-21 lecture topics identified per theme. The resultant data were analysed for similarities and differences in pharmacology curricula across the degree programs. RESULTS: While all lecture themes were taught across degree programs, curriculum content differed with respect to the breadth and hours of coverage. Overall, lecture themes were taught most broadly in medicine and with greatest coverage in pharmacy. Reflecting a more traditional approach, lectures were a dominant teaching method (at least 90% of courses). Sixty-three percent of science courses provided practical classes but such sessions occurred much less frequently in other degree programs, while tutorials were much more common in pharmacy degree programs (70%). Notably, problem-based learning was common across medical programs. Considerable diversity was found in the types of summative assessment tasks employed. In science courses the most common form of in-semester assessment was practical reports, whereas in other programs pen-and-paper quizzes predominated. End-of-semester assessment contributed 50-80% to overall assessment across degree programs. CONCLUSION: The similarity in lecture themes taught across the four different degree programs shows that common knowledge- and competency-based learning outcomes can be defined for pharmacology. The authors contend that it is the differences in breadth and coverage of material for each lecture theme, and the differing teaching modes and assessment that characterise particular degree programs. Adoption of pharmacology knowledge-based learning outcomes that could be tailored to suit individual degree programs would better facilitate the sharing of expertise and teaching practice than the current model where pharmacology curricula are degree-specific.

Rapid Rescoping and Adaptation: An Evaluation of the Impact of COVID-19 on Postgraduate Medical Student Research Projects.

The COVID-19 pandemic has adversely affected tertiary science and medical education, with significant impact on research-related activities. Research projects are a mandatory requirement of the Doctor of Medicine (MD) Program at the University of Sydney, and medical student projects are delivered across multiple sites in metropolitan and rural New South Wales, Australia. Several cohorts of medical students had projects that were affected by COVID-19. The aims of this study were to determine the impact of COVID-19 on medical student research projects and describe the measures taken to rescope projects, to support students in meeting the learning objectives of the program. Mandatory submission statements for all medical student research project scientific reports for 2020-2022 were examined for reports of the effect of COVID-19 on the project, including COVID-19 related delays, downsizing and the need to change research project types. During the study period, a total of 760 student reports were submitted, of which 217 (28.7%) were affected by COVID-19. About 50% were significantly delayed, 30% were downsized, and 6% required completely new projects. Rescoping arrangements implemented facilitated the successful completion of projects. Overall, the final student grades for the research projects were unaffected by COVID-19 or the related project rescoping. Whilst significantly impacted by COVID-19, medical student research projects were completed with provision of appropriate rescoping plans and academic support. Ensuring projects have a documented contingency plan secured projects as the pandemic progressed and will be a useful safeguard for all future project delivery.

Enhancing Behavior Change Skills in Health Extension Workers in Ethiopia: Evaluation of an Intervention to Improve Maternal and Infant Nutrition.

Maternal and infant nutrition are problematic in areas of Ethiopia. Health extension workers (HEWs) work in Ethiopia's primary health care system, increasing potential health service coverage, particularly for women and children, providing an opportunity for health improvement. Their roles include improving maternal and infant nutrition, disease prevention, and health education. Supporting HEWs' practice with 'non-clinical' skills in behavior change and health communication can improve effectiveness. This intervention study adapted and delivered a UK-developed training intervention for Health Extension Workers (HEWs) working with the United Nations World Food Programme in Ethiopia. The intervention included communication and behavioral training adapted with local contextual information. Mixed methods evaluation focused on participants' reaction to training, knowledge, behavior change, and skills use. Overall, 98 HEWs were trained. The intervention was positively received by HEWs. Pre-post evaluations of communication and behavior change skills found a positive impact on HEW skills, knowledge, and motivation to use skills (all p < 0.001) to change women's nutritional behavior, also demonstrated in role-play scenarios. The study offered substantial learning about intervention delivery. Appropriate cultural adaptation and careful consideration of assessment of psychological constructs are crucial for future delivery.

Vasorelaxation elicited by endogenous and exogenous hydrogen sulfide in mouse mesenteric arteries.

H2S causes vasorelaxation however there is considerable heterogeneity in the reported pharmacological mechanism of this effect. This study examines the contribution of endogenously released H2S in the regulation of vascular tone and the mechanism of H2S-induced vasorelaxation in small resistance-like arteries. Mesenteric arteries from C57 and eNOS-/- mice were mounted in myographs to record isometric force. Vasorelaxation responses to NaHS were examined in the presence of various inhibitors of vasorelaxation pathways. Expression and activity of the H2S-producing enzyme, cystathionine-γ-lyase (CSE), were also examined. CSE was expressed in vascular smooth muscle and perivascular adipose cells from mouse mesenteric artery. The substrate for CSE, L-cysteine, caused a modest vasorelaxation (35%) in arteries from C57 mice and poor vasorelaxation (10%) in arteries from eNOS-/- mice that was sensitive to the CSE inhibitor DL-propargylglycine. The fast H2S donor, NaHS, elicited a full and biphasic vasorelaxation response in mesenteric arteries (EC50 (1) 8.7 µM, EC50 (2) 0.6 mM), which was significantly inhibited in eNOS-/- vessels (P < 0.05), unaffected by endothelial removal, or blockers at any point in the NO via soluble guanylate cyclase and cGMP (NO-sGC-cGMP) vasorelaxation pathway. Vasorelaxation to NaHS was significantly inhibited by blocking K+ channels of the KCa and KV subtypes and the Cl-/HCO3- exchanger (P < 0.05). Further experiments showed that NaHS can significantly inhibit voltage-gated Ca2+ channel function (P < 0.05). The vasorelaxant effect of H2S in small resistance-like arteries is complex, involving eNOS, K+ channels, Cl-/HCO3- exchanger, and voltage-gated Ca2+ channels. CSE is present in the smooth muscle and periadventitial adipose tissue of these resistance-like vessels and can be activated to cause modest vasorelaxation under these in vitro conditions.

Vascular Myography to Examine Functional Responses of Isolated Blood Vessels.

Vascular myography is an in vitro technique used to examine functional responses of isolated blood vessels. This classical pharmacological technique has been in use for over a century. The assay technique studies changes in isometric tone of large and small vessels, arteries and veins, and tissues from genetic or disease models. This chapter describes the apparatus required, tissue collection methods, and the mounting of the tissues in the chambers of both large organ baths and the small vessel myograph. Considerations of the experimental conditions and design are discussed as well as the analysis of the collected data.

Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepiride.

PURPOSE: The aim of this study was to investigate the effects of the type-4 dipeptidyl peptidase (DPP-4) inhibitors linagliptin and vildagliptin as well as the sulfonylurea glimepiride on endothelium-dependent relaxation of aortae from female db/db mice with established hyperglycemia to determine whether these treatments were able to attenuate diabetes-induced endothelial dysfunction. MATERIALS AND METHODS: The mice were treated with glimepiride (2 mg/kg po per day, weeks 1-6, n=12), glimepiride plus vildagliptin (glimepiride 2 mg/kg po per day, weeks 1-6; vildagliptin 3 mg/kg po per day, weeks 4-6, n=11), glimepiride plus linagliptin (glimepiride 2 mg/kg po per day, weeks 1-6; linagliptin 3 mg/kg po per day, weeks 4-6, n=11) or linagliptin (3 mg/kg po per day, weeks 1-6, n=12). Endothelium-dependent relaxation using acetylcholine was assessed in the absence and presence of pharmacological tools (TRAM-34 1 µM; apamin 1 µM; N-nitro-L-arginine [L-NNA] 100 µM; 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one [ODQ] 10 µM) to distinguish relaxation mediated by nitric oxide (NO). RESULTS: Linagliptin was associated with a significant improvement in endothelium-dependent relaxation (ACh Rmax; db/db 41±1%, linagliptin 73±6%, p<0.05). The enhanced response was maintained in the presence of TRAM-34+ apamin (ACh Rmax; db/db 23±6%, linagliptin 60±6%, p<0.01), ie, when the endothelium-dependent relaxation was mediated by NO. There was no evidence for a contribution from KCa channel opening to responses under any conditions. Glimepiride had no effect on endothelium-dependent relaxation when given alone (ACh Rmax 38±3%). The addition of linagliptin or vildagliptin to glimepiride did not significantly improve endothelium-dependent relaxation. All treatments caused some decrease in aortic superoxide production but the effect of linagliptin was significantly greater than glimepiride (linagliptin 534±60 relative luminescence unit [RLU], glimepiride 1471±265 RLU, p<0.05). CONCLUSION: Linagliptin is superior to glimepiride in regard to the preservation of endothelium-dependent relaxation in the presence of hyperglycemia and the improvement in endothelial function in response to linagliptin treatment is associated with greater antioxidant activity compared to glimepiride.

H2S causes contraction and relaxation of major arteries of the rabbit.

OBJECTIVE: Cardiovascular disease (CVD) caused by atherosclerosis remains a worldwide burden. Hydrogen sulfide is a promising new therapeutic avenue for the treatment of CVD, however reports show exogenous H2S has both vasodilator and vasoconstrictor effects depending on organ examined, and in vitro studies in animal models which are not resistant to developing atherosclerosis are limited. We sought to determine if rabbit arteries constricted or dilated to hydrogen sulfide. MATERIAL AND METHODS: The aorta, carotid, renal and iliac arteries were harvested from New Zealand White rabbits (n=4) and subjected to a concentration response curve to the fast H2S releaser NaHS. In addition, a bolus dose of NaHS was used to determine if further dilation was achievable after maximum dilation to acetylcholine similar to nitric oxide donors. Further, NaHS was used to determine if H2S could impair homocysteine induced endothelial dysfunction. RESULTS: Blood vessels relaxed poorly to NaHS and contracted at higher doses. A bolus dose of NaHS relaxed then contracted the aorta, however a bolus dose of NaHS after maximal relaxation to acetylcholine caused marked contraction. NaHS did not prevent homocysteine induced vascular dysfunction. CONCLUSION: NaHS at low doses caused minor relaxation of rabbit blood vessels, indicating a possible therapeutic benefit for low dose H2S in the cellular milieu.

Chronic NaHS treatment decreases oxidative stress and improves endothelial function in diabetic mice.

Hydrogen sulphide (H2S) is endogenously produced in vascular tissue and has anti-oxidant and vasoprotective properties. This study investigates whether chronic treatment using the fast H2S donor NaHS could elicit a vasoprotective effect in diabetes. Diabetes was induced in male C57BL6/J mice with streptozotocin (60 mg/kg daily, ip for 2 weeks) and confirmed by elevated blood glucose and glycated haemoglobin levels. Diabetic mice were then treated with NaHS (100 µmol/kg/day) for 4 weeks, and aortae collected for functional and biochemical analyses. In the diabetic group, both endothelium-dependent vasorelaxation and basal nitric oxide (NO•) bioactivity were significantly reduced ( p < 0.05), and maximal vasorelaxation to the NO• donor sodium nitroprusside was impaired ( p < 0.05) in aorta compared to control mice. Vascular superoxide generation via nicotine adenine dinucleotide phosphate (NADPH) oxidase ( p < 0.05) was elevated in aorta from diabetic mice which was associated with increased expression of NOX2 ( p < 0.05). NaHS treatment of diabetic mice restored endothelial function and exogenous NO• efficacy back to control levels. NaHS treatment also reduced the diabetes-induced increase in NADPH oxidase activity, but did not affect NOX2 protein expression. These data show that chronic NaHS treatment reverses diabetes-induced vascular dysfunction by restoring NO• efficacy and reducing superoxide production in the mouse aorta.

Decreased vascular H2S production is associated with vascular oxidative stress in rats fed a high-fat western diet.

A Western-style high-fat diet is known to cause vascular dysfunction and oxidative stress. H2S contributes to the regulation of vascular function and acts as a vasoprotective molecule; however, the effects of high-fat diet on vascular H2S production and function are not known. The aim of this study was to investigate the effects of high-fat diet on vascular function and H2S production. Wistar hooded rats were fed a western diet (WD, 21 % fat) or control rat chow (6 % fat) for 12 weeks. At the end of the experiment, the aorta was collected for assessing vascular function and NO and H2S bioavailability. Superoxide anion production was quantitated by lucigenin-enhanced chemiluminescence. The expression of NADPH oxidase subunit Nox2 and the H2S-producing protein cystathionine-γ-lyase (CSE) were examined by Western blotting. WD rats had significantly higher body weight and body fat than control (p < 0.001). Endothelial function and NO bioavailability were significantly reduced in the WD group (p < 0.05), but vascular smooth muscle cell function was unaffected. Vascular superoxide production and Nox2 expression were significantly increased in the aorta from WD rats. L-Cysteine-induced vasorelaxation was reduced in the WD group (p < 0.05) and insensitive to the inhibition of the CSE. In addition, vascular H2S bioavailability and CSE expression were significantly reduced in the aorta from WD rats (p < 0.01). These data show that fat feeding induces vascular oxidative stress and a reduction in endothelial function. Furthermore, there is a reduced capacity for both basal and stimulated vascular H2S production via CSE in fat fed rats.

Hydrogen sulfide treatment reduces blood pressure and oxidative stress in angiotensin II-induced hypertensive mice.

Hydrogen sulfide (H2S) is increasingly recognized as a gasotransmitter with protective effects in the cardiovascular system. The aim of the study was to examine the effects of chronic NaHS treatment on blood pressure, vascular function and oxidative stress in an in vivo model of hypertension and oxidative stress. Male C57Bl6/J mice were rendered hypertensive with 0.7 mg kg(-1) per day angiotensin II (AngII) for 14 days administered via implanted mini-pumps. The mice were treated with NaHS (10 µmol kg(-1) per day) to deliver H2S or an inhibitor of cystathionine-γ-lyase, DL-propargylglycine (PPG 30 mg kg(-1) per day) via intraperitoneal (i.p.) injection. Systolic blood pressure was measured and vascular function examined by myography. Vascular superoxide production was measured by lucigenin-enhanced chemiluminescence. AngII infusion significantly increased systolic blood pressure (P < 0.001). This increase was significantly attenuated by treatment with NaHS (P < 0.001). Both aortic endothelial function and NO bioavailability were significantly attenuated in the AngII group (P < 0.01) but this attenuation was reversed by NaHS treatment. Similarly, aortic superoxide anion production was significantly enhanced by AngII (P < 0.01), and this was reversed by NaHS treatment, and also exacerbated by PPG treatment (P < 0.001). These data show that in a mouse model of hypertension and oxidative stress induced by AngII, exogenous H2S treatment in vivo reduces blood pressure, endothelial dysfunction and vascular oxidative stress, while inhibiting endogenous H2S production in vivo is deleterious. This furthers the evidence that H2S is a vasoprotective molecule that may be a useful treatment target in cardiovascular disease.

Enzyme-catalysed synthesis of galactosylated 1D- and 1L-chiro-inositol, 1D-pinitol, myo-inositol and selected derivatives using the beta-galactosidase from the thermophile Thermoanaerobacter sp. strain TP6-B1.

The products from the enzymatic beta-D-galactopyranosylation of 1D-chiro-inositol, 1D-pinitol, 1D-3-O-allyl-4-O-methyl-chiro-inositol, 1D-3,4-di-O-methyl-chiro-inositol, 1L-chiro-inositol and myo-inositol in combined yields ranging from 46% to 64% have been obtained using the beta-galactosidase isolated from an anaerobic extreme thermophile, Thermoanaerobacter sp. strain TP6-B1 and p-nitrophenyl beta-D-galactopyranoside as the donor. Analysis of the products from these reactions reveals information about the acceptor preferences of the enzyme.

Hydrogen sulfide protects endothelial nitric oxide function under conditions of acute oxidative stress in vitro.

The aim of this study was to examine the ability of H2S, released from NaHS to protect vascular endothelial function under conditions of acute oxidative stress by scavenging superoxide anions (O2(-)) and suppressing vascular superoxide anion production. O2(-) was generated in Krebs' solution by reacting hypoxanthine with xanthine oxidase (Hx-XO) or with the O2(-) generator pyrogallol to model acute oxidative stress in vitro. O2(-) generation was measured by lucigenin-enhanced chemiluminescence. Functional responses in mouse aortic rings were assessed using a small vessel myograph. NaHS scavenged O2(-) in a concentration-dependent manner. Isolated aortic rings exposed to either Hx-XO or pyrogallol displayed significantly attenuated maximum vasorelaxation responses to the endothelium-dependent vasodilator acetylcholine, and significantly reduced NO bioavailability, which was completely reversed if vessels were pre-incubated with NaHS (100 µM). NADPH-stimulated aortic O2(-) production was significantly attenuated by the NADPH oxidase inhibitor diphenyl iodonium. Prior treatment of vessels with NaHS (100 nM-100 µM; 30 min) inhibited NADPH-stimulated aortic O2(-) production in a concentration-dependent manner. This effect persisted when NaHS was washed out prior to measuring NADPH-stimulated O2(-) production. These data show for the first time that NaHS directly scavenges O2(-) and suppresses vascular NADPH oxidase-derived O2(-) production in vitro. Furthermore, these properties protect endothelial function and NO bioavailability in an in vitro model of acute oxidative stress. These results suggest that H2S can elicit vasoprotection by both scavenging O2(-) and by reducing vascular NADPH oxidase-derived O2(-) production.

Hydrogen sulfide as a vasculoprotective factor.

Hydrogen sulfide is a novel mediator with the unique properties of a gasotransmitter and many and varied physiological effects. Included in these effects are a number of cardiovascular effects that are proving beneficial to vascular health. Specifically, H2S can elicit vasorelaxation, prevention of inflammation and leukocyte adhesion, anti-proliferative effects and anti-thrombotic effects. Additionally, H2S is a chemical reductant and nucleophile that is capable of inhibiting the production of reactive oxygen species, scavenging and neutralising reactive oxygen species and boosting the efficacy of endogenous anti-oxidant molecules. These result in resistance to oxidative stress, protection of vascular endothelial function and maintenance of blood flow and organ perfusion. H2S has been shown to be protective in hypertension, atherosclerosis and under conditions of vascular oxidative stress, and deficiency of endogenous H2S production is linked to cardiovascular disease states. Taken together, these effects suggest that H2S has a physiological role as a vasculoprotective factor and that exogenous H2S donors may be useful therapeutic agents. This review article will discuss the vascular effects and anti-oxidant properties of H2S as well as examine the protective role of H2S in some important vascular disease states.

Chronic NaHS Treatment Is Vasoprotective in High-Fat-Fed ApoE(-/-) Mice.

Hydrogen sulfide is emerging as an important mediator of vascular function that has antioxidant and cytoprotective effects. The aim of this study was to investigate the role of endogenous H2S and the effect of chronic exogenous H2S treatment on vascular function during the progression of atherosclerotic disease. ApoE(-/-) mice were fed a high-fat diet for 16 weeks and treated with the H2S donor NaHS or the cystathionine- γ -lyase (CSE) inhibitor D,L-propargylglycine (PPG), to inhibit endogenous H2S production for the final 4 weeks. Fat-fed ApoE(-/-) mice displayed significant aortic atherosclerotic lesions and significantly impaired endothelial function compared to wild-type mice. Importantly, 4 weeks of NaHS treatment significantly reduced vascular dysfunction and inhibited vascular superoxide generation. NaHS treatment significantly reduced the area of aortic atherosclerotic lesions and attenuated systolic blood pressure. Interestingly, inhibiting endogenous, CSE-dependent H2S production with PPG did not exacerbate the deleterious vascular changes seen in the untreated fat-fed ApoE(-/-) mice. The results indicate NaHS can improve vascular function by reducing vascular superoxide generation and impairing atherosclerotic lesion development. Endogenous H2S production via CSE is insufficient to counter the atherogenic effects seen in this model; however exogenous H2S treatment has a significant vasoprotective effect.

Effect of type 1 diabetes on the production and vasoactivity of hydrogen sulfide in rat middle cerebral arteries.

Hydrogen sulfide (H2S) is produced endogenously in vascular tissue and has both vasoregulation and antioxidant effects. This study examines the effect of diabetes-induced oxidative stress on H2S production and function in rat middle cerebral arteries. Diabetes was induced in rats with streptozotocin (50 mg/kg, i.v.). Middle cerebral artery function was examined using a small vessel myograph and superoxide anion generation measured using nicotinamide adenine dinucleotide phosphate (NADPH)-dependent lucigenin-enhanced chemiluminescence. Cystathionine-γ-lyase (CSE) mRNA expression was measured via RT-PCR. Diabetic rats had elevated blood glucose and significantly reduced cerebral artery endothelial function. Maximum vasorelaxation to the H2S donor NaHS was unaffected in diabetic cerebral arteries and was elicited via a combination of K(+), Cl(-), and Ca(2+) channel modulation, although the contribution of Cl(-) channels was significantly less in the diabetic cerebral arteries. Vasorelaxation to the H2S precursor l-cysteine and CSE mRNA were significantly increased in diabetic cerebral arteries. Cerebral artery superoxide production was significantly increased in diabetes, but this increase was attenuated ex vivo by incubation with the H2S donor NaHS. These data confirm that cerebral artery endothelial dysfunction and oxidative stress occurs in diabetes. Endogenous H2S production and activity is upregulated in cerebral arteries in this model of diabetes. Vasorelaxation responses to exogenous H2S are preserved and exogenous H2S attenuates the enhanced cerebral artery generated superoxide observed in the diabetic group. These data suggest that upregulation of endogenous H2S in diabetes may play an antioxidant and vasoprotective role.