Reflex syncope in the UK Armed Forces.

INTRODUCTION: Reflex syncope is the most common subtype of syncope and, despite not being associated with increased mortality, often results in significant morbidity and costly diagnostics. Reflex syncope can be of concern for certain occupational groups and may be exacerbated by some occupations. Reflex syncope in the military is anecdotally common but the extent in the UK Armed Forces (UKAF) is unknown. The aim of this study was to assess the incidence and prevalence of reflex syncope in the UKAF. METHODS: A retrospective search of the Defence Medical Information Capability Programme using prespecified read-codes was performed at defence primary healthcare centres over the period of 1 January 2019 to 1 January 2020. Data were obtained on 76 103 service personnel (SP) (53% of the UKAF). RESULTS: The overall syncope case rate for the UKAF was 10.5 per 1000 person-years (p-yrs). In comparing services there was a significantly increased risk of syncope in the British Army (10.7 per 1000 p-yrs) compared with the Royal Air Force (8.6 per 1000 p-yrs) (p=0.0365), SP who served overseas (16.7 per 1000 p-yrs) in comparison with UK medical centres (10.3 per 1000 p-yrs) (p<0.0001), and British Army units that regularly took part in State Ceremonial and Public Duties (15.8 per 1000 p-yrs vs 10.2 per 1000 p-yrs) (p=0.0035). Army training units conferred a significantly reduced risk of syncope (p<0.0001). CONCLUSIONS: These data are the first to define the incidence and prevalence of syncope in the UKAF. Orthostasis and heat are probable triggers, although recruits are potentially protected. These data offer opportunities to improve the health and well-being of SP, with economic, logistical and reputational benefits for the UKAF. Further research to identify personnel at risk of future syncopal events may allow for targeted use of countermeasures.

Risk factors for reflex syncope in the British Army.

INTRODUCTION: Reflex syncope in the UK Armed Forces is reportedly higher than comparable militaries and civilian populations and is significantly more common in soldiers who take part in State Ceremonial and Public Duties (SCPD) compared with other British Army service personnel (SP). This study aimed to investigate individual susceptibility factors for syncope in soldiers who regularly take part in SCPD. METHODS: A retrospective cohort study was performed in 200 soldiers who perform SCPD. A questionnaire was undertaken reviewing soldiers' medical history and circumstances of any fainting episodes. A consented review of participants' electronic primary healthcare medical record was also performed. Participants were divided into two groups (syncope, n=80; control, n=120) based on whether they had previously fainted. RESULTS: In the syncope group orthostasis (61%) and heat (35%) were the most common precipitating factors. The most common interventions used by soldiers were to maintain hydration (59%) and purposeful movements (predominantly 'toe wiggling'; 55%). 30% of participants who had previously fainted did not seek definitive medical attention. A history of migraines/headaches was found to increase the risk of reflex syncope (OR 8.880, 1.214-218.8), while a history of antihistamine prescription (OR 0.07144, 0.003671-0.4236), non-white ethnicity (OR 0.03401, 0.0007419-0.3972) and male sex (OR 0.2640, 0.08891-0.6915) were protective. CONCLUSION: This is the first study, in the British Army, to describe, categorise and establish potential risk factors for reflex syncope. Orthostatic-mediated reflex syncope is the most common cause in soldiers who regularly perform SCPD and this is further exacerbated by heat exposure. Soldiers do not use evidence-based methods to avoid reflex syncope. These data could be used to target interventions for SP who have previously fainted or to prevent fainting during SCPD.

Histamine, mast cell tryptase and post-exercise hypotension in healthy and collapsed marathon runners.

PURPOSE: Heat stress exacerbates post-exercise hypotension (PEH) and cardiovascular disturbances from elevated body temperature may contribute to exertion-related incapacity. Mast cell degranulation and muscle mass are possible modifiers, though these hypotheses lack practical evidence. This study had three aims: (1) to characterise pre-post-responses in histamine and mast cell tryptase (MCT), (2) to investigate relationships between whole body muscle mass (WBMM) and changes in blood pressure post-marathon, (3) to identify any differences in incapacitated runners. METHODS: 24 recreational runners were recruited and successfully completed the 2019 Brighton Marathon (COMPLETION). WBMM was measured at baseline. A further eight participants were recruited from incapacitated runners (COLLAPSE). Histamine, MCT, blood pressure, heart rate, body temperature and echocardiographic measures were taken before and after exercise (COMPLETION) and upon incapacitation (COLLAPSE). RESULTS: In completion, MCT increased by nearly 50% from baseline (p = 0.0049), whereas histamine and body temperature did not vary (p > 0.946). Systolic (SBP), diastolic (DBP) and mean (MAP) arterial blood pressures and systemic vascular resistance (SVR) declined (p < 0.019). WBMM negatively correlated with Δ SBP (r = - 0.43, p = 0.046). For collapse versus completion, there were significant elevations in MCT (1.77 ± 0.25 µg/L vs 1.18 ± 0.43 µg/L, p = 0.001) and body temperature (39.8 ± 1.3 °C vs 36.2 ± 0.8 °C, p < 0.0001) with a non-significant rise in histamine (9.6 ± 17.9 µg/L vs 13.7 ± 33.9 µg/L, p = 0.107) and significantly lower MAP, DBP and SVR (p < 0.033). CONCLUSION: These data support the hypothesis that mast cell degranulation is a vasodilatory mechanism underlying PEH and exercise associated collapse. The magnitude of PEH is inversely proportional to the muscle mass and enhanced by concomitant body heating.

Patterns of anti-inflammatory drug use and risk of dementia: a matched case-control study.

BACKGROUND AND PURPOSE: There is limited primary-care-based evidence about a potential association between anti-inflammatory therapy and dementia subtypes. The present study addressed this limitation by using electronic health records from a large primary care database. METHOD: A case-control study was implemented using electronic medical records. Cases had a diagnosis of dementia between 1992 and 2014. Up to four controls matched on age, gender, family practice and index date were selected for each case. Use of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoid drugs represented the exposure variables. Primary outcome measures included all-cause dementia and main dementia subtypes, including Alzheimer disease (AD), vascular dementia (VaD) and Lewy body dementia (LBD). Data were analysed using conditional logistic regression. RESULTS: The study identified 31,083 patients with AD, 23,465 with VaD and 1694 with LBD. Ever-used NSAIDs were associated with a modest increase in the risk of all-cause dementia (odds ratio 1.04, 95% confidence interval 1.02-1.05, P < 0.006), whilst no association was apparent for ever-used glucocorticoids (0.98, 0.96-1.01, P = 0.152). There was no evidence for an association between NSAIDs and AD (1.03, 0.99-1.06, P = 0.07) or LBD (1.13, 0.99-1.29, P = 0.08). However, a significant increase in the risk for VaD (1.33, 1.29-1.38, P < 0.001) was observed. Similar patterns emerged for glucocorticoid therapy. CONCLUSION: In a large primary care population, there was no robust evidence for a potential association between anti-inflammatory drugs and risk of AD or LBD. NSAIDs and glucocorticoid drugs were associated with higher risk of VaD.

A technical assessment of pulse wave velocity algorithms applied to non-invasive arterial waveforms.

Non-invasive assessment of arterial stiffness through pulse wave velocity (PWV) analysis is becoming common clinical practice. However, the effects of measurement noise, temporal resolution and similarity of the two waveforms used for PWV calculation upon accuracy and variability are unknown. We studied these effects upon PWV estimates given by foot-to-foot, least squared difference, and cross-correlation algorithms. We assessed accuracy using numerically generated blood pressure and flow waveforms for which the theoretical PWV was known to compare with the algorithm estimates. We assessed variability using clinical measurements in 28 human subjects. Wave shape similarity was quantified using a cross correlation-coefficient (CCCoefficient), which decreases with increasing distance between waveform measurements sites. Based on our results, we propose the following criteria to identify the most accurate and least variable algorithm given the noise, resolution and CCCoefficient of the measured waveforms. (1) Use foot-to-foot when the noise-to-signal ratio ≤10%, and/or temporal resolution ≥100 Hz. Otherwise (2) use a least squares differencing method applied to the systolic upstroke.

Association of bone turnover markers and arterial stiffness in pre-dialysis chronic kidney disease (CKD).

Vascular calcification (VC) is highly prevalent in CKD and leads to increased vascular stiffness and cardiovascular disease (CVD). Non-traditional cardiovascular risk factors include abnormal bone turnover and/or dysregulation of the calcification inhibitors, although their relative contribution remains unclear. We investigated the association between bone turnover, the calcification inhibitors (matrix gla protein; MGP and Fetuin-A), and the phosphate regulating hormone; fibroblast growth factor-23 (FGF-23) and arterial stiffness in pre-dialysis CKD patients. One hundred and forty-five patients with CKD stages 1-4 (74 M, 71 F) aged (mean [SD]) 53 [14] years were studied. Bone turnover markers (bone-specific alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase (TRACP)) and MGP, Fetuin-A and FGF-23 were determined. BMD was measured at the lumbar spine (LS), femoral neck (FN), forearm (FARM) and total hip (TH). Arterial stiffness was assessed by contour analysis of digital volume pulse (SI(DVP)). There was a significant positive correlation between TRACP:BALP ratio and SI(DVP) ( r=0.19, p=0.023). Following multi-linear regression analysis, significant associations were seen between serum BALP (p=0.037), TRACP (p=0.009) and TRACP:BALP ratio (p=0.001) and SI(DVP) independently of traditional CVD risk factors. No significant relationship between SI(DVP) and MGP, Fetuin-A and FGF-23 was observed. A significant negative correlation was seen between BMD at the FARM and SI(DVP) in CKD stage 4 (r=-0.35, p=0.024). The association remained significant following correction for age, gender and cardiovascular risk factors (p=0.029). Our data suggest a link between imbalances in bone turnover and arterial stiffness in pre-dialysis CKD. Longitudinal studies are needed to evaluate the clinical usefulness of these bone turnover markers as predictors of CVD in CKD.

A prospective case-controlled cohort study of endothelial function in patients with moderate to severe psoriasis.

BACKGROUND: There is well-documented evidence that patients with moderate and severe psoriasis have a significantly increased risk of cardiovascular disease (CVD). While this risk can, at least in part, be attributed to the high prevalence of traditional risk factors in the population with psoriasis, some epidemiological evidence suggests it may be independent of these. OBJECTIVES: This prospective, case-controlled study investigates whether psoriasis is a risk factor for CVD using two, validated, sensitive markers of CVD, endothelial dysfunction and high-sensitivity C-reactive protein (hsCRP). METHODS: Patients were recruited from a tertiary referral psoriasis clinic and exclusion criteria included established CVD and/or conventional risks for CVD. Preclinical CVD was assessed using flow-mediated brachial artery dilatation, which measures endothelial dysfunction, and hsCRP, a serological marker of atherosclerosis. RESULTS: Sixty-four patients (22%) out of a total of 285 consecutive patients attending the severe psoriasis clinic were entered into the study. One hundred and sixty-one (56%) were excluded following identification of cardiovascular risk; 39 of the 161 (24%) had at least two cardiovascular risk factors. A further 16 (6%) patients were excluded because of established CVD. No statistically significant difference in endothelial dysfunction was observed between patients with psoriasis (n = 60) and healthy controls (n = 117) (P = 0·508). The hsCRP level was, however, significantly elevated in the psoriasis group (2·828 mg L(-1), SEM 0·219; controls 0·728 mg L(-1), SEM 0·142; P < 0·05). CONCLUSION: This large, investigative study is the first to assess endothelial function in patients with psoriasis after exclusion of traditional risk factors for CVD. These data suggest that psoriasis per se is not a risk factor for CVD and that elevated hsCRP is possibly independent of atheroma risk. There was a high prevalence of traditional risk factors in our population with severe psoriasis.

Infliximab improves vascular stiffness in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have increased cardiovascular mortality. Tumour necrosis factor alpha (TNFalpha)-blocking therapy has been shown to reduce RA disease activity measures and joint damage progression. Some observational studies suggest that TNFalpha blockade reduces mortality and incidence of first cardiovascular events. The mechanisms contributing to these outcomes are unclear. This study assessed the effects of infliximab treatment on vascular stiffness and structure in patients with RA. METHODS: A post hoc analysis of longitudinal data from a randomised placebo controlled study evaluated the effect of infliximab on vascular assessments. 26 patients received intravenous infliximab (3 mg/kg) at weeks 0, 2, 6 and every 8 weeks thereafter to week 54. Patients were followed up to 56 weeks of infliximab therapy with assessments of RA disease activity, cardiovascular risk factors, vascular stiffness (pulse wave velocity (PWV)), carotid intima media thickness (CIMT) and carotid artery plaque (CAP). Univariate analyses of changes over time by repeated measures analysis of variance (ANOVA) were followed by multivariate time-series regression analysis (TSRA) if changes were seen. RESULTS: PWV was significantly lower (better) after 56 weeks of treatment with infliximab (ANOVA p<0.01, TSRA p<0.01). However, CIMT (ANOVA p = 0.50) and CAP (chi(2) = 4.13, p = 0.88) did not change over the study period. Multiple cardiovascular risk measures did not change with treatment and did not correlate with changes in measures of vascular structure. CONCLUSIONS: Arterial stiffness improves with infliximab treatment in RA. This change may help explain the improved cardiovascular disease survival in patients with RA receiving TNFalpha-blocking therapy.

Homocysteine, migration and early vascular impairment in people of African descent.

OBJECTIVES: A gradient of increased vascular risk with migration exists across the African diaspora. We investigated the hypothesis that differences in homocysteine/folic acid status contribute to this increased risk. DESIGN: Community cohort study of 73 Afro-Caribbeans in the United Kingdom and 151 matched Afro-Caribbeans in Jamaica with no conventional vascular risk factors. METHODS: Subjects were compared for baseline characteristics, vascular risk profile, homocysteine (tHcy), folate and B(12) concentrations. Endothelium-dependent vasodilatation was assessed by measuring the absolute change from baseline in the reflection index (RI) of the digital volume pulse during intravenous infusion of albuterol (5 microg/min, Delta RI(ALB)) and glyceryltrinitrate (GTN) (5 microg/min, Delta RI(GTN)). Carotid intima media thickness (CIMT) was measured ultrasonographically in the distal 1 cm of the common carotid artery. RESULTS: UK Afro-Caribbeans had higher tHcy (mean difference 2.3 (95% confidence interval 1.3 to 3.4) micromol/l) and lower folate (mean difference 3.2 (95% CI 1.8 to 4.7) microg/l) levels. Delta RI(ALB) was 5.1 (95% CI 2.5 to 7.6) percentage points lower and CIMT 0.124 (95% CI 0.075 to 0.173) mm greater in UK Afro-Caribbeans. Higher tHcy and lower folate concentrations correlated with impaired Delta RI(ALB) and increased CIMT. A 1 microg/l increase in folate concentration was associated with 0.3 (95% CI 0.1 to 0.5) percentage point increase in Delta RI(ALB) and 0.002 (95% CI 0.001 to 0.006) mm decrease in CIMT, independent of blood pressure, smoking and vascular risk profile. CONCLUSIONS: Lower folate concentrations in UK compared with West Indian African-Caribbeans may contribute to the higher stroke risk seen in UK African-Caribbean people.

Effects of selective and non-selective cyclo-oxygenase inhibition on endothelial function in patients with rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is associated with increased cardiovascular disease (CVD) risk that has been attributed to endothelial dysfunction and inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase (COX)-2 inhibitors have been shown in some studies to improve endothelial function in subjects without RA. The aim of this study was to investigate the effects of COX inhibition on endothelial function in patients with RA. METHODS: Patients with RA (n = 37) were randomized to receive a 2-week course of either indomethacin (75 mg bd), rofecoxib (12.5 mg bd), or placebo in a double-blind study. Endothelial function was measured using flow-mediated dilation (FMD) of the brachial artery in response to reactive hyperaemia. Arterial stiffness was also assessed using pulse wave analysis (PWA) through the measurement of the aortic augmentation index (AIx). Measurements of vascular function and inflammatory markers were taken before and at the end of the treatment period. RESULTS: There were no significant differences in changes in FMD, AIx, blood pressure (BP), serum creatinine, erythrocyte sedimentation rate (ESR), or high-sensitivity C-reactive protein (hsCRP) between groups. However, compared with the other treatment groups, there was a tendency for systolic BP to decrease in the placebo group (p = 0.063) and for creatinine to increase in the indomethacin and rofecoxib groups after treatment (p = 0.054). CONCLUSIONS: This study suggests that COX inhibition by indomethacin or rofecoxib do not improve endothelial function in patients with RA.

Effect of fat distribution on endothelial-dependent and endothelial-independent vasodilatation in healthy humans.

AIM: The present study aims to explore the relationship between inflammatory cytokines, plasma lipids, insulin, blood pressure (BP), total adiposity/markers of fat distribution and endothelial function in healthy people across a wide range of body fatness. METHODS: Seventy-three healthy people (44 women; age range: 24-64 years) with body mass index (BMI) range of 18.6-73.1 kg/m2 were recruited. All participants underwent assessment of conduit artery endothelial-dependent vasodilatation by using flow-mediated vasodilatation (FMD) of the brachial artery and endothelial-independent vasodilatation to sublingual GTN. They had blood taken for measurement of plasma markers of glucose homeostasis (fasting insulin and glucose), systemic inflammation (interleukin-6 (IL-6), C-reactive protein (CRP) and tumour necrosis factor-alpha receptor 2 (TNF-alpha R2)) and lipids (low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides). Morphometric assessment (waist circumference, BMI and waist-to-hip ratio (WHR)) and systolic and diastolic arterial pressure were also measured. RESULTS: Markers of total body fat/fat distribution (waist circumference, BMI and WHR), inflammation (IL-6, CRP and TNF-alpha R2), metabolism (fasting insulin, HDL, LDL and triglycerides) and BP (systolic and diastolic) correlated with FMD. Among these measurements, WHR was the only independent predictor of FMD (r2 = 0.30; p = 0.0001). CONCLUSIONS: WHR is an important marker of endothelial dysfunction in healthy people across a wide range of body fatness.

The long-term effects of tibolone on aortic stiffness and endothelial function.

OBJECTIVE: To investigate the effect of 10 years of treatment with tibolone on aortic stiffness and endothelial function. DESIGN: Cross-sectional study of women currently participating in an open-label, non-randomized study of the long-term efficacy of tibolone. A total of 113 recently postmenopausal women were recruited in 1988. Fifty-eight agreed to take tibolone 2.5 mg daily and 55 were followed during the study as matched controls (who chose not to take any form of hormone replacement therapy (HRT) for the duration of the study). The groups were matched for age, weight and time since last menstrual period. SETTING: A Central London Teaching Hospital. SUBJECTS: After 10 years, 60 women remained in the study, 32 in the tibolone group and 28 in the control group. All of these women were invited to participate in this pilot study and attend the Menopause Research Unit. Fourteen women from each group agreed to attend. The main outcome measures were aortic stiffness, measured by pulse wave velocity, and endothelial function, as assessed by flow-mediated dilatation of the brachial artery. RESULTS: Pulse wave velocity was significantly lower in the tibolone group (10.4 +/- 1.2) than in the control group (11.6 +/- 1.2), p = 0.042. The flow-mediated dilatations were similar in both groups. CONCLUSION: In this study, long-term use of tibolone over 10 years has a beneficial effect on aortic stiffness. The differences seen in brachial artery vasoreactivity failed to reach statistical significance. Whether this is a true indication of the effects of long-term tibolone on brachial artery vasoreactivity will only be determined by performing a larger, placebo-controlled, randomized study.

Block of inward rectifying K+ channels (KIR) inhibits bradykinin-induced vasodilatation in human forearm resistance vasculature.

OBJECTIVE: To investigate the possible involvement of inward rectifying K(+) channels (K(IR)) in the response of human resistance vessels to bradykinin in vivo. METHODS AND RESULTS: Drugs were administered via the brachial artery in healthy male volunteers and forearm blood flow was measured by venous occlusion plethysmography. Inhibition of K(IR) by barium chloride (4 micromol min(-1)) alone or with additional inhibition of Na(+)/K(+) ATPase (ouabain 2.7 micromol min(-1)) reduced responses to bradykinin (30 pmol min(-1)), by 26+/-8.3% and 36+/-7.2%, respectively (each P<0 0.05). Barium with ouabain plus inhibitors of prostaglandin (PG) and nitric oxide synthesis inhibited but did not abolish responses to bradykinin (51+/-2.8% inhibition; P<0.01); norepinephrine (240 pmol min(-1)) caused similar reduction of baseline blood flow, as did this combination of inhibitors, but did not significantly inhibit the response to bradykinin. Barium plus ouabain did not significantly reduce responses to acetylcholine or albuterol. CONCLUSIONS: A component of the vasodilator response to bradykinin in human forearm vasculature is mediated by K(IR). The possible involvement of inward-rectifying K+ channels (KIR) in the action of bradykinin was investigated by administering drugs via the brachial artery in healthy men. Barium selectively inhibited the forearm blood flow response to bradykinin, indicating that a component of this response is mediated by KIR.

Lack of effect of oral vitamin C on blood pressure, oxidative stress and endothelial function in Type II diabetes.

Type II diabetes is characterized by increased oxidative stress, endothelial dysfunction and hypertension. We investigated whether short-term treatment with oral vitamin C reduces oxidative stress and improves endothelial function and blood pressure in subjects with Type II diabetes. Subjects ( n =35) received vitamin C (1.5 g daily in three doses) or matching placebo for 3 weeks in a randomized, double-blind, parallel-group design. Plasma concentrations of 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)), a non-enzymically derived oxidation product of arachidonic acid, were used as a marker of oxidative stress. Endothelial function was assessed by measuring forearm blood flow responses to brachial artery infusion of the endothelium-dependent vasodilator acetylcholine (with nitroprusside as an endothelium-independent control) and by the pulse wave responses to systemic albuterol (endothelium-dependent vasodilator) and glyceryl trinitrate (endothelium-independent vasodilator). Plasma concentrations of vitamin C increased from 58+/-6 to 122+/-10 micromol/l after vitamin C, but 8-epi-PGF(2alpha) levels (baseline, 95+/-4 pg/l; after treatment, 99+/-5 pg/l), blood pressure (baseline, 141+/-5/80+/-2 mmHg; after treatment, 141+/-5/81+/-3 mmHg) and endothelial function, as assessed by the systemic vasodilator response to albuterol and by the forearm blood flow response to acetylcholine, were not significantly different from baseline or placebo. Thus treatment with vitamin C (1.5 g daily) for 3 weeks does not significantly improve oxidative stress, blood pressure or endothelial function in patients with Type II diabetes.

Determination of age-related increases in large artery stiffness by digital pulse contour analysis.

The stiffness of the aorta can be determined by measuring carotid-femoral pulse wave velocity (PWV(cf)). PWV may also influence the contour of the peripheral pulse, suggesting that contour analysis might be used to assess large artery stiffness. An index of large artery stiffness (SI(DVP)) derived from the digital volume pulse (DVP) measured by transmission of IR light (photoplethysmography) was examined. SI(DVP) was obtained from subject height and from the time delay between direct and reflected waves in the DVP. The timing of these components of the DVP is determined by PWV in the aorta and large arteries. SI(DVP) was, therefore, expected to provide a measure of stiffness similar to PWV. SI(DVP) was compared with PWV(cf) obtained by applanation tonometry in 87 asymptomatic subjects (21-68 years; 29 women). The reproducibility of SI(DVP) and PWV(cf) and the response of SI(DVP) to glyceryl trinitrate were assessed in subsets of subjects. The mean within-subject coefficient of variation of SI(DVP), for measurements at weekly intervals, was 9.6%. SI(DVP) was correlated with PWV(cf) ( r =0.65, P <0.0001). SI(DVP) and PWV(cf) were each independently correlated with age and mean arterial blood pressure (MAP) with similar regression coefficients: SI(DVP)=0.63+0.086 x age+0.042 x MAP ( r =0.69, P <0.0001); PWV(cf)=0.76+0.080 x age+0.053 x MAP ( r =0.71, P <0.0001). Administration of glyceryl trinitrate (3, 30 and 300 microg/min intravenous; each dose for 15 min) in nine healthy men produced similar changes in SI(DVP) and PWV(cf). Thus contour analysis of the DVP provides a simple, reproducible, non-invasive measure of large artery stiffness.

Divergent effects of vitamin C on relaxations of rabbit aortic rings to acetylcholine and NO-donors.

1. Vitamin C may influence NO-dependent relaxation independently of effects on oxidant stress. 2. We investigated effects of vitamin C (0.1 -- 10 mmol l(-1)) on relaxation of pre-constricted rabbit aortic rings to acetylcholine (ACh), authentic NO and the NO-donors glyceryl trinitrate (GTN), nitroprusside (NP) and S-nitroso-N-acetyl-penicillamine (SNAP). DETCA (2 -- 6 mmol l(-1)), a cell permeable inhibitor of endogenous Cu-Zn superoxide dismutase (SOD) was used to increase intracellular superoxide anion (O(2)(-)). 3. Vitamin C reduced the response to ACh (71 +/- 7% inhibition of maximum relaxation at 10 mmol l(-1)) and inhibited relaxation to authentic NO. Vitamin C inhibited relaxation to GTN but potentiated relaxations to NP and SNAP, causing a parallel shift to a lower concentration range of the log dose-response curve by approximately one log unit at the highest dose. 4. Vitamin C increased the concentration of NO in bath solution (plus EDTA, 1.0 mmol l(-1)) following the addition of SNAP from 53 +/- 14 to 771 +/- 101 nmol l(-1) over the range 0.1-3.0 mmol l(-1). 5. DETCA inhibited relaxation to ACh (71 +/- 9% inhibition of maximum relaxation). This inhibition was abolished by a cell permeable SOD mimetic, but not by vitamin C. DETCA inhibited relaxation to SNAP but not that to NP nor to GTN. 6. Vitamin C inhibits endothelium-dependent relaxations of rabbit aortic rings to ACh and authentic NO and does not reverse impaired relaxation resulting from increased intracellular oxidant stress. Vitamin C potentiates relaxation to the NO-donors NP and SNAP by a mechanism that could involve release of NO from nitrosothiols.

Quantitative aspects of the inhibition by N(G)-monomethyl-L-arginine of responses to endothelium-dependent vasodilators in human forearm vasculature.

1. N(G)-monomethyl-L-arginine (L-NMMA) constricts human forearm resistance vasculature and selectively attenuates vasodilator responses to endothelium-dependent vasodilators. Incomplete inhibition of such responses could be due to an inadequate dose of L-NMMA or to NO-independent vasodilator mechanisms. 2. This study sought to determine doses of L-NMMA that are maximally effective in reducing basal and stimulated forearm blood flow. Drugs were infused via the brachial artery in 32 healthy men. Acetylcholine (11 - 330 nmol min(-1)) was compared with albuterol (0.33 - 10 nmol min(-1)), and nitroprusside (1.7 - 20 nmol min(-1)). 3. The effect of L-NMMA on basal flow approached maximum (53+/-2% reduction) at a dose of 16 micromol min(-1). L-NMMA (16 micromol min(-1)) did not significantly influence responses to nitroprusside, but antagonized acetylcholine and albuterol (each P<0.001, by repeated measures analysis of variance). 4. Inhibition of acetylcholine by L-NMMA (16 micromol min(-1)) was strongly influenced by acetylcholine dose (73+/-7% inhibition at 11 nmol min(-1), P<0.01; 4+/-11% inhibition at 330 nmol min(-1), P=NS, Student's paired t-test). Significant inhibition of albuterol was observed at all doses. 5. A higher dose of L-NMMA (64 micromol min(-1)) did not significantly inhibit the response to acetylcholine (330 nmol min(-1)). Responses to this dose of acetylcholine were unaffected by a cyclo-oxygenase (COX) inhibitor (indometacin) alone but combined COX and NO inhibition attenuated acetylcholine responses by 42+/-19%, implying that there is a compensatory increase in the contribution of prostaglandins or NO to acetylcholine-induced dilatation when one or other pathway is inhibited.